Percutaneous or permucous medicinal formulations used for elimination smoking habit as combination of active components containing nicotine

FIELD: medicine.

SUBSTANCE: invention describes a percutaneous or permucous medicinal formulation used in treatment of nicotine dependence or elimination from the smoking habit. Proposed medicinal formulation comprises nicotine, nicotinic salt, a derivative of nicotine or substance enhancing effect of nicotine in combination with at least one additional substance effecting on the central nervous system. Oral dosing an additional substance effecting on the central nervous system excludes adverse effects and providing a simple and safety intake of drug for patients.

EFFECT: improved and valuable properties of formulation.

10 cl

 

The invention relates to percutaneous or crosslisted medications for the treatment of nicotine addiction or get rid of the habit of Smoking, nicotine, a nicotine salt, a derivative of nicotine or substance, the reinforcing effect of nicotine, in combination with an additional active ingredient.

The invention additionally relates to the use of such formulations for the treatment of nicotine addiction, with the aim of nicotine replacement or to get rid of the habit of Smoking and also to the use of nicotine and/or its salts or derivatives with the aim of obtaining percutaneous or crosslisted dosage forms for the treatment of nicotine dependence.

Despite the generally known harmful effects of Smoking on the health of smokers escape from nicotine addiction for most of them is extremely difficult. The main reason for this are the symptoms of nicotine withdrawal symptoms that occur after stopping the intake of nicotine by Smoking. Thus, getting rid of this habit easier to implement in case the need for nicotine is satisfied, at least at the stage of weaning from Smoking, in other words, for example, as part of nicotine replacement therapy. Is the consumption of nicotine provide, for example, by using nicotine h is Ebronah medical systems, known as nicotine patches. Such patches capable of delivering nicotine into the body through the skin, resulting in increased levels in plasma and thereby it becomes possible to suppress the occurrence of symptoms of nicotine withdrawal. As a result it facilitates Smoking cessation.

However, it was found that the physical addiction to nicotine, many smokers accompanied by psychological dependence, which cannot be eliminated only by substitution of nicotine. In many cases, physiological dependence causes of relapse.

In this regard, it should be noted that according to numerous clinical research application of nicotine in combination, in particular, with antidepressant can improve the results of the habit of Smoking. Perhaps the success of the treatment of nicotine addiction, at least partly depends on the treatment of psychological dependence. Nevertheless, capable of receiving psychopharmacological agents is also associated with some problems, namely the risk of side effects and the danger of excessive and insufficient dosage.

In the application WO 96/00072 disclosed percutaneous and cresselia pharmaceutical compositions comprising nicotine in combination with caffeine or its derivatives and used DL is getting rid of the habit of Smoking. Presumably, this combination is a great recognition among smokers who wish to stop Smoking. The said combination additionally aims to prevent the weight gain that often accompanies the process of weaning from Smoking. However, caffeine is not able to affect the overcoming of psychological dependence. On the contrary, the side effects caused by caffeine, such as irritability, nervousness or muscle tremor, associated with the risk of more frequent occurrence of relapses.

Thus, the present invention is the creation of nicotine dosage forms, while providing the possibility of receiving additional active substance, preferably, antidepressant to struggle with the psychological dependence as part of the treatment of nicotine addiction. When receiving such additional active substance should preferably be excluded side effects, and patients should be provided with the possibility of a simple and reliable reception.

This task unexpectedly resolved by percutaneous or crosslisted dosage forms containing nicotine, a nicotine salt, a derivative of nicotine or substance, the reinforcing effect of nicotine, in combination, at least one additional current substances is m, as an additional active substance (substances) they contain at least one substance that acts on the Central nervous system. Accordingly, percutaneous or cresselia dosage form according to the invention are a combination of the active substance, i.e. nicotine or a nicotine salt, a derivative of nicotine or substances that enhance the action of nicotine, in combination, at least one additional active substance acting on the Central nervous system.

Using the dosage forms according to the invention provide a continuous consumption of the patient over a specified period of time dose of nicotine required for its replacement, as well as the consumption of substances acting on the Central nervous system, such as an antidepressant or other psychopharmaceuticals means to suppress psychological dependence or fight it. Particularly preferably the consumption of active substances occurs through the combined drug percutaneous or through mucous membranes. Thus the patient is not required to take additional oral pharmaceutical drugs to combat the psychological dependence. Thus, it should be assumed that the patient's condition improved by the use of the value of a single pharmaceutical preparation, containing a combination of active substances.

In addition, the use of substances acting on the Central nervous system through the skin (or mucous membranes), allows to establish effective levels in the blood plasma, which support during the entire period of use. This is important because, especially in the case of the use of substances acting on the Central nervous system, treatment success substantially depends on the presence of constant levels of such substances in the blood plasma. Through percutaneous or crosslisted use according to the invention mainly prevent the occurrence of unwanted side effects as a result of exceeding or under-terapevticheskii effective dosage. In addition, predominantly excluded abuse contained in the dosage form active ingredients, for example, psychopharmacological agents.

Dosage form according to the invention additionally provides a continuous percutaneous or crosslisted consumption of nicotine or a derivative of nicotine, resulting in plasma establish and maintain an appropriate level of nicotine content with a view to its replacement as part of the treatment of nicotine dependence.

Target the level of content is of icotine in the blood is in the range from 1 ng/ml to about 100 ng/ml, preferably, from 10 ng/ml, 70 ng/ml, particularly predpochtitelno, from 10 to 30 ng/ml Should be aware that these values may vary in individual patients. Specialist in the art known methods to control the release of active substances from percutaneous or crosslisted dosage forms in order to achieve the desired values. In this regard, the desired level of nicotine concentration in the blood plasma should preferably be made no later than 1 hour, more preferably, not later than 30 minutes after application.

Substance that acts on the Central nervous system and is present in the dosage forms according to the invention in addition to nicotine, preferably, is an active ingredient selected from the group of psychopharmacological agents, including such groups of active substances, as antidepressants, tranquilizers, nootropics, brain, psychotonic and psihomimetiki. Particularly preferred in this case are the active ingredients selected from the group of antidepressants, it has been established that they are the most acceptable from the point of view of overcoming the psychological addiction. The invention additionally relates to nicotine dosage forms of the type specified above, containing casestudydetail active substances two or more psychopharmaceuticals from among the above-mentioned groups of active substances.

Additionally substance that acts on the Central nervous system, chosen in particular from the group comprising these groups of active substances, as phenothiazines, azafenidin, tioksantena, butyrophenones, diphenylbutylpiperidines, derivatives iminodibenzyl derived iminostilbene, derivatives dibenzocycloheptadiene derived dibenzodiazepine derived dibenzoxepin, benzodiazepines, indole derivatives, derivatives of phenethylamine derivatives of hypericin.

In addition, the invention applies in particular to those containing nicotine percutaneous or crosslisted dosage forms that contain more substance that acts on the Central nervous system, which is chosen from the group comprising such active substances as chlorpromazine, perphenazine, sulpiride, clozapine, clomipramine, trimipramine, desipramine, imipramine, doxepin, risperidone, reserpine, maprotiline, mianserin, lofepramine, tranilcipromin, moclobemide, amitriptyline, paroxetine, promethazine, flupentixol, oxitriptan, viloxazine, meprobamate, hydroxyzine, buspirone, fenetylline, methylphenidate, prolintane, fenfluramine, fluvoxamine, meclofenoxate provided nicergoline, piracetam, pyritinol, amfebutamone, as well as salts and derivatives of these compounds.

Salt of nicotine and derivatives of nicotine, which can be used the change in dosage forms according to the invention, preferably, include hydrochloride nicotine, dihydrochloride nicotine, nicotine sulfate, nicotine bitartrate, nicotine zinc chloride and salicylate nicotine separately or in combination, or in combination with nicotine.

As substances that enhance the action of nicotine, i.e. substances which have the effect not the nicotine receptor, in addition to the nicotine, it is preferable to use lobelin, succinylcholine and other relaxers peripheral muscles.

Specialists in the art known dose of the active substance and the level of its concentration in the blood plasma, applicable to the treatment of psychological dependence. Preferably, the dose of a substance acting on the Central nervous system, chosen in accordance with the dose of nicotine that is present in the dosage form, so that the contents of both active substances in the blood plasma to the maximum extent consistent with the specific, therapeutically favorable level and to provide uniform release of the active substance within a specified period of use.

According to one embodiments of the invention percutaneous dosage forms are transdermal therapeutic system (TTS) containing active substances patch adhered to the skin of the patient and visual the approving active substances through the skin. In General, such a system is impermeable to active substances substrate, a container for the active substance, preferably glued under pressure and connected to the substrate, and a protective layer which is removed before use. The capacity for the active substance contains a combination of at least two active substances, namely, nicotine salts, nicotine-derived nicotine or substances that enhance the action of nicotine, and as a component (components) additional active substance is also at least one substance that acts on the Central nervous system, which are selected from substances or groups of substances mentioned above.

The capacity for the active substance what, containing the active substances dissolved or dispergirovannom, consists mainly of polymers that form the basis of active substances. Such polymers are also referred to as a polymer basis. The capacity for the active substance preferably has the ability to stick when pressed, due to the nature of the used polymeric bases or more impurities, which are substances to enhance the stickiness.

In addition, the surface of the container for the active substance, drawn to the skin, can also be glued with pressure adhesive is Loy. In the simplest embodiment, the container for the active substance the TTS according to the invention is a single layer of polymer base. Based on this, what may have capacity for the active substance with a multilayer structure consisting of at least two layers of polymeric bases. In this case, the two polymer layers preferably contain different active ingredients, for example, one of the layers of Foundation capacity for the active substance as an active substance contains nicotine, and the second layer bases as the second reactant in accordance with the invention contains an antidepressant.

Particularly preferred polymeric bases used in what are copolymers of acrylate and a mixture of rubber and resin, synthetic rubber, polyvinyl acetate, polyvinylpyrrolidone, silicone polymers, cellulose derivatives, hot melt adhesives and a variety of other substances whose effect on the skin of a person is not undesirable. It is also possible to use mixtures of different polymers.

The polymer base of the active substance may optionally include auxiliary substances and additives, in particular, well-known specialists in the field of technology additives that enhance penetration through the skin.

In addition to described the th higher capacity for the active substance, The TTS according to the invention has a substrate that is impermeable to the active substance, and a removable protective film, also impermeable to the active substance.

The materials used for the manufacture of the substrate, include a large number compatible with the skin of polymer films, such as, for example, films of polyvinyl chloride, vinyl acetate, vinyl acetate, polyethylene, polypropylene or cellulose derivatives. Particularly preferred materials for the substrate include polyesters, particularly strength. In certain cases, the substrate also put an additional layer, for example, by vacuum deposition using metal or other forming a diffusion barrier additives, such as silicon dioxide, aluminum oxide or similar substances known to specialists in this field of technology.

For the manufacture of removable protective layer of what in principle is the use of substances used in the substrate, with the proviso that the surface of such layer is subjected to appropriate processing, for example, by the method of fertilizeruse, due to which it can be separated from the adhesive by pressing the adhesive layer, which it protects, and is removed before application of the TTS. In addition, as the removable protective layer may also be used other materials, such as, for example, babatana polytetrafluoroethylene paper, cellophane, polyvinyl chloride and the like.

Above what can be made known to experts in the art of ways. Usually get a solution or melt of a polymeric base, in which is dissolved or uniformly dispersed active ingredients. Then the composition containing the active ingredients, applied on the substrate in the form of a film, dried, and cover with an additional layer of film. The resulting laminate is cut into individual patches. The square patches are preferably chosen so that each patch contains half the daily dose or the total daily dose or two - or three-day nicotine and/or combinations of active substances (e.g., antidepressant).

In an additional embodiment of the invention the dosage form that contains nicotine and at least one substance that acts on the Central nervous system, made in the form crosslisted dosage forms. Cressilia dosage forms of this kind can be used, for example, in the oral cavity for sublingual or buccal application. In this case, the active substance is absorbed through the mucous membrane, bypassing the digestive tract.

Cressida dosage form according to the invention containing nicotine in combination with one of the KJV is anutech active substances, preferably, consists of a flat carrier of the active substance in the form of a film, foil or plate and has the ability to be linked with the mucous membranes. This ensures the adhesion of the dosage form with the surface during the period of its application. The ability to hook the mucous membrane can be achieved by adding relevant subsidiary polymers which preferably have the ability to swell in water, and their examples include starch, carboxymethylcellulose, hydroxypropylcellulose, polyacrylic acid, polyvinylpyrrolidone, polymers of polyoxyethylene, ethylcellulose or propylethylene, alginates, pectins or natural rubbers.

Dosage forms according to the invention combine the advantages of combination therapy, because they contain nicotine or a nicotine salt, a derivative of nicotine or substance, reinforcing action of nicotine, used for replacement therapy, and substance that acts on the Central nervous system, used for the treatment of psychological dependence, with the advantages of percutaneous or crosslisted applications, respectively. For these reasons they can be successfully used for the treatment of nicotine addiction, get rid of the habit of Smoking and replacement therapy. In the best of the e from the known patches, containing nicotine as the active substance, pharmaceutical form according to the invention not only allows the substitution of nicotine, but also simultaneously to treat the psychological component of nicotine dependence.

Dosage forms according to the invention is preferably used for injection of nicotine or substances related to nicotine, in combination with an appropriate antidepressant or other substance, applicable to the treatment of psychological dependence and acting on the Central nervous system of the patient through the skin or mucous membranes as part of the treatment, with the goal of getting rid of the habit of Smoking.

1. Percutaneous or Cressida dosage form for the treatment of nicotine addiction or get rid of the habit of Smoking, nicotine, a nicotine salt, a derivative of nicotine or substance, the reinforcing effect of nicotine, in combination, at least one additional active ingredient, characterized in that as an additional active substance (substances) it contains at least one substance that acts on the Central nervous system, which is chosen from the group of psychopharmacological agents, including tranquilizers, nootropics, brain and psihomimetiki, when atomiclevel levels of nicotine in the blood is in the range from 1 ng/ml to about 100 ng/ml, preferably, from 10 ng/ml to about 70 ng/ml, particularly preferably from 10 ng/ml to 30 ng/ml, and is achieved not later than 1 h after application of the mentioned dosage forms.

2. Dosage form according to claim 1, characterized in that it contains a derivative of nicotine or a nicotine salt, which is preferably chosen from the group comprising hydrochloride nicotine, nicotine dihydrochloride, nicotine sulfate, nicotine bitartrate, nicotine zinc chloride and salicylate nicotine.

3. Dosage form according to claim 1, characterized in that it contains a substance, the reinforcing effect of nicotine, which, preferably, are selected from the group including nicotine, lobelin, succinylcholine and other relaxers peripheral muscles.

4. Dosage form according to any one of preceding claims 1 to 3, characterized in that it also contains an additional substance that acts on the Central nervous system, which is selected from Pechatnikov and antidepressants.

5. Dosage form according to any one of preceding claims 1 to 4, characterized in that the additional substance that acts on the Central nervous system, which are selected from the group including these groups of active substances, as phenothiazines, azafenidin, tioksantena, butyrophenones, diphenylbutylpiperidines, derivatives iminodibenzyl derived iminostilbene, produced the water dibenzocycloheptadiene, derivatives dibenzodiazepine derived dibenzoxepin, benzodiazepines, indole derivatives, derivatives of phenethylamine derivatives of hypericin.

6. Dosage form according to any one of preceding claims 1 to 4, characterized in that the additional substance that acts on the Central nervous system, which are selected from the group comprising active ingredients chlorpromazine, perphenazine, sulpiride, clozapine, clomipramine, trimipramine, desipramine, imipramine, doxepin, risperidone, reserpine, maprotiline, mianserin, lofepramine, tranilcipromin, moclobemide, amitriptyline, paroxetine, promethazine, flupentixol, oxitriptan, viloxazine, meprobamate, hydroxyzine, buspirone, fenetylline, methylphenidate, prolintane, fenfluramine, fluvoxamine, meclofenoxate provided nicergoline, piracetam, pyritinol, amfebutamone, as well as salts of these compounds.

7. Dosage form according to any one of preceding claims 1 to 6, characterized in that it provides a percutaneous flow of active substances, such dosage form preferably is a transdermal therapeutic system, which is impermeable to active substances substrate, a container for the active substance, preferably glued under pressure and containing nicotine, a nicotine salt, a derivative of nicotine and substance, reinforcing de is due to nicotine, and also, optionally, at least one substance that acts on the Central nervous system, and a protective layer which is removed before use.

8. Dosage form according to any one of preceding claims 1 to 6, characterized in that it provides crosslist receipt of active substances, such dosage form preferably is a flat carrier of the active substance in the form of a film, foil or plate and has the ability to be linked with the mucous membranes, the ability to be linked with the mucous provide by adding auxiliary polymers, which are preferably chosen from the group comprising starch, carboxymethyl cellulose and polyacrylic acid.

9. The use of percutaneous or crosslist dosage forms containing at least one active substance selected from the group consisting of nicotine, a nicotine salt and succinylcholine, in combination, at least one additional active ingredient, which is selected from the group including chlorpromazine, chlorprothixene, flupentixol, prolintane, benzodiazepines, buspirone, meprobamate, hydroxyzine, nicergoline, phenothiazines, tioksantena, butyrophenones, sulpiride, reserpine and clozapine, as a drug for the treatment of nicotine zavisimost and, replacement nicotine and getting rid of the habit of Smoking.

10. Applying at least one active substance which is selected from the group consisting of nicotine, a nicotine salt and succinylcholine, in combination, at least one additional active ingredient, which is selected from the group including chlorpromazine, chlorprothixene, flupentixol, prolintane, benzodiazepines, buspirone, meprobamate, hydroxyzine, nicergoline, phenothiazines, tioksantena, butyrophenones, sulpiride, reserpine and clozapine, for the manufacture of transdermal therapeutic systems or crosslist dosage forms for the treatment of nicotine addiction, get rid of the habit of Smoking or nicotine replacement.



 

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EFFECT: valuable medicinal properties of compounds and agent.

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FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

Fumaric acid amides // 2290946

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, namely, to using fumaric acid amides of the formula (I): These compounds are used in preparing a medicinal agent designated for treatment of autoimmune diseases, response reactions "transplant against host", treatment of diseases mediated by NfkappaB, and to fumaric acid amides of the formula (I) and to a medicinal agent comprising fumaric acid amide of the formula (I) taken in the dose corresponding to 1-500 mg of fumaric acid as measured for a single dose and designated for treatment abovementioned diseases. Fumaric acid amides and a medicinal agent comprising thereof are characterized by absence of systemic adverse effect of body and resistance against hydrolysis that allows avoiding their multiply dosing.

EFFECT: valuable medicinal properties of agents.

19 cl, 2 tbl, 3 ex

FIELD: medicine, stomatology, ambulatory anesthesiology.

SUBSTANCE: method involves administration of phenotropil in the dose 25 mg by sublingual route. Method provides significant reducing psychoemotional stress in patients for shorter period under conditions of ambulatory stomatological reception based on optimally selected dose of preparation and route of its administration. Invention can be used in realization of premedication in patients with different degree of expression of psychoemotional stress.

EFFECT: improved method of premedication.

3 ex

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