RU2593585C1 - Method of treating tobacco smoking and other forms of nicotine addiction, as well as prevention of recurrent tobacco smoking - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Disclosed is a method of treating tobacco smoking and other forms of nicotine addiction, as well as preventing recurrent tobacco smoking, using an agent containing an agent based on cytisine and auxiliary substances by intranasal spraying before, during or immediately after introduction of nicotine; agent contains 1 mg/ml to 100 mg/ml cytisine and it is introduced into body in form of fractional doses, each of which ranges from 25 to 500 mcl.

EFFECT: technical result consists in duration of action of method, reducing probability of developing side effects, elimination of effects of nicotine, responsible for maintaining dependence and almost complete quitting of smoking of patient with control analysis after 12 months.

5 cl, 3 dwg

Description

FIELD OF TECHNOLOGY

The invention relates to medicine, namely to means for the treatment of tobacco smoking and other forms of nicotine addiction and methods for their use.

BACKGROUND OF THE INVENTION

Nicotine is the main psychoactive substance found in tobacco leaves and is responsible for the formation and maintenance of this type of chemical dependence. Currently, the main drugs used to treat smoking are various nicotine receptor agonists, including nicotine itself in the form of plasters, chewing gum, absorbable tablets and inhalers. In addition to nicotine, two nicotine receptor agonists have clinical use - varenicline and cytisine. Another agonist of nicotine receptors, lobelia, has been studied very little - a multicenter study of the effectiveness of sublingual lobelin tablets, conducted by Dynagen in 1997, did not confirm the clinical efficacy of lobelin. The efficacy of methods for specific pharmacological blockade of nicotine receptors by means of a nicotinic receptor antagonist of mecamylamine or immunization with antibodies to nicotine is also not expressed (Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013 May 31; 5: CD009329.doi: 10.1002 / 14651858.CD009329.pub2).

Earlier, a method was proposed for using “as needed” fractional doses of nicotinic receptor agonists based on signs of a developing or approaching withdrawal state (US Patent 5,780,051, July 14, 1998). This method is based solely on the ability of nicotine and other nicotinic receptor agonists to suppress withdrawal symptoms and thereby prevent nicotine intake in an undesirable manner, such as smoking.

NICOTINE. The efficacy of nicotine therapy in the treatment of smoking has been studied in numerous double-blind, randomized, placebo-controlled trials (Stead LF, Perera R, Bullen C, Mant D, Hartmann-Boyce J, Cahill K, Lancaster T. Nicotine replacement therapy for smoking cessation. Cochrane Database of Systematic Reviews 2012, Issue 11. Art.No .: CD000146. DOI: 10.1002 / 14651858.CD000146.pub4.). Nicotine preparations were found to be more effective than placebo both in clinical indicators of the duration of the period of complete abstinence (i.e., complete abstinence from smoking) and biochemical parameters (for example, the content of carbon monoxide in expired air, the concentration of cotinine in plasma or urine) .

The main disadvantage of treatment with nicotine-containing drugs is their limited long-term effectiveness. If during therapy, the state of complete abstinence can reach 50-75% of patients (Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev. 2013 May 31; 5: CD009329. doi: 10.1002 / 14651858.CD009329.pub2), then 3-6 months after the end of therapy, this indicator decreases to 5-10% (Scherphof CS, van den Eijnden RJJM, Engels RCME, Vollebergh WAM. Long-term efficacy of nicotine replacement therapy for smoking cessation in adolescents: A randomized controlled trial. Drug and Alcohol Dependence 140 (2014) 217-220). Such limitations of long-term effectiveness are characteristic of substitution therapy and therefore are more or less equally likely for various dosage forms containing nicotine.

Among the disadvantages of substitution therapy with nicotine-containing drugs are also side effects associated with the need to ensure a relatively constant concentration of nicotine in the body at a level adequate to stimulate nicotine receptors. Due to the variety of subtypes of nicotine receptors, an effective concentration of nicotine to a more or less equal extent leads to stimulation of subtypes of nicotine receptors responsible for both the therapeutic effect and side effects in the central nervous system and other tissues and organs.

VARENIKLIN. In 2006, the Pfizer company Chantix / Champix (the active active principle - varenicline) was registered in the United States and European Union countries as a treatment for smoking. A meta-analysis of a significant number of clinical studies shows that varenicline is one of the most effective treatments for smoking (Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 2013 May 31; 5: CD009329.doi: 10.1002 / 14651858.CD009329.pub2).

The efficacy of varenicline is associated with its properties as a partial nicotinic receptor agonist - agonistic activity should be sufficient to prevent and suppress the withdrawal state (“replacement therapy”), while in the presence of nicotine the positively supporting and euphoric effect of the latter should be limited (Rollema H, Soi JW , Chambers LK, Hurst RS, Stahl SM, Williams KE (2007) Rationale, pharmacology and clinical efficacy of partial agonists of [alpha] 4 [beta] 2 nACh receptors for smoking cessation. Trends in Pharmacological Sciences 28: 316-325).

The main disadvantage of varenicline therapy is the need for the constant presence of a substance in the body to ensure its mechanism of action. As a likely consequence, post-marketing studies have identified a relationship between varenicline and depression, suicidal ideation and behavior, and cardiovascular effects (Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews 2012, Issue 4 Art. No .: CD006103. DOI: 10.1002 / 14651858.CD006103.pub6). The latter are most likely to be of greater clinical significance, since the severity of neuropsychiatric side effects can be of little significance (Thomas KH, Martin RM, Knipe DW, Higgins JPT, Gunnell D. Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis. BMJ 2015; 350: h1109.doi: 10.1136 / bmj.h1109).

Although the nicotinic receptor subtype containing the α4 and β2 subunits is assigned the most important role for therapeutic efficacy, the selectivity of varenicline for this subtype is limited, which probably determines the development of side effects (Arias HR, Feuerbach D, Targowska-Duda K, Kaczor AA, Poso A, Jozwiak K. Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptor subtypes. Potential mechanism underlying partial agonism at human α4β2 and α3β4 subtypes. Biochim Biophys Acta 2015; 1848: 731-41).

CITIZIN. This drug is officially registered as a medication for nicotine addiction (Etter JF, Lukas RJ, Benowitz NL, West R, Dresler CM. Cytisine for smoking cessation: A research agenda. Drug and Alcohol Dependence 2008; 92: 3-8). According to the mechanism of action, cytisine is very close to varenicline, but it possibly penetrates the central nervous system worse when administered systemically (Rollema H, Soy JW, Chambers LK, Hurst RS, Stahl SM, Williams KE (2007) Rationale, pharmacology and clinical efficacy of partial agonists of [alpha] 4 [beta] 2 nACh receptors for smoking cessation. Trends in Pharmacological Sciences 28: 316-325). Studies in laboratory animals have shown the effectiveness of systemic administration of cytisine in classical models of nicotine addiction - a model of intravenous self-administration of nicotine, a method of drug differentiation of nicotines as a training stimulus, an activation model of the intracerebral reward system (Igari M, Alexander JC, Ji Y, Qi X, Papke RL, Bruijnzeel AW. Varenicline and cytisine diminish the dysphoric-like state associated with spontaneous nicotine withdrawal in rats. Neuropsychopharmacology 2014; 39: 455-465; Radchenko EV, Dravolina OA, Bespalov AY. Agonist and antagonist effects of cytisivo in 2015; 95: 206-214). Using these methods, as well as methods for analyzing locomotor activity, both the nicotine-like properties of cytisine and its ability to suppress the effectiveness of nicotine were demonstrated (Radchenko EV, Dravolina OA, Bespalov AY. Agonist and antagonist effects of cytisine in vivo. Neuropharmacology 2015; 95: 206 -214). These properties of cytisine as a partial agonist of nicotinic receptors are consistent with data obtained for varenicline (Rollema H, Soe JW, Chambers LK, Hurst RS, Stahl SM, Williams KE (2007) Rationale, pharmacology and clinical efficacy of partial agonists of [alpha] 4 [beta] 2 nACh receptors for smoking cessation. Trends in Pharmacological Sciences 28: 316-325).

Clinical studies indicate significant clinical efficacy of cytisine (Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No .: CD006103. DOI: 10.1002 / 14651858.CD006103 .pub6). Comparative studies of cytisine and other nicotinic receptor agonists have not been carried out (with the exception of Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, Parag V, Bassett B, Bullen C. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014; 371: 2353-62), but an analysis of clinical and economic indicators indicates the likely equivalence of cytisine and varenicline (Leaviss J, Sullivan W, Ren S, Everson-Hock E, Stevenson M, Stevens JW. What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation. Health Technol Assess 2014; 18 (33)).

The disadvantages of the existing therapy for smoking and other forms of nicotine addiction when using both cytisine and other nicotinic receptor agonists are as follows.

First, having limited selectivity for nicotinic receptor subtypes, these substances, when administered systemically, affect not only the receptors responsible for the formation and maintenance of nicotine addiction and are located in the central nervous system, but also peripheral receptors, the interaction with which can determine the development of side effects. effects, preventing the effective dosing of these drugs.

Secondly, the disadvantages of these drugs is the need for a long daily intake of tablets, which supports the likelihood of side effects at a relatively stable level.

Thirdly, although substances such as varenicline and cytisine are partial agonists and are able to block the effects of nicotine (Radchenko EV, Dravolina OA, Bespalov AY. Agonist and antagonist effects of cytisine in vivo. Neuropharmacology 2015; 95: 206-214; Rollema H, Soy JW, Chambers LK, Hurst RS, Stahl SM, Williams KE (2007) Rationale, pharmacology and clinical efficacy of partial agonists of [alpha] 4 [beta] 2 nACh receptors for smoking cessation. Trends in Pharmacological Sciences 28: 316-325) , their clinical efficacy is based on the ability to replace nicotine, and antagonistic properties are not fully manifested, exerting a biological effect both in the presence of nicotine and in its absence e, creating the prerequisites for side effects.

Fourth, substitution therapy creates a relatively short therapeutic effect - after the end of therapy, the rate of relapse of tobacco increases, almost comparing with the placebo control groups (Agboola SA, Coleman T, McNeill A, Leonardi-Bee J. Abstinence and relapse amongst smokers who use varenicline in a quit attempt - a pooled analysis of randomized controlled trials. Addiction 2015; Apr 6. doi: 10.1111 / add.12941).

A known method of reducing the need for smoking or tobacco use by using a multi-component intraoral dosage form comprising an ingredient for the treatment of tobacco dependence, selected from the group consisting of: varenicline, bupropion, nortriptyline, doxepin, fluoxetine, imipramine, moclobemide and / or cytisine (Application for RF invention No. 20111119494 based on the international application (publication WO 2010/044736, PCT SE 2009/051163).

The method consists in administering a multi-component dosage form by means of oral sprays, nasal sprays, transdermal patches, inhalers, lozenges, tablets and parenteral methods, subcutaneous and transmucosal methods, tobacco use, and / or behavioral therapy.

The method contributes to quitting smoking by introducing a substance simulating nicotine in any form from the dosage form into saliva in the oral cavity and absorption into the patient’s systemic bloodstream.

For this method, the above disadvantages are typical (systemic effects with the likelihood of developing systemic side effects and corresponding contraindications, the possibility of an overdose).

The mechanism of action is based on nicotine replacement, while the long-term effectiveness of substitution therapy with nicotine-containing drugs is quite low.

SUMMARY OF THE INVENTION

The invention is directed to the development of an effective and easy-to-use method using an agent including cytisine for the treatment of tobacco smoking and other forms of nicotine addiction, providing a duration of action.

1. A method has been developed for the treatment of tobacco smoking and other forms of nicotine addiction with an agent containing an active principle based on cytisine and excipients. The agent contains from 1 mg / ml to 100 mg / ml of cytisine in a solution containing excipients, the agent is administered into the body in divided doses, each of which contains from 25 to 500 μl, by intranasal injection before, during or immediately after application nicotine.

The developed method provides the predominant intake of cytisine in the body at a time when the patient, by smoking tobacco or in another way, increases the concentration of nicotine in tissues whose nicotine receptors are responsible for the development of nicotine addiction. Thus, this method limits the concentration of cytisine in the body at a time when there is no need to neutralize the effects of nicotine, which reduces the likelihood of side effects.

The developed method of intranasal administration of cytisine provides a more favorable ratio of central and peripheral effects, which reduces the likelihood of side effects.

Typically, the drug is administered immediately before the introduction of nicotine (for example, by smoking tobacco), however, if necessary, delayed administration is possible (for example, while smoking tobacco).

For administration, the agent is used in a solution consisting of components approved for use in healthcare for intranasal administration.

The solution for intranasal injections contains: cytisine in an amount of from 1 mg / ml to 100 mg / ml.

The solution contains auxiliary substances, wt%: mineral salts (0.05-2%), antioxidant (0.01-0.2%), preservative (0.01-0.2%), cosolvent (0.01-10% ), acidity regulator (up to pH 5.0-8.0), water (up to 100%).

The concentration of cytisine in the solution can be reduced to 1 mg / ml or increased to 100 mg / ml since: a) the resulting single dose of cytisine is directly dependent on the single injection volume, which can vary from 25 to 500 μl, b) the injection can produced in one nostril or both, c) the effectiveness of absorption depends on the state of the nasal mucosa, d) the ratio of the amount of cytisine that enters the systemic circulation after absorption from the nasal mucosa and the amount penetrating the central nervous system can depend on the physical co-chemical properties of the solution, the composition of the solution and the size of the injected or sprayed particles.

EMBODIMENTS FOR CARRYING OUT THE INVENTION.

As solutions, examples of compositions containing sodium hydrogen phosphate and sodium dihydrogen phosphate - acidity regulators, EDTA, methyl paraben and propyl paraben - preservatives, sodium chloride - salt, polysorbate - cosolvent, citric acid antioxidant are given.

EXAMPLES OF COMPOSITION:

Composition Example 1

The content of cytisine in the solution is 40 mg / ml

EDTA - 10 mg

Citric Acid - 30 mg

Sodium hydrogen phosphate - 600 mg

Sodium dihydrogen phosphate - 750 mg

Methylparaben - 300 mg

Propylparaben - 75 mg

Sodium chloride - 8400 mg

Polysorbate 800 mg

Purified water - up to 1000 ml

Composition Example 2

The content of cytisine in the solution is 1 mg / ml

The composition of the solution.

EDTA - 10 mg

Citric Acid - 10 mg

Sodium hydrogen phosphate - 200 mg

Sodium dihydrogen phosphate - 250 mg

Methylparaben - 300 mg

Propylparaben - 7 mg

Sodium chloride - 8400 mg

Polysorbate 500 mg

Purified water - up to 1000 ml

Composition Example 3

The content of cytisine in the solution is 100 mg / ml

The composition of the solution.

EDTA - 10 mg

Citric Acid - 40 mg

Sodium hydrogen phosphate - 600 mg

Sodium dihydrogen phosphate - 750 mg

Methylparaben - 300 mg

Propylparaben - 7.5 mg

Sodium chloride - 8400 mg

Polysorbate 500 mg

Purified water - up to 1000 ml.

APPLICATION OF TREATMENT FOR TOBACCO SMOKING.

Immediately prior to tobacco smoking, an agent containing 40 mg / ml of cytazine based on a solution of composition 1 is administered by intranasal injection into each nostril of 100 μl. The procedure is repeated before each act of smoking (cigarettes or other nicotine-containing product).

APPLICATION OF MEANS FOR PREVENTION OF TOBACCO SMOKING RECESSES.

Immediately prior to smoking tobacco, a composition containing cytisine is administered by intranasal injection into each nostril of 100 μl of an aqueous solution of cytisine (40 mg / ml). The procedure is performed only before the act of smoking (cigarettes or other nicotine-containing product).

The following are studies confirming the use of a cytisine solution intranasally to achieve target receptors in the central nervous system.

The experiments used male Wistar runoff rats (Laboratory animal nursery RAMS Rappolovo, St. Petersburg, Russia). (-) - nicotine hydrogen tartrate (Sigma-Aldrich Co., USA) was dissolved in phosphate buffer (pH = 7.4). A nicotine solution (0.6 mg / kg) was prepared immediately prior to injection and was administered in a volume of 1 ml / kg. Cytisine (Sequoia Research Product Ltd, Pangbourne, UK) was dissolved in a 0.9% aqueous NaCl solution at a rate of 30 mg / ml.

Several series of experiments were carried out using different methods of intranasal administration of cytisine: using a polyethylene tube mounted on a microsyringe needle or a high pressure syringe (Penn-Century, INC., USA; Model AO-250) with a microspray (Penn-Century, INC ., USA; Model IA-1C s / n 2970).

Tests were performed with intranasal administration of a solution of cytisine (30 mg / ml) or a solvent (0.9% aqueous solution of NaCl) 15 minutes before boarding and 10 minutes before administration of nicotine. The order of the tests was determined according to the "Latin square" scheme. When using a microsprayer, each rat (average rat weight: 249 ± 3.7 at the beginning of the experiment; 341 ± 7.2 at the end of the experiment) was injected with 25 μl, and using a microsyringe - 40 μl. Thus, in the first case, each rat (weighing 250 g) received 0.75 mg (about 3 mg / kg), and in the second, 1.2 mg (about 4.8 mg / kg).

Statistical processing of the obtained data was performed using the statistical software package SPSS (version 16, USA). When paired comparisons of two repeated measurements performed paired t-test; in the case of multiple repeated measurements, analysis of variance followed by post hoc comparisons. Intergroup comparisons (Bonferroni test) were carried out only under the condition that a significant effect was revealed by the analysis of variance. Differences were considered significant at P <0.05.

Experiment No. 1 "Locomotor activity"

Rats sensitive to the stimulating effect of nicotine (0.6 mg / kg) were selected for the experiment, for which the motor activity of animals under the influence of nicotine was evaluated for 7 days. The duration of the tests was 60 minutes. Figure 1 shows the horizontal locomotor activity of the corresponding groups of rats on the 7th day of nicotine administration and, after receiving nicotine (0.6 mg / kg, sc) and cytisine with a microsyringe, led to a small (about 10%), but statistically significant decrease horizontal movements of rats compared to baseline.

In FIG. Figure 1 shows the effect of intranasal administration of cytisine on the potentiation of motor activity of rats by nicotine. Nicotine (NIC; 0.6 mg / kg, s / c) was injected 5 min before landing in the boxes of "Actometer". Cytisine (CIT) with its solvent (P-L) was administered 15 minutes before the experimental session by injection using a silicone tube mounted on an insulin syringe needle (gray bars). The ordinates show the average values (M ± m) of the number of consecutive intersections of the photosensor rays for 60 min of the test. * P <0.05 (Student's test) compared with baseline (7th day of nicotine administration, black bars). N = 19. The results indicate that cytisine can be used intranasally to achieve target receptors in the central nervous system.

Experiment No. 2 "Drug differentiation"

Rats were trained in the procedure of drug differentiation and during control sessions with a training dose of nicotine and saline, the number of clicks on the reinforced pedal exceeded 95% of the total number of presses on both pedals per session. When conducting generalization tests, increasing the dose of nicotine dose-dependently increased the likelihood of rats choosing the “nicotine” pedal, but did not affect the frequency of the operant reaction. Cytisine also had nicotine-like discriminatory stimulatory properties both in the systemic route of administration and in the case of intraventricular and intranal administration (Fig. 2).

In FIG. Figure 2 shows the discriminatory stimulatory properties of cytisine in rats trained to distinguish nicotine. Nicotine, cytisine or their solvent (P) was administered 5 minutes before the session either subcutaneously (upper graph) or topically (lower graph). The ordinate axis is the% of the nicotine pedal selection (M ± m). N = 8. On the abscissa axis is the dose of nicotine or cytisine in mg / kg (upper graph) or micromole (lower graph). Black circles - nicotine, white squares - subcutaneous or intraventricular administration of cytisine, black squares - intranasal administration of cytisine.

The results obtained indicate that with intranasal administration of a solution containing cytisine, it has a specific and dose-dependent activity, which reflects its effect on target receptors in the central nervous system. The drug differentiation method can be used to determine effective doses of cytisine.

Experiment No. 3 "Intravenous self-introduction"

Rats were trained in the procedure for intravenous self-administration of nicotine (0.01 mg / kg nicotine per injection, three-hour sessions). After developing a stable self-introduction skill (criterion of at least 10 nicotine infusions per hour), the animals were injected with cytisine or its solvent intraventricularly at the same time as each nicotine infusion, and the experimental sessions were extended to 6 hours. Daily administration of cytisine led to a gradual fading of the skill of self-administration.

In FIG. 3 shows the intravenous self-administration of nicotine against the background of the introduction of cytisine. Cytisine (intraventricular, 0.03 micromoles per injection) or its solvent was administered simultaneously with intravenous infusions of nicotine. After each nicotine infusion for 10 minutes, operant reactions (depressing the pedal) were recorded, but they had no consequences (“time out”). The ordinate axis is the total number of times the nicotine pedal is pressed (M ± m) in six hours. N = 12. On the abscissa axis are the consecutive days of the experiment (K is the last day of developing the skill of self-administration of nicotine, 1-14 are the days of administration of cytisine and its solvent).

The results obtained indicate that, when directly introduced into the central nervous system, cytisine is capable of causing the phenomenon of pharmacogenic quenching of the previously learned skill of intravenous self-administration of nicotine. These data indicate that, due to the properties of the partial agonist, cytisine is able to suppress the effects of nicotine, which are responsible for maintaining dependence, which can lead to a gradual quenching of nicotine dependence.

INDUSTRIAL APPLICABILITY

Example. Patient X., born in 1969, began smoking from the age of 19. I smoked cigarettes "Lucky Strike" 20-25 pieces a day. Tried to quit on my own, failed. The patient was asked to use the intranasal administration of fractional doses of cytisine administered in solution in an effective dose immediately before or during smoking (50 μl per reception). The patient was advised to constantly wear a solution of cytisine together with cigarettes in order to ensure the highest possible percentage of smoking episodes with the introduction of cytisine. After 4 weeks of therapy, the number of cigarettes smoked daily was reduced to 4-5. The patient was recommended to continue therapy. Over the next year, the number of cigarettes smoked daily remained at a low level and, after a follow-up analysis, after 12 months, the patient almost completely quit smoking. The treatment effect is confirmed by the absence of nicotine metabolites in the urine and exhaled air, as well as the evidence of family members.

COMPOSITION OF THE PRODUCT corresponds to composition 1 comprising 40 mg / ml of cytisine in solution.

Claims (5)

1. A method of treating tobacco smoking and other forms of nicotine addiction with an agent containing an active principle based on cytisine and excipients, characterized in that the agent contains from 1 mg / ml to 100 mg / ml of citisine in an aqueous solution containing excipients, the agent is administered the organism in the form of fractional doses, each of which is from 25 to 500 μl, by intranasal injection before, during or immediately after the introduction of nicotine. 2. The method according to p. 1, characterized in that the tool is administered simultaneously with the introduction of nicotine while smoking tobacco. 3. The method according to p. 1, characterized in that the tool is administered after the introduction of nicotine immediately after smoking tobacco. 4. The method according to p. 1, characterized in that the tool is administered by inhalation. 5. The method according to p. 1, characterized in that the agent is administered in an amount of 1 mg / ml to 100 mg / ml of cytisine in a solution containing auxiliary substances in wt.%: Mineral salts (0.05-2%), antioxidant ( 0.01-0.2%), preservative (0.01-0.2%), cosolvent (0.01-10%), acidity regulator (up to pH 5.0-8.0), water (up to 100 %).

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