Liquid pharmaceutical composition comprising nicotine for administration into mouth cavity

FIELD: pharmacy.

SUBSTANCE: invention proposes a liquid pharmaceutical composition containing nicotine in any form for administration into the mouth cavity and alkalinized with a buffer and/or by regulation of pH value. Administration is carried out preferably by spraying and the most preferably by sublingual spraying. Also, invention relates to a method for preparing the indicated composition. Use of indicated composition in therapy, such as therapy for treatment of addiction to tobacco.

EFFECT: valuable pharmaceutical properties of composition.

51 cl, 11 ex

 

The technical FIELD

The present invention relates to liquid pharmaceutical compositions for delivering nicotine to a subject. Also the present invention relates to a method and system for delivery of nicotine, as well as to receive and use this liquid pharmaceutical compositions.

BACKGROUND of the INVENTION

Tobacco addiction and its decrease

In recent years, with awareness of the harmful effects of tobacco Smoking has conducted a number of campaigns and programmes of government agencies and various health groups and other interested organizations in order to disseminate information about the harmful health effects resulting from tobacco Smoking. Moreover, in recognition of the harmful effects of Smoking has implemented many programs to try to reduce the frequency of Smoking.

Nicotine is an organic compound and is the principal alkaloid of tobacco. Nicotine is the main active ingredient of tobacco used in cigarettes, cigars, snuff tobacco and similar products. However, nicotine is also a drug, addictive, and therefore, smokers, usually for some time manifested a strong tendency to relapse after successful Smoking cessation. Nicotine is I who is the world's second most used drug after the caffeine in coffee and tea.

The main problem in tobacco Smoking is a huge health impact. It is now estimated that diseases associated with Smoking, cause 3-4 million deaths per year. In the report of the US Surgeon General's 1988 "the effects of Smoking on health (The Health Consequences of Smoking) it is estimated that only in the United States, about 300,000 deaths each year are caused by diseases associated with cigarette Smoking. In fact, at present, excessive Smoking is regarded as one of the major health problems worldwide. Such terrible consequences of Smoking tobacco have prompted many medical associations and health authorities to adopt serious measures against the use of tobacco.

Even despite the fact that currently, tobacco Smoking is declining in many developed countries, it is difficult to imagine how society will be able to rid the world's second most used drug.

The most useful thing that can make a chain smoker, is to reduce or preferably even a complete cessation of Smoking. Experience shows, however, that most smokers find it extremely difficult, because typically the tobacco Smoking leads to addiction or deadlift. The who's International classification of Diseases there is a diagnosis called tobacco addiction. Other organizations, such as American is Kai Psychiatric Association, call this addictive Nicotine Addiction. Usually believe that such difficulties associated with Smoking cessation, arise from the fact that heavy smokers are dependent on nicotine. The most important risk factors are, however, substances that are formed during the burning of tobacco, such as carcinogenic resinous products, carbon monoxide, aldehydes and hydrogen cyanide.

The effects of nicotine

Introduction nicotine can give satisfaction, and the usual way is Smoking, as Smoking, such as cigarettes, cigars or pipes, or nochange or chewing tobacco. However Smoking is dangerous to health and, therefore, it is desirable to provide an alternative enjoyable way of introducing nicotine, which can be used to facilitate Smoking cessation and/or be used as a replacement area.

When Smoking cigarettes, nicotine is rapidly absorbed into the bloodstream of the smoker and reaches the brain within ten seconds after inhalation. The rapid absorption of nicotine gives the user quick satisfaction or peak. Then satisfaction lasts over time Smoking cigarettes and for some time after. Toxic, toxic, carcinogenic and causes the habit of the nature of the area makes attempts search method is in, compositions and devices that help to get rid of the habit of Smoking.

Nicotine is an addictive poisonous alkaloid C5H4NC4H7NCH3derived from tobacco plants. Nicotine is also used as an insecticide. Approximately forty milligrams of nicotine can kill an adult human (Merck Index).

Products, nicotine replacement

One possibility of reducing Smoking is the nicotine delivery in the form or manner, other than Smoking, and developed some products to fulfill this goal. Compositions containing nicotine, are currently the main method of treatment of Tabukashvili.

