RU2541312C2 - Pharmaceutical composition, method for preparing and device for using it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a composition for treating nicotine addiction by means of an electronic device intended to simulate tobacco smoking. A pharmaceutical composition for treating nicotine addiction by means of the electronic device comprising a cartridge simulating tobacco smoking with the use of vapour or fog generating compound containing water, glycerol, propylene glycol, contains citric acid additionally, as well as varenicline, or anabasin hydrochloride, or cytisin taken in certain relations. A method for preparing the pharmaceutical composition by mixing water, glycerol, propylene glycol and citric acid, as well as varenicline, or anabasin hydrochloride, or cytisin. The cartridge of the electronic device for simulating tobacco smoking. A method of treating nicotine addiction by means of simulating tobacco smoking by means of the electronic device.

EFFECT: pharmaceutical composition described above enables treating nicotine addiction effectively.

4 cl, 2 dwg, 5 tbl, 15 ex

Description

This invention relates to a pharmaceutical composition for delivering a medicinal agent by inhalation into human blood, a method for its preparation and a device for its use in the treatment of various diseases.

Inhalation - inhalation of medicinal substances for therapeutic purposes. It is useful to resort to such a treatment at the first sign of acute and chronic diseases of the upper respiratory tract (rhinitis - rhinitis, tonsilitis - tonsillitis, inflammation of the pharyngeal mucosa - pharyngitis, bronchitis - bronchitis and lungs - pneumonia), as well as to prevent and eliminate attacks of bronchial asthma.

Currently, three main types of inhalers are used in medical practice: steam, ultrasonic and compressor. The last two are combined by the term "nebulizers" from the Latin word nebula - fog, cloud. They do not generate vapors, but a stream of aerosol consisting of microparticles of an inhaled solution.

The action of steam inhalers is based on the effect of evaporation of a medicinal substance. The use of steam inhalers has several disadvantages: firstly, when heated, part of the active medicinal substances inevitably collapses, and secondly, hot inhalation cannot be used at temperatures above 37.5 ° C. In steam inhalers, only volatile solutions can be used, most often essential oils. This significantly narrows the range of possible components for steam inhalation.

Ultrasonic inhaler (ultrasound) is a device that allows you to spray drugs in the form of a fine aerosol, which when inhaled penetrates the most inaccessible areas of the lungs. For inhalation, you can use decoctions of medicinal herbs, alkaline solutions such as Borjomi degassed mineral water, aqueous solutions of essential oils, etc.

Not so long ago, electronic devices for simulating tobacco smoking (EUIT) were invented [US Pat. application RU 2336002, publ. 10/20/2008, bull. No. 29] by generating steam or mist, which may not contain nicotine, and when inhaled, it tastes like real tobacco smoking. EUITs are manufactured in the form of devices that externally simulate cigarettes, cigars, smoking pipes, etc., and are essentially an inhaler. The design of the EUIT is based on a cartridge (reservoir) containing a vapor-fogging liquid composition and a steam or fog generator called an “atomizer” [US 2011/0011396 A1 (2011), US 7832410 B2 (2010)].

There are two types of liquid sprayers. Atomizer with heating element and atomizer with ultrasonic atomizer. Currently, the second type is used only in models from some manufacturers of the penstyle class. In all other cases, an atomizer with a heating element is usually used [http://www.ecig-news.ru/history/evolution-means/print:page,1,21-evolyuciya-elektronnoy-sigarety.html].

Some models of electronic cigarettes have disposable vaporizers. At the same time, they are included in the composition of the cartridges, so when the cartridge is changed, the heating element also changes. Such a design (cartridge + atomizer) is called a cartomizer [http://www.electro-dym.ru/; http://www.cybersmoke.ru/index.php?categoryID=558.].

Atomizers include an evaporator (heating element, for example a nichrome spiral) or an ultrasonic atomizer [http://www.ecig-news.ru/history/evolution-means/print:page,1,21-evolyuciya-elektronnoy-sigarety in their design. html].

The atomizer from the vapor- and fog-forming liquid composition of the cartridge (reservoir) forms an imitation of smoke that enters the lungs. Only if classic smoke is a cloud of small solid particles and tar, then the composition produced by the electronic cigarette is a fog - a suspension of tiny droplets of liquid in a vapor-air mixture. This fog is heated to the temperature of the smoke of a regular cigarette in order to bring smoker's sensations as close as possible to their usual sensations.

The atomizer comes into operation if you just drag on. The air flow sensor connected to the microprocessor includes a heating element or an ultrasound generator [http://megarama.ru/ustrojstvo-elektronnoj-sigarety-i-uxod-za-nej.html].

Closest to the claimed invention in terms of vapor-fogging composition and design is an electronic device for the prevention of nicotine addiction [RU 103062, publ. November 16, 2010, marketed under the name “Supersmoker”], comprising a cartridge (reservoir) filled with a fibrous or porous mass, for example, synthetic winterizer, holding the liquid composition inside the cartridge and dispensing it.

The smoke-generating composition includes water, polyalcohols (glycols, glycerins), flavorings, nicotine and other additives. For example, the composition [http://ru.wikipedia.org/wiki/%D0%AD%D0%BB%D0%B5%D0%BA%D1%82%D1%80%D0%BE%D0%BD% D0% BD% D0% B0% D1% 8F_% D1% 81% D0% B8% D0% B3% D0% B0% D1% 80% D0% B5% D1% 82% D0% B0], containing:

propylene glycol 55-62%,

glycerin 30-35%,

nicotine 0-36 mg / ml,

flavoring 2-4% and water,

or composition [http://www.janty.su/safety/], containing:

propylene glycol 52% -66%

food flavor 0% -8%

vanilla extract 1.5%

medical nicotine

- no strength 0%

- low strength 0.4% to 0.6%

- average strength 0.9% to 1.1%

- high strength 1.3% to 1.6%

linalool 6%

glycerin 20%

tabanon 1.5%

2,5-dimethylpyrazine 1%

2-acetylpyrazine 1%.

An electronic cigarette is an identical replacement for traditional cigarettes. It is assumed that at first the electronic cigarette simply replaces the smoker's regular cigarettes. Further, a complete release from nicotine addiction is possible by gradually reducing the nicotine content to zero.

The disadvantages of the above formulations include the lack of antioxidants and medicinal principles. When part of the vapor-, fog-forming liquid composition gets on the heating element, some of its constituent components inevitably collapse, forming oxidative products that are harmful to health.

Applicants do not know the composition for simulating smoking, additionally containing a medicinal beginning for the treatment of various diseases.

The technical result of the invention is to create a pharmaceutical composition for an electronic device simulating tobacco smoking (EUIT), containing various medicinal principles and with enhanced functionality when used.

Studies have shown that it is possible to add various medicinal substances to the composition that simulates tobacco smoking.

The subject of this invention is a pharmaceutical composition based on a steam-, fog-forming liquid composition for an electronic device that simulates smoking, additionally including in an effective amount an antioxidant and / or a drug source.

This invention allows the use of a drug source, including rapidly metabolized in the liver or unsuitable for introduction into the blood using the gastrointestinal tract.

The subject of this invention is a pharmaceutical composition containing a drug selected from anti-narcotic drugs, immunomodulators, nootropic, anxiolytic (anti-anxiety), antipsychotic, antidepressant, anti-allergic, anti-asthma, antiviral, antimicrobial, anti-cancer and cardioretic drugs, in men.

The best results are achieved when using a medicinal agent selected from the range of Calcium Compromate, Axitinib, Aminalon, Anabazin hydrochloride, AVN-211, Varenicline, Vemurafenib, Viagra, Gabapentin, Gileniya, Disulfiram, Zanamivir, Carnosine, Carbamazepine, Oselitfilzibalib, Crizotivibox, Crizotivibox, Crizotiribalib, Citalopam hydrobromide, Cytisine, Escitolapam oxalate.

The following are the preferred drug principles used in this invention, their names, molecular mechanism of action and therapeutic group, taken [https://integrity.thomson-pharma.com/integrity/xmlxsl/pk_prod_list.xml_prod _list_card_p ...].

Calcium Compromate (Acamprosate calcium, Aotal, Campral, Zulex, 3-Acetamido-1-propanesulfonic acid calcium salt, Calcium bis (N-acetylhomotaurinate), 3- (Acetylamino) -1-propanesulfonic acid salt (2: 1)) - Molecular Mechanism of Action: Drugs Acting on Glutamate Receptors (Metabotropic; mgluR), NMDA Antagonists; Therapeutic group: Neurologic Drugs (Miscellaneous), Psychiatric Disorders (Not Specified), Treatment of Tinnitus, Treatment of Alcohol Dependency Treatment of Bulimia, Treatment of Substance Dependency.

Axitinib (Axitinib, N-Methyl-2- [3- [2- (2-pyridyl) vinyl] -1H-indazol-6-ylsulfanyl] benzamide) - Molecular Mechanism of Action: PDGFR Inhibitors, VEGFR-1 (Flt-1) Inhibitors, VEGFR-2 (FLK-1 / KDR) Inhibitors, VEGFR-3 (FLT4) Inhibitors; Therapeutic group: Breast Cancer Therapy, Cancer of Unspecified Body Location / System, Colorectal Cancer Therapy, Endocrine Cancer Therapy, Gastric Cancer Therapy, Liver Cancer Therapy, Melanoma Therapy, Non-Small Cell Lung Cancer Therapy, Pancreatic Cancer Therapy, Renal Cancer Therapy, Respiratory / Thoracic Cancer Therapy, Solid Tumors Therapy.

Aminalon (Aminalon, gamma-aminobutyric acid)

Anabazine hydrochloride (Anabasine hydrochloride, Gamibasin, alpha-Piperidyl-beta-pyridine hydrochloride, 3- (2-Piperidyl) pyridine hydrochloride) - Molecular mechanism of action: nicotinic receptor agonist; Therapeutic Group: Aid to Smoking Cessation.

AVN-211 - Molecular Mechanism of Action: Selective 5-HT ₆ receptor antagonist; Therapeutic group: treatment of cognitive impairment, schizophrenia, Alzheimer's disease.

Varenicline (Varenicline, Champixб Chantix, 7,8,9,10-Tetrahydro-6Н-6,10-methanoazepino [4,5-g] quinoxaline L-tartrate, 7,8,9,10-Tetrahydro-6Н-6, 10-methanopyrazino [2,3-h] [3] benzazepine L-tartrate) - -Molecular mechanism of action: partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors; Therapeutic group: Antidepressants, Treatment of Alcohol Dependency, Aid to Smoking Cessation, Treatment of Cocaine Dependency, Neurologic Drugs (Miscellaneous).

Vemurafenib (Vemurafenib, N- [3- [5- (4-Chlorophenyl) -1H-pyrrolo [2,3-b] pyridin-3-ylcarbonyl] -2,4-difluorophenyl] propane-1-sulfonamide) - Molecular Mechanism Actions: Raf kinase Inhibitors; Therapeutic group: Colorectal Cancer Therapy, Endocrine Cancer Therapy, Melanoma Therapy.

Viagra (Viagra, Sildenafil citrate, Duromist, Patrex, Penegra, Revatio, Wan Ai Ke, 5- [2-Ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) phenyl] -1-methyl-3-propyl-6, 7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-7-one Citrate) - Molecular mechanism of action: phosphodiesterase type 5 (PDE5) inhibitor - Therapeutic group: Cardiovascular Diseases (Not Specified), Treatment of Chronic Obstructive Pulmonary Diseases (COPD), Agents for Diabetes Insipidus, Heart Failure Therapy, Hematopoiesis Disorders Therapy, Treatment of Interstitial Lung Diseases, Lymphoma Therapy, Agents for Muscular Dystrophy, Oncolytic Drugs, Treatment of Pulmonary Hypertension, Treatment of Stroke, Treatment of Dysmenorrheilea, Treatment Dysfunction, Treatment of Female Sexual, Dysfunction, Vasodilators.

Gabapentin (Gabapentin, Gabapen, Gabapentin GR, Gabapentin-ER, Gralise, Neurentin, Neurontin, Serad, 2- [1- (Aminomethyl) cyclohexyl] acetic acid) - Molecular mechanism of action: Calcium Channels (Voltage-Gated) alpha2 / delta- 1 Subunit Ligands, Calcium Channels (Voltage-Gated) alpha2 / delta-2 Subunit Ligands; Therapeutic Group: Analgesic Drugs, Antiepileptic Drugs, Diabetic Neuropathy, Agents for Fibromyalgia, Treatment of Migraine, Prophylactic Treatment of Neuropathic Pain, Treatment of Sleep Disorders, Treatment of Smoking Cessation, Aid to Treatment of Alcohol Dependency, Treatment of Hot Flushes, Treatment of Substance Dependency.

Gilenia (Gilenia, Gilenya, Fingolimod hydrochloride, 2-Amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol hydrochloride) - Molecular mechanism of action: Lysophospholipid edg1 (S1P1) Receptor Agonists, Lysophospholipid edg3 ( S1P3) Receptor Agonists, Lysophospholipid edg6 (S1P4) Receptor Agonists, Lysophospholipid edg8 (S1P5) Receptor Agonists, Sphingosine Kinase 1 (SphK1) Inhibitors; Therapeutic group: Asthma Therapy, Immunosuppressants, Agents for Multiple Sclerosis, Treatment of Neuropathy, Treatment of Transplant Rejection.

Disulfiram (Disulfiram, Antabuse, Tetraethylthiuram disulfide, Tetraethylthioperoxydicarbonic diamide, Bis (diethylthiocarbamoyl) disulfide) - Molecular mechanism of action: Aldehyde Dehydrogenase Inhibitor, DNA Methyltransferase 1 (DNA Methyltransferase1) Therapeutic group: Treatment of Alcohol Dependency, Treatment of Cocaine Dependency, Anticataract Agents, Melanoma Therapy, Prostate Cancer Therapy, Solid Tumors Therapy.

Zanamivir (Zanamivir, Relenza, N-Acetyl-2,3-didehydro-4-deoxy-4-guanidinoneuraminic acid, 5-Acetamido-2,3-didehydro-3,4,5-trideoxy-4-guanidmo-alpha-D -glycero-D-galacto-2-nonulopyranosonic acid) - Molecular Mechanism of Action: Neuraminidase (Sialidase) Inhibitors; Therapeutic Group: Anti-Influenza Virus Drugs.

Carnosine (Camosine, L-Camosine, beta-Alanyl-L-histidine) - Molecular Mechanism of Action: AGE Inhibitors (Maillard's Reaction Inhibitors); Therapeutic group: Cognition Disorders, Treatment of Heart Failure Therapy, Immunomodulators, Neurologic Drugs (Miscellaneous), Psychiatric Disorders (Not Specified).

Carbamazepine (Carbamazepine, Bipotrol, Epitol, Equetro, Finlepsin, Neurotop retard, Tegretal, Tegretol, Tegretol CR, Tegretol-XR, Timonil (retard), Trimonil (sustained release), Carbatrol (sustained-release), 5H-Diben f] azepine-5-carboxamide) - Molecular Mechanism of Action: Sodium Channel Blockers; Therapeutic group: Treatment of Alcohol Dependency, Neuropathic Pain, Treatment of Bipolar Disorder, Treatment of Anti epileptic Drugs.

Crizotinib (Crizotinib, 3- [1 (R) - (2,6-Dichloro-3-fluorophenyl) ethoxy] -5- [1- (4-piperidinyl) -1H-pyrazol-4-yl] pyridin-2-amine ) - Molecular mechanism of action: ALK Inhibitors, HGFR (MET; c-Met) Inhibitors; Therapeutic group: Lymphoma Therapy, Non-Small Cell Lung Cancer Therapy, Solid Tumors Therapy.

Oseltamivir carboxylate (Oseltamivir carboxylate, (3R, 4R, 5S) -4-Acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid) Molecular Mechanism of Action: Neuraminidase (Sialidase) Inhibitors; Therapeutic Group: Anti-Influenza Virus Drugs.

Rifalazil (Rifalazil, (2S, 16Z, 18E, 20S, 21S, 22R, 23R, 24R, 25S, 26R, 27S, 28E) -25-Acetoxy-5,12,21,23-tetrahydroxy-27-methoxy-2, 4,16,20,22,24,26-heptamethyl-10- [4- (2-methylpropyl) piperazin-1-yl] -2,7- (epoxypentadeca-1,11,13-trienimino) -1,2 -dihydro-6H-benzofuro [4,5-a] phenoxazine-1,6,15-trione) - Therapeutic group: Antibacterial Drugs, Antimycobacterial Agents, Treatment of Peripheral Vascular Disease.

Citalopam hydrobromide (Citalopram hydrobromide, Nitalapram, Apertia, Celexa, Cipram, Cipramil, Elopram, Lupram, Prisdal, Sepram, Seropram, 1- (3-Dimethylaminopropyl) -1- (4-fluorophenyl) -5-phthalancarbonrobromitrolone 3-Dimethylaminopropyi) -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile monohydrobromide) - Molecular mechanism of action: 5-HT Reuptake Inhibitors; Therapeutic Group: Autism, Treatment of Antidepressants, Treatment of Huntington's Disease, Treatment of Alcohol Dependency, Treatment of Mood Disorders,

Anxiolytics, Treatment of Bipolar Disorder.

Cytisine (Cytisine, (-) - Cytisine, Cytisine, Cytiton, Laburnin, Sophorine, Ulexine, Tabex, (1R) -1,2,3,4,5,6-Hexahydro-8H-1,5-methanopyrido [1, 2-a] [1,5] diazocin-8-one) - Molecular mechanism of action: Nicotinic alpha4beta2 Partial Agonists; Therapeutic Group: Aid to Smoking Cessation, Antidepressants.

Escitolapam oxalate (Escitalopram oxalate, (+) - (S) -Citopram oxalate, Cipralex, Entact, Gaudium, Esertia, Lexapro, Seroplex, (+) - 1 (S) - [3- (Dimethylammo) propyl] -1- ( 4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbonitrile oxalate) - Molecular mechanism of action: 5-HT Reuptake Inhibitors; Therapeutic group:

Treatment for Social Phobia, Antidepressants, Treatment of Obsessive-Compulsive Disorder (OCD), Psychiatric Disorders (Not Specified), Anxiolytics, Treatment of Generalized Anxiety Disorder (GAD).

Best results are achieved when citric acid is used as an antioxidant.

The subject of the present invention is also a method for producing a new pharmaceutical composition by mixing an antioxidant and / or a medicinal agent with components of a vapor-, fog-forming composition of an electronic device for simulating smoking.

The subject of this invention is a cartridge containing, as a vapor, fog-forming composition, a new pharmaceutical composition.

The subject of this invention is an electronic device for simulating smoking, for delivering a pharmaceutical composition to the upper respiratory tract, to the lungs and blood of a patient by simulating smoking.

The use of an electronic device for simulating smoking, for delivering a pharmaceutical composition to the upper respiratory tract, into the lungs and thereby into the patient’s blood, by simulating smoking, is unknown to the inventors, it allows the drug to be delivered to the upper respiratory tract, lungs and blood and treating patients using the appropriate drug onset.

The main drawback of the known EUITs is that upon evaporation of a vapor-, fog-forming composition in the atomizer on the heating element (incandescent coil), some of the components of this composition inevitably collapse, forming oxidation products harmful to the body.

The use in accordance with this invention EUIT, the cartridge of which contains as a vapor, fog-forming composition, a new pharmaceutical composition containing an antioxidant, can significantly reduce or eliminate the formation of oxidative products harmful to the body, including the products of oxidation of the drug beginning.

The subject of this invention is a method for treating a patient’s disease by delivering a new pharmaceutical composition to the upper respiratory tract, to the lungs and blood of a patient by simulating smoking using an electronic tobacco smoking simulation device, and

The subject of this invention is a method for the treatment of nicotine addiction;

The subject of this invention is a method for the treatment of drug dependence;

The subject of this invention is a method for treating diseases of the central nervous system;

The subject of this invention is a method for the treatment of acute respiratory diseases;

the subject of this invention is a method for the treatment of chronic inflammatory processes of the respiratory tract, chronic bronchitis, bronchial asthma, chronic pharyngitis;

The subject of this invention is a method for the treatment of allergic diseases;

The subject of this invention is a method for the treatment of alcohol dependence;

The subject of this invention is a method for treating men suffering from erectile dysfunction;

The subject of this invention is a method for the treatment of multiple sclerosis;

The subject of this invention is a method for the treatment of cancer, including lung cancer;

the subject of this invention is a method for the treatment of tuberculosis.

The invention is illustrated, but not limited to, by the following drawings and examples.

Figure 1 shows an electronic device that simulates tobacco smoking "Supersmoker", with a section along AA, in accordance with the patent for utility model No. 103062U.

Figure 2 - cartridge electronic device that simulates smoking "Supersmoker", in the context.

An electronic device simulating smoking consists of a metal shell 1 with an accumulator 2 located in it and interconnected by electric contacts, a steam generator 3, equipped with an LED 4, at least one microprocessor 5 and an air flow sensor 6. Made as a unit with the shell 1 a sprayer 7 with a heater 8 and a cartridge 9 located therein, containing a smoke-generating composition 10 inside. The heater 8 is partially placed in the cartridge 9 with a minimum clearance relative to it, for allowing evaporation of the smoke-generating composition 10. The shape of the cartridge and the system of holes 11 allow air to flow between its walls and the walls of the steam generator 3, at the end of which at least one hole 11 is made, and the electrical contact between the battery 2 and the steam generator 3 is possible, as well as the possibility charging the battery. The connection of the battery, steam generator, LED with at least one microprocessor and an air flow sensor can be made using heat-resistant wires 12. To ensure air circulation and reliable mounting of the cartridge 9 in the atomizer 7, it is equipped with guide ribs 13 (figure 2), evenly spaced around the perimeter of the cartridge.

In the process of manufacturing the cartridge 9, its chamber is filled with the smoke-generating composition of the present invention, the cartridge is sealed and inserted into the atomizer 7. After the atomizer 7 is connected to the housing 1, the EMF is ready for use. After the cartridge becomes empty during use, it can be replaced with another cartridge containing the smoke-generating composition.

The device operates as follows, the device is triggered when an air stream of at least 10 ml / s is drawn in through the nozzle 11 of the atomizer 7 by triggering the air stream sensor 6. After that, the power is supplied from the battery 3 through the microprocessor 5 to the steam generator 3. In this case, the LED 4 lights up and the heater 8 glows, contributing to the abundant evaporation of the smoke-generating composition 10 from the cartridge 9. The thick vapor resulting from the evaporation is picked up by the air flow and through the opening 11 of the races ylitelya 7 is transferred to the lungs user.

Examples 1-13. The compositions of the pharmaceutical compositions and the ratio of nicotine, drug start and the oxidized form of the drug start (*) in the smoke of the Supersmoker electronic cigarette, manufactured in accordance with Utility Model Patent No. 103062U. Any other EUIT design similar to that specified may be used.

The components for each pharmaceutical composition of items 1–13 in Table 1 are mixed in the indicated ratio and the cartridges are filled with Supersmoker electronic cigarettes [http://www.supersmoker.com/]. The "smoke" obtained as a result of smoking simulation is passed through a layer of cotton wool 15 mm thick and 15 mm in diameter. The volume of air passed through an electronic cigarette is from 1.5 to 2.0 liters. The “smoke” delayed by the cotton filter is washed off with 1.5 ml of ethyl alcohol. The obtained ethanol solution was analyzed by LC MS method on a system including: a Shimadzu Analytical HPLC SCLlOAvp chromatograph, a Gilson 215 autosampler, ELSD (evaporative light scattering detector) Sedex 75 (55), a PE SCIEX API 165 mass spectrometer (150).

The main chromatographic and mass spectrometric parameters of the LC MS system used for sample analysis:

- column Waters X-Bridge C18 3.5 µm, 4.6 × 150 mm;

- the volume of the sample introduced into the chromatographic column is 5.0 μl;

- solvent A - water with 0.05% trifluoroacetic acid;

- solvent B - acetonitrile with 0.05% trifluoroacetic acid;

- gradient elution in the system water: acetonitrile:

0,01 min - controller start;

15.10 min - pump B% - 95.0;

19.40 min - pump B% - 95.0;

19.70 min - pump B% - 5.0;

20.05 min - controller stop;

- pause time for balancing the column, s - 40;

- volumetric flow rate of the eluent - 0.50 ml / min;

- wavelengths for measuring the optical density of the samples on a UV detector: 215 nm and 254 nm;

- scan time of the mass spectrum, min - 20.0;

- range of recorded masses, m / z - 100 ... 1000;

- scan time of the mass spectrum by the detector, s - 1.0.

The ratio of nicotine, drug onset and the oxidized form of the drug onset in ethanol solutions is determined by the areas of their corresponding peaks in the chromatogram. The results are presented in table 1.

Table 1 The compositions of the pharmaceutical compositions and the ratio of nicotine, the drug beginning and the oxidized form of the drug beginning (*) in the "smoke" EUIT according to LC MS analysis. No. The composition of the pharmaceutical composition % of the mass. Like the weight (M + H) Peak area (XIC), × 10 ⁵ units. The ratio of components in the "smoke" one** Propylene glycol 48.0 No oxidized nicotine detected Glycerol 39.0 Water 11.5 Nicotine 1,5 162 163 60.0 2 Propylene glycol 48.0 Anabazine: * = 17: 1 Glycerol 39.0 Water 10.5 Anabazine 2,5 162 163 116.0 176 * 177 * 7.0 * 3 Propylene glycol 48.0 Anabazine: * = 89: 1 Glycerol 39.0 Water 5.5 Lemon 5,0 Anabazine 2,5 162 163 53.0 176 * 177 * 0.6 * four Propylene glycol 48.0 Cytisine: * = 1.3: 1 Glycerol 39.0 0.1N aqueous HCl 10.5 Cytisine 2,5 190 191 6.8 204 * 205 * 5.3 * 5 Propylene glycol 48.0 Citizin: * = 3.5: 1 Glycerol 39.0 Water 5.5 Lemon 5,0 Cytisine 2,5 190 191 25.9 204 * 205 * 7.4 * 6 Propylene glycol 48.0 Only the oxidized form of varenicline Glycerol 39.0 0.1N aqueous HCl 10.5 Varenicline 2,5 211 212 No 225 * 226 * 96.4 * 7 Propylene glycol 48.0 Varenicline: * = 10: 1 Glycerol 39.0 Water 5.5 Lemon 5,0 Varenicline 2,5 211 212 59.0 225 * 226 * 5.8 * 8 Propylene glycol 48.0 212 27 Nicotine: Varenicline: * = 5.6: 1: 1.2 Glycerol 39.0 226 31 Water 9.0 163 151 Nicotine 1,5 162 163 151 Varenicline 2,5 211 212 27 225 * 226 * 31 9 Propylene glycol 48.0 Nicotine: Varenicline: * = 5.5: 1: 0.7 Glycerol 39.0 Water 4.0 Lemon 5,0 Nicotine 1,5 162 163 107 Varenicline 2,5 211 212 eighteen 225 * 226 * 12* 10 Propylene glycol 48.0 Oxidized form of Viagra not found Glycerol 39.0 Water 10.5 Viagra 2.5 474 475 0.7 eleven Propylene glycol 48.0 Oxidized form AVN-211 not detected Glycerol 39.0 Water - 0.1 n HCl 11.5 AVN-211 1,5 333 334 7.0 12 Propylene glycol 87.0 162 Oxidized form of Anabazine not found Water 10.5 Anabazine 2,5 162 163 4.4 176 * 177 * - 13 Glycerol 87.0 Anabazine: * = 23.9: 1 Water 10.5 Anabazine 2,5 162 163 35.8 176 * 177 * 1,5 * oxidized form of the corresponding drug beginning **prototype

As can be seen from table 1, the drug, included in the pharmaceutical compositions that are used in EUI (mixture No. 2, 4, 8, 10-13), like nicotine in the prototype (mixture No. 1), when simulated smoking pass into "smoke "And, therefore, will enter the upper respiratory tract, lungs and blood of the patient.

Moreover, the use of pharmaceutical compositions (mixtures No. 3, 5, 7, 9) containing an antioxidant (citric acid), leads to a significant decrease in the content of oxidized forms of Anabazin, Citizin and Vareniklin. This can be seen from a comparison of the ratio of the content in the smoke of Anabazin, Citizin and Varenicline and their oxidized forms in the above compositions (mixtures No. 3, 5, 7, 9) with similar pharmaceutical compositions (mixtures No. 2, 4, 6, 8), in which antioxidant was absent.

Note that when using a pharmaceutical composition containing Viagra as a medicinal agent (mixture No. 10), no products of its oxidation were found in the smoke.

Example 14. The study of the effect of Viagra by inhalation (simulation of smoking) on sexual behavior in rats. The study was conducted on 16 males and 16 female Sprague Dawley rats aged 6-8 weeks. The drug was administered by inhalation using a nebulizer at a dose of 1 mg / kg. The dose of the study drug was selected based on the dose used in clinical practice. Dose recounts were performed according to Frerich (1996): the maximum therapeutic dose recommended for use in humans is 50 mg per 70 kg of human weight, which is 0.71 mg / kg. Given metabolic coefficients, the therapeutic dose in rats weighing 200 g is 4.9 mg / kg (0.71 * 39 / 6.5). Since the administration of the drug was carried out by inhalation, and with this route of administration, absorption is much higher, the dose for administration was chosen 5 times less than that used in the clinic.

The drug was administered to males 20 minutes before replanting to the female. The sexual behavior of males and females in a pair was evaluated by the number of different types of cages. In males, various types of cages were recorded. 1. Simple cage - approaching the male to the female and grasping the front legs of its sides. 2. Cage with pressing - a simple cage, complemented by a pelvic hind touch of the male back of the lower body of the female. 3. Zadka with intromission.

In females, the presence of a lordosis reaction was assessed - a substitution posture characterized by a backward curvature of the spine with raising the head, lowering the chest part and raising the sacrum and base of the tail. The nature of the lordosis reaction in response to the corresponding behavior of the male was evaluated in points: 0 - the absence of lordosis reaction, + weakly expressed lordosis reaction and ++ well-marked lordosis reaction. In addition, the duration of the lordosis reaction was recorded by recording the time spent by the female in the position of substitution. In the absence of a lordosis reaction in the female, the female was replaced with 2-3 simple cages of the male.

It was found that this drug significantly enhanced the erectile function of males, significantly and statistically significantly increasing the main indicators of this process - the number of cages with pressure and, especially, the cage with intromissions. In comparison with control animals, in which there was almost no cage with intromission during the 30-minute observation period, the drug at a dose of 1 mg / kg caused not only their appearance, but also a significant number of them (an average of 7.8 cages per 30 minutes )

table 2 The effect of Viagra on the sexual behavior of rats Groups Types of cages (quantity in 30 minutes) Simple cage Pressed cage Zadka with intromissions The control 6 ± 1.31 3.63 ± 1.19 0.88 ± 1.13 Viagra 1 mg / kg 1.75 ± 0.89 & 6.38 ± 1.6 & 7.75 ± 2.12 &

Thus, Viagra, when inhaled at a dose of 1 mg / kg, enhances the erectile function of males.

Example 15. The study of the effect of Anabazine (hydrochloride) and Citizine upon inhalation (simulating smoking) on nicotine dependence. The study was conducted on 32 male mice of the CD1 line at the age of 6-8 weeks. The drugs were administered by inhalation using the nebulizer Anabazin at a dose of 0.001 mg / kg, Citizine at a dose of 0.7 mg / kg. Doses of the studied drugs were selected based on the doses used in clinical practice. Recalculation of doses was carried out according to Frerich (1996). For Anabazin, the maximum therapeutic dose recommended for use in humans is 0.024 mg per 70 kg of human weight. Given metabolic coefficients, the therapeutic dose in 22 g mice is 0.004 mg / kg. For Cytisine, the maximum therapeutic dose recommended for use in humans is 18 mg per 70 kg of human weight. Since the administration of the drug was carried out by inhalation, and with this route of administration, absorption is much higher, the dose for administration was chosen 5 times less than that used in the clinic.

The drug was administered to males 20 minutes before exposure to animals with cigarette smoke after the formation of nicotine addiction. 4 groups of animals were used (see table 3).

Table 3 Group Information Group number A drug Number of animals Dose (mg / kg) Males one Intact 8 0 2 Placebo 8 0 3 Anabazine 8 0.001 four Cytisine 8 0.7

Animals of groups 2-4 were addicted to tobacco smoke. The experiment was carried out as follows: within ten days, a connection was established between tobacco production and certain environmental conditions, and on the 11th day, the “Place preference” test was performed. Both stages were carried out using a special installation consisting of light and dark chambers of the same size, connected by a passage. The texture of the floor in the cells is different. Normally, the mouse prefers to be in a dark chamber. During the development of the connection between the preparation of the drug and certain environmental conditions, the passage between the cameras is closed. The animals chamber was filled with tobacco smoke (groups 2-4) and after 15 minutes they were placed in one of the cells for 60 minutes. Animals from the intact group were not fumigated, and from the experimental groups when placed in a dark chamber, animals were not fumigated, and in the bright one, the mice breathed tobacco smoke. The animals were placed in light and dark chambers alternated from day to day. Animals from the intact group were placed in a bright chamber on the 1st, 3rd, 5th, 7th and 9th days of the experiment, and on the 2nd, 4th, 6th, 8th and 10th days - into a dark chamber. Animals from experimental groups - on the contrary. Thus, tobacco smoking of experimental animals was carried out on the 2nd, 4th, 6th, 8th and 10th days of the experiment.

On the 11th day of the experiment, the “Preference for a place” test was performed. For this, the door between the light and dark cameras in the installation was opened. Animals did not receive substances before the test. For the test, the animal was placed in a bright chamber and the latent period of the first entry into the dark chamber and the total residence time in the bright chamber were recorded for two minutes. During the formation of the dependence, an increase in the length of stay of animals in the light chamber will be observed, since it was the animal that was planted in the light chamber after introducing the substance on which the dependence forms, in our case tobacco smoke.

After this, the animals with the formed dependence were divided into groups and the experiment was continued with the exposure of the animals with tobacco smoke (maintenance of dependence) and the administration of drugs. The drug was administered by inhalation using a nebulizer 20 minutes before fumigating the animals.

To register the withdrawal syndrome on the 18th and 24th day of the experiment, mice were tested using the cross-shaped elevated maze technique. The elevated cruciform labyrinth is a standard technique for studying stress and anxious behavior in mice. This is a labyrinth raised above the floor with two open and two closed sleeves.

The experiments study the behavioral conflict between the inborn fear of mice for open spaces in mice. It is believed that an open sleeve is chosen by animals with reduced anxiety.

Recorded indicators:

1) total time spent in open sleeves (s);

2) time spent in the center (s);

3) total time spent in dark sleeves (s);

4) hanging from the open arms of the maze (quantity);

5) peeping from the closed arms of the labyrinth (quantity);

6) stands in a dark sleeve;

7) bowel movements (number of boluses).

Inhalation of Anabazin at a dose of 0.001 mg / kg and Citizin at a dose of 0.7 mg / kg 20 minutes before smoking animals on the background of the formed nicotine dependence caused a significant shortening of the time spent by the animals in the bright compartment. The results show that the studied drugs reduce the nicotine dependence formed in mice (table 4).

Table 4 Indicators of the test "seat preference" on the 18th day after drug administration latent period, s time in a light chamber, s total time in the light chamber, s The control 8.5 ± 2.51 19.38 ± 6.78 27.88 ± 8.54 Placebo 31 ± 9.99 & 64.38 ± 11.53 & 95.38 ± 18.64 & Anabazine at a dose of 0.001 mg / kg 12.63 ± 1.32 & 25.75 ± 2.87 38.38 ± 3.96 Citizine at a dose of 0.7 mg / kg 10.88 ± 1.11 24.63 ± 2.93 35.5 ± 3.12

In addition, these drugs relieve symptoms of withdrawal symptoms that appear after the cancellation of cigarettes. 5 days after the animals stopped receiving nicotine, in the group of animals that received placebo as a treatment, an extension of the time spent in the closed sleeve was observed, the animals did not go into the open sleeve. These indicators speak in favor of a significant increase in animal anxiety, which is one of the signs of withdrawal.

In animals that were injected with the studied drugs against the background of the formed nicotine addiction, the behavior does not differ from intact animals 5 days after canceling exposure to cigarette smoke. This fact indicates a weakening of nicotine withdrawal after inhalation administration of Anabazin and Citizin.

Table 5 Indicators on the 24th day (5 days after cancellation of exposure to cigarette smoke) The control Placebo Anabazine at a dose of 0.001 mg / kg Citizine at a dose of 0.7 mg / kg Being in the center, with 13.88 ± 13.54 7.13 ± 3.18 9.13 ± 2.5 16 ± 4.68 Being in a closed sleeve, with 151.63 ± 14.08 172.88 ± 3.18 & 161.63 ± 4.44 150 ± 7.34 Being in an open sleeve, with 14.5 ± 6.32 0 ± 0 & 9.25 ± 2.39 14 ± 3.76 Number of Racks 2.25 ± 2.12 0 ± 0 & 2.25 ± 0.75 3.88 ± 1.23 Number of Hangings 0 ± 0 0 ± 0 1.25 ± 0.62 1.5 ± 0.76 Number of peeks 0.75 ± 1.04 1.63 ± 2.83 0.25 ± 0.16 2.38 ± 0.68 Defecation (number of boluses) 0.88 ± 1.36 4.25 ± 3.24 & 1.88 ± 0.48 0.75 ± 0.37

Claims (4)

1. The pharmaceutical composition for the treatment of nicotine addiction using an electronic device containing a cartridge that simulates smoking, based on a steam-, fog-forming composition containing water, glycerin, propylene glycol, characterized in that it further comprises citric acid, as well as Varenicline, or Anabazine hydrochloride , or Citizin, taken in the following ratio, wt.%:
Propylene glycol 48.0 Glycerol 39.0 Water 5.5 Lemon acid 5,0
Varenicline, or Anabazine Hydrochloride,
or cytisine 2.5 2. The method of obtaining the pharmaceutical composition according to claim 1 by mixing water, glycerol, propylene glycol and citric acid, as well as Varenicline, or Anabazine hydrochloride, or Citizine. 3. The cartridge of an electronic device simulating tobacco smoking, containing the pharmaceutical composition according to claim 1. 4. A method of treating nicotine addiction by simulating smoking using an electronic device containing a cartridge according to claim 3.

Images