When using the known products success in achieving the reduction of the frequency of Smoking was relatively small. The state of the technology includes both behavioral approaches and pharmacological approaches. More than 80% of tobacco smokers is that you first stop Smoking after applying some behavioral or pharmacological approaches to reduce the frequency of Smoking by yourself, usually starting again and return to the habit of Smoking to their previous level area for approximately one year.

As an aid to those who wish to stop Smoking, there are several ways and forms of products, replacing the x nicotine, available on the market such as nicotine chewing gum according to US 3845217. Have been described several ways and means to reduce the desire of the subject to use tobacco, which include the stage of introducing the subject of nicotine or its derivatives, as described, for example, in US 5939100 (nicotine-containing microspheres) and US 4967773 (nicotine-containing pellet).

The effect of pH on the absorption of nicotine discuss, for example, Eur J Clin Pharmacol, vol.56, 2001, pages 813-818, L. Molander et al, "Pharmacokinetic investigation of a nicotine sublingual tablet". Although the effect of pH on the liquid compositions of nicotine for introduction into the oral cavity is not described.

Report on the application of a skin patch for transdermal administration of nicotine (Rose, in Pharmacological Treatment of Tobacco Dependence, (1986) pp. 158-166, Harvard Univ. Press). Nicotine-containing skin patches, which are widely used at the present time, may cause local irritation, and the absorption of nicotine is slow and prone to the influence of skin blood flow.

Report on nicotine-containing drops in a nose (Russell et al., British Medical Journal, vol. 286, p. 683 (1983); Jarvis et al., British Journal of Addiction, vol. 82, p. 983 (1987)). Nose drops, however, are difficult to introduce and not suitable for use at work or in other public places. Methods of administration of nicotine by delivering directly into the nasal cavity by spraying known from US 4579858, DE 3241437 and WO/9312764. However there may be a local section shall agenie nose when using nasal compositions of nicotine. The difficulty of introducing also leads to the unpredictability of the dose of nicotine.

For vapor absorption of nicotine is known devices for inhalation, similar to cigarettes, as proposed in US 5167242. Aerosol for delivery of nicotine into the lungs is described in DE 3241437.

Sprays for oral cavity containing nicotine are known in the technical field, for example, according to US 6024097, which describes a way to help the smoker in quitting the habit of Smoking, according to which use a multitude of aerosol dispensers containing a gradually decreasing concentration of nicotine. The spray is designed for introduction into the oral cavity. The liquid in the dosing mainly consists of nicotine and alcohol.

Similar spray to the oral cavity described in US 5810018, where, in addition, the aerosol contains a gradually increasing concentration of at least one selected stimulator.

In WO 98/24420 describe the aerosol device with the active component and the gas displacer. The device can be used, for example, for sublingual administration. Nicotine is mentioned as an active ingredient in a wide "long list" of drugs. However, no examples of compositions of nicotine.

US 5721257 describes a method of treatment of a condition amenable to treatment with nicotine, including the first treatment with nicotine, administered transdermal, and vtoro the treatment of nicotine enter through the mucous membrane. It is established that the introduction through the mucous membrane can be performed by means of an aerosol on the shell of the nasal cavity. Not described in the introduction into the oral cavity.

WO 97/38663 describes buccal aerosol spray using a non-polar solvent. Nicotine is mentioned as the only useful active ingredient in this spray.

Similarly US 5955098 describes buccal non-polar spray, where the nicotine may be the active ingredient.

None of the known spray to the oral cavity does not contain a buffer and/or means of regulating the pH.

Prior art and problems in it

The means and methods do not meet the requirements of certain users of tobacco. In particular, such means and methods typically do not provide a sufficiently rapid absorption of nicotine without any side effects.

This means that none of the known means and methods do not meet any of the following well-known NRT requirements Russel et al.:

I: Fast shipping or rush of nicotine, fast enough for the positive subjective effects of nicotine, in contrast to the modern nicotine chewing gum and patches, leads to a more rapid release of the pull, and

II: More rapid liberation is dated thrust provides the best traction control, and

III: the Best traction control should lead to a higher percentage complete cessation (see Russell, M.A.H., Stapleton, J.A. and Feyerabend C. Nicotine boost per cigarette as the controlling factor of intake regulation of smokers; In: Clark et al. (Eds.) Effects of Nicotine on Biological Systems II, Advances in Pharmacological Sciences, Birkhauser Verlag, Basel, (1995) 233-238).

In light of the above problems, there is a strong need and interest in developing the means and methods of introducing nicotine to get a quick response from the person suffering from nicotine cravings, or to ensure a feeling of satisfaction from Smoking without Smoking, so you can also avoid the problems associated with the resources and methods of the prior art. The present invention meets a specified need and interest.

BRIEF description of the INVENTION

In light of the above drawbacks of the known technology, when attempting delivery of nicotine to a subject to obtain a rapid absorption through the mucous membrane in the oral cavity of the subject, the present invention provides a new and improved product, systems and methods of obtaining rapid absorption of nicotine through the mucous membrane in the oral cavity of the subject.

The objectives of the present invention is the provision of efficient and effective product, as well as methods and systems for the rapid absorption of nicotine from the subject to avoid the disadvantages is anee known products and processes. The present invention also sufficiently satisfies the above requirements Russel et al.

Therefore, the present invention relates to a method for delivering nicotine in any form to a subject, comprising administration to the subject a liquid pharmaceutical composition containing nicotine in any form in the oral cavity of a subject and allowing the nicotine in any form to be absorbed into the circulation of a large circle (systemic circulation) of the subject, mainly by rapid buccal absorption of nicotine, as well as to a method for the specified liquid pharmaceutical compositions.

The present invention also relates to a method for reducing the need to smoke or to use a substance containing tobacco, and/or provide a quick sense of satisfaction from Smoking without Smoking, comprising the stage of replacing, at least partially, of a substance containing tobacco, specified liquid pharmaceutical composition, introduction to the subject a liquid pharmaceutical composition containing nicotine in any form in the oral cavity of a subject and allowing the nicotine to be systemically absorbed with the subject mainly by buccal absorption of nicotine.

In addition, the present invention relates to a system for delivering nicotine in any form sub is KTU, includes the specified liquid pharmaceutical composition and at least one other tool to help reduce the need to smoke or use tobacco, as well as to the system to ensure reducing the need to smoke or use tobacco in a different way, and/or maintain the feeling of satisfaction from Smoking without Smoking area, containing a liquid pharmaceutical composition as described above and at least one other method of getting reduce the need to smoke or use tobacco in any other way. This system can be a system, where at least one other way is chosen from the group consisting of injection by means of chewing gum, nasal sprays, transdermal patches, inhalation devices, pellets, tablets and parenteral methods, subcutaneous methods, intravenous methods, rectal methods, vaginal methods and the introduction of a mucous membrane; or other use of tobacco.

The present invention provides a flexible, convenient and discrete application in comparison with other means for delivery of nicotine through the mucous membrane, for example, chewing gum, cakes and tablets. It is not necessary to chew or suck. In addition, and unlike other dosage forms for insertion through the mucus is thuja shell, this liquid pharmaceutical composition delivers nicotine in a form that can be absorbed directly behind the cheek of the subject. Known compositions for nasal delivery of nicotine are uncomfortable - side-effects include runny nose, irritation of the nose and eye irritation. Nicotine chewing gum, cakes and tablets need to undergo phase transformation, including, for example, mastication, disintegration (decay), melting and/or dissolution, before you come in directly absorbable form. Nicotine patch provides a separate introduction, but does not provide the rapid absorption of nicotine.

The product of the present invention is padmalochan by buffering and/or pH regulation so that the introduction of liquid pharmaceutical compositions the pH of the liquid in the oral cavity was increased by 0.3 to 4 pH units, or preferably increased by 0.5 to 2.5 pH units.

The use of this product according to the present invention allows to quickly deliver nicotine in any form to a subject, and provides for rapid and/or sustained and/or complete reduction of the urge to smoke or use tobacco and/or providing a feeling of satisfaction from Smoking without Smoking, similar to the feeling of satisfaction from Smoking, get a pic the e regular Smoking or use of tobacco.

LIST of FIGURES

Fig. 1 is a graph showing the concentration in the venous blood plasma nicotine after two different routes of administration of nicotine. For both routes of administration of one single dose was administered in zero time. Further doses were not introduced. In this study involved 50 people, all consuming nicotine. "Spray" is a 200 ál liquid pharmaceutical composition according to the above example 4, sprayed under the tongue. This unit dose contains 3.5 mg of nicotine, measured as a free base. "Microtab" represents one pill Nicorette®Microtab, containing 4 mg of nicotine, measured as the free base. Nicorette®Microtab is pharmacologically equivalent of chewing Nicorette gum®. "Spray" contains a buffer. "Microtab ' does not contain a buffer. In the case of "spray", the liquid pharmaceutical composition is held in the mouth for one minute before swallowing. In the case of "microtab", the tablet hold under the tongue to dissolve. Each symbol corresponding graph represents one measurement of nicotine in venous blood plasma.

In Fig. 2 shows the average concentrations in plasma after sublingual introduction of three liquid pharmaceutical compositions with a pH of 6, 7 and 8.5, with the NGOs. For each composition 200 ál sprayed under the tongue in zero time. For all three of these compositions, the concentration of nicotine was 10 mg/ml, i.e. each spray dose of 200 μl as described above, contains 2 mg of nicotine calculated as free base. Composition with a pH of 8.5 is a composition by the following example 1. Compositions with pH 7 and pH 6 is a composition by the following example 2 and example 3, respectively.

In Fig. 3 matched the profile of nicotine in venous blood plasma versus time of a single dose of common chewing Nicorette gum®, high power (4 mg), with a corresponding profile in the plasma when Smoking "light" cigarettes with low nicotine content). One objective of the present invention is to obtain a composition of nicotine for buccal application, providing a profile of the Republic of Kazakhstan, closest to the profile of the Republic of Kazakhstan for cigarettes, than can be achieved when applying the known compositions of nicotine for buccal application.

In Fig. 4 shows the average level of the "urge to smoke" (thrust) 52 smokers volunteers in a randomized open study that measured and recorded on a visual analogue scale (VAS) as a function of time when used the same composition and, as shown in Fig. 1. The thrust levels were recorded directly after Smoking one cigarette during abstinence for 7 hours before administration of nicotine products. The levels are then recorded more often within 1 hour after injection. This study also observed heart rate. This Fig. 4 clearly shows that the present invention provides a more rapid decrease in the level of urge to smoke than demonstrate the present buccal compositions of nicotine. For example, approximately 2 minutes after administration of the composition according to the present invention, the thrust level was decreased by 50%. When Nicorette®Microtab 50% reduced thrust level was reached only after more than 10 minutes after injection.

DETAILED description of the INVENTION

Definitions

The terms "tobacco", "substance containing tobacco" and similar terms in this description represent substances for any type of tobacco use, including Smoking, inhaling or chewing, what is it used for, in particular, cigarettes, cigars, pipe tobacco, snuff and chewing tobacco.

The term "rapid reduction of the urge to smoke or use tobacco" in this description refers to the original installation of the subject in such a way as to reduce the urge to smoke or use tobacco.

The term "short-term" has the Rel is relevant to non-permanent change of biological and/or physiological condition, after a certain period of time specified state is returned to its state or action to the specified changes.

The term "buccal" or "buccal" in this description refers to the whole or any part of the soft tissue of the oral cavity.

The term "liquid of the oral cavity" in this description refers to the saliva and/or saliva, mixed with a certain quantity of liquid pharmaceutical compositions.

The term "frequency injection" in this description refers to the introduction of one or more single doses of liquid pharmaceutical compositions within the same time interval, time interval depends on the needs of the subject receiving the introduction, the specified time interval ranges from a few seconds to about ten minutes.

The buffer agent and a means of regulating the pH

Absorption (adsorption) of nicotine from the oral cavity into the systemic circulation depends on saliva pH and pKa of nicotine, which is approximately 7.8. If you know that saliva pH 6,8 only about 10% of the nicotine in saliva is in free base form. Therefore, in order to accelerate the absorption of nicotine in the free base form, which is the form predominantly absorbed through the mucosa, saliva pH should be increased. At pH 8.8 to about 90% nor Tina in saliva is in free base form.

Consequently, and in accordance with the invention, the liquid pharmaceutical composition padmalochan buffering (superiorem) and/or regulation of pH. This can be achieved by including a physiologically acceptable buffer substances or agents, or by other means. Other means involve buffering by any component in the product, which normally cannot act as a buffer agent, such as sambovenezuela additive and/or form of nicotine, regulating pH.

When buffering and/or pH regulation in such a way as to increase the pH of the saliva, the absorption of nicotine is changed, for example, increases in comparison with the absorption of nicotine, when saliva is not padmalochan by buffering and/or pH regulation. Also, since the absorption of nicotine through the mucous membrane in the oral cavity in accordance with the present invention is faster than that for nicotine, which is not buffered and/or not having the pH adjusted in accordance with the present invention, a smaller amount of nicotine eaten and reaches the gastrointestinal (LCD) tract. The nicotine that reaches LCD tract and undergoes first pass metabolism, which reduces the amount of additional intake of intact nicotine, reducing the degree of absorption of nicotine. This lake is achet, the kinetics of absorption of nicotine, which is not injected together with the buffer in accordance with the present invention, is typically slower and bioavailability are generally lower than in the introduction together with the buffer.

Buffering may apply one or more buffering agents selected from the group consisting of carbonates, including bicarbonate or sesquicarbonate, glycinate, phosphate, glycerol or citrate of an alkali metal such as potassium or sodium, or ammonium, or mixtures thereof.

In other embodiments, embodiments of the invention can be used citrate trisodium or tripotassium and mixtures thereof.

Still other variants of embodiments of the invention may contain a phosphate, such as trisodium phosphate, acid phosphate disodium; and tripotassium phosphate, acid phosphate of dicale hydrochloride and calcium, glycinate sodium; and mixtures thereof.

Preferred buffering agents are carbonates, glycine chelates and phosphates of alkali metals.

Regulation of pH can also be achieved through the use of regulating the pH of the forms of nicotine, for example, the free bases of nicotine.

The amount of the buffer agent or agents in a liquid pharmaceutical composition in specific embodiments, the embodiment is preferably sufficient to increase saliva pH is above 7, as defined above, and to maintain the pH with the young in the mouth above 7, for example, pH 7-11. In other words, presents a liquid pharmaceutical composition to be padmalochan by buffering and/or pH regulation so that when administered to a subject the pH of the liquid in the oral cavity of the subject briefly increased by about 0.3-4 pH units, preferably about 0.5 to 2.5 pH units. The amount of buffering agent(s)required to achieve this increase in pH is easily calculated by the specialist in this field.

Nicotine can be presented in various forms, for example in different complexes or salts or in the form of free base.

The active ingredient

In accordance with the invention, the product is a liquid pharmaceutical composition contains nicotine in any form to ensure rapid absorption of nicotine through the mucous membrane in the oral cavity of a subject to obtain a reduction of the urge to smoke and/or use of tobacco, and/or quick peak nicotine" and/or "rapid action of nicotine in the head". Thus, can also be achieved by system maintenance level of nicotine.

Nicotine should be present in a form soluble in saliva, to facilitate subsequent absorption of nicotine from the saliva in the oral cavity into the circulation of a large circle (systemic circulation) of the subject.

In preferred embodiments, is oblasenia of the invention, nicotine in any form is mainly selected from the group consisting of the free base form of nicotine salts, nicotine-derived nicotine compounds include nicotine or nicotine in any form non-covalent binding; and mixtures thereof.

In addition, a connection of inclusion may be a cyclodextrin, such as β-cyclodextrin.

More precisely, the salt of nicotine may be the tartrate, acid tartrate, citrate or malate.

In accordance with the invention, the absorption of nicotine through any tissue or mucous membrane of the oral cavity is improved compared with the absorption obtained using liquid nicotine-containing pharmaceutical compositions, free from alkalizing buffer agents or free from alkalizing pH regulating means.

Nicotine can act as a stimulant, for example, obtaining a rapid decrease in the urge to smoke or use tobacco.

In relation to nicotine, mean nicotine, 3-(1-methyl-2-pyrrolidinyl)pyridine, in its basic form, including synthetic nicotine, as well as extracts of nicotine from the tobacco plant, or parts thereof, such as the genus Nicotiana, separately or in combination; or a pharmaceutically acceptable salt.

The most preferred embodiment of the invention includes the nicotine free base form or motorstore the Oh pharmaceutically acceptable salt, or in combination include, such as a cyclodextrin complex, for example, β-cyclodextrin. Any other suitable pharmaceutically acceptable form can also be used.

Known and can be used numerous salt of nicotine, for example, salts shown in Table 1, such as, preferably, tartrate, acid tartrate, citrate, malate and/or hydrochloride.

Table 1.
Possible acid used for the formation of salts of nicotine
AcidThe molar ratio* acid:nicotine
Ant2:1
Acetic3:1
Propionic3:1
Oil3:1
2-Matlakala3:1
3-Matlakala3:1
Valerian3:1
Lauric3:1
Palmitic3:1
Wine2:1
Lemon2:1
Apple2:1
Sorrel2:1
Benzoic1:1
GE is mizinova 1:1
Gallic1:1
Phenylacetic3:1
Salicylic1:1
Phthalic1:1
Picric2:1
Sulfosalicylic1:1
Tanning1:5
Pectin1:3
Alginic1:2
Salt2:1
Platinochloride1:1
Kremneva.liliya1:1
Pyruvic2:1
Glutamic1:1
Aspartic1:1
* recommended for production

The amount of nicotine in the liquid pharmaceutical composition

Nicotine in any form in accordance with the invention is composed in the composition to obtain the subject of the dose needed to achieve the effect. The effect may be to provide the feeling of satisfaction of Smoking without Smoking. Another effect of the input nicotine in any form may be reducing the urge to smoke or use tobacco.

The effect can also be a combination of reduction specified urge the security feeling of the satisfaction of Smoking without Smoking. The amount of nicotine should be sufficient to enable this effect in the subject. This number can, of course, vary from subject to subject.

In accordance with the invention, variants of the embodiment, the liquid pharmaceutical compositions contain nicotine in such concentrations that the amount of nicotine delivered at each introduction, is about 0.05 to 10 mg per nicotine in the form of a free base, preferably about 0.25 to 6 mg, and most preferably about 0.5-4 mg

The release and absorption of nicotine

Current pharmaceutical forms for oral administration of nicotine usually provide slow release and slow absorption of nicotine than Smoking. The slow absorption of nicotine provides tmaxi.e. the point in time when the nicotine content has a maximum level, measured in venous blood plasma after a single dose after about 30-45 minutes after injection.

The time to achieve a feeling of satisfaction or reduce the urge to smoke or use tobacco after the introduction of an individual, but is usually in the existing pharmaceutical forms for administration of nicotine he can be reached in about 30 minutes, when considered as a match with max. In accordance with the present invention, a feeling of satisfaction can be achieved through a shorter period of time due to the rapid absorption through the mucous membrane in the oral cavity due to buffering and/or pH regulation and the lack of stages, limiting the speed, such as the melting of the tablet or pellet, disintegration (disintegration and dissolution of tablets or lozenges and masticate chewing gum with subsequent dissolution of the drug.

The liquid phase

The liquid phase of this liquid pharmaceutical compositions may contain water. The liquid phase may also contain alcohol, such as ethanol, glycerol, propylene glycol and polyethylene glycol, or a mixture thereof. It can also include one or more lipids. In addition, it may include a mixture of the above ingredients.

Other additives to the liquid pharmaceutical composition

Other additives can be optionally added to the liquid pharmaceutical compositions.

Optional additives include one or more stabilizing additives, such as additives selected from the group consisting of antioxidants, including vitamin E, i.e. Tocopherols, vitamin C, i.e. ascorbic acid and its salts, sodium pyrosulphite, equivalent, bottled hydroxyanisol; and preservatives, including parab the us, the benzalkonium chloride, chlorbutanol, benzyl alcohol, beta-phenethyl alcohol, chloride of cetylpyridinium; and chelating agents such as EDTA; and Galaev, such as propylgallate.

Additional optional additives include one or more additives selected from the group consisting of:

- reinforcing agents, such as azone;

- vitamins, such as vitamins C and E;

- minerals such as fluoride, especially sodium fluoride, monitoroff sodium and fluoride tin;

agents against odor, such as zinc and cyclodextrins;

- propellants, such as 1,1,2,2-Tetrafluoroethane (HFC-134a), optional liquefied, and 1,1,1,2,3,3,3-Heptafluoropropane (HFC-227), optional liquefied;

- sweeteners, including one or more synthetic sweetening agents and/or natural sugars, such as sweeteners selected from the group consisting of artificial sweeteners, such as saccharin and its sodium and potassium salts, aspartame, Acesulfame and its potassium salt, thaumatin and glycyrrhizin;

- polyhydric alcohols, such as sorbitol, xylitol, mannitol and glycerin;

- monosaccharides, including glucose (also called dextrose), fructose (also called levulose) and galactose);

- disaccharides including sucrose, lactose (also called milk sugar) and maltose (also called malt sugar is);

- mixtures of sugars, including liquid glucose syrup, for example, hydrolysates of starch, containing a mixture of mainly dextrose, maltose, dextrin and water, invert sugar syrup, for example, sucrose, inverted invertase containing a mixture of dextrose, levulose and water; syrups high in sugar, such as molasses extracts, honey and malt; and mixtures thereof;

- taste and/or flavoring agents, such as agents selected from the group consisting of essential oils obtained by distillation, solvent extraction or cold pressed fresh or dried flowers, buds, leaves, stems, fruits, seeds, rind, bark or root, for example, peppermint, curly mint, eucalyptus, simalube, nyali, cloves, cardamom, cinnamon, bitter almond, coriander, cumin, ginger, juniper, orange, orange, lemon, grapefruit, Mandarin, bergamot, thyme, fennel and rosemary;

- natural flavour and flavouring agents, including diluted solutions of essential oils or concentrates of flavoring components of natural origin, for example, fruits, berries, nuts, spices, mint, tobacco, cocoa, coffee, tea, vanilla, licorice, caramel, butterscotch, honey, wine, spirits and soft drinks,

- a synthetic flavoring and aromatic agents, consisting of mixtures of helices is their substances, including hydrocarbons, alcohols, aldehydes, esters, ketones, ethers and oxides, mixed up comparable with natural taste, for example, fruits, berries, nuts, spices, mint, tobacco, cocoa, coffee, tea, vanilla, licorice, caramel, butterscotch, honey, wine, spirits and non-alcoholic beverages;

and mixtures thereof.

Surfactants

One or more compounds liquid pharmaceutical compositions can be dissolved in one or more surface-active agents and/or emulsifying agents, such as nonionic, cationic, anionic or zwitter-ionic surfactants, including amphiphilic block copolymers, or mixtures thereof.

Specifically, one or more compounds liquid pharmaceutical compositions can be dissolved in one or more surfactants selected from nonionic surfactants, including poloxamer, for example:

- poly(oxypropylene)-poly(oksietilenom) block copolymers, alkalemia ethers of polyoxyethylene, polyoxyethylene derivatives of castor oil, esters of fatty acids and sorbitan of polyoxyethylene mono - and diglycerides and their esters, stearates of polyoxyethylene, polyglyceryl esters of fatty acids (including polyglycerylmethacrylate acid (PGPR)) and esters of sorbitol and girn the th acid,

cationic surfactants, including secondary, Quaternary and tertiary ammonium compounds and cationic phospholipids,

- anionic surfactants, including salts of fatty acids, lactylate, especially stearylamine sodium and/or calcium sulfates Akilov, sulfonates Akilov, ethanol and anionic phospholipids, such as phosphatidylserine,

- zwitter-ionic surfactants, including zwitter-ionic phospholipids, such as phosphatidylcholine and phosphatidylethanolamine,

or mixtures thereof,

preferably, surfactants or their mixtures are non-ionic.

The method of delivering nicotine in any form to a subject

In accordance with the invention, a method of delivering nicotine in any form to a subject involves the following stages:

an introduction to the subject of product liquid pharmaceutical compositions containing nicotine in any form in accordance with the invention, in the oral cavity of a subject, and

b) allowing the nicotine in any form in the liquid pharmaceutical composition to be mixed with the saliva in the oral cavity and absorbed (absorbed) in the blood plasma of the subject, mainly by buccal absorption.

One alternative embodiment of the invention leads to tmaxnicotine in venous blood of the subject after about 3-30 minutes.

Another VA who iant embodiment of the invention leads to t maxnicotine in venous blood of the subject after about 3-20 minutes.

In yet another variant embodiment of the invention the specified nicotine in any form is absorbed, leading to tmaxnicotine in venous blood of the subject after about 3-15 minutes.

A method of obtaining a reduction of the urge to smoke or use tobacco

A method of obtaining a reduction of the urge to smoke or use tobacco-containing substances and/or provide feelings of satisfaction from Smoking without Smoking in accordance with the invention involves the following stages:

a) replace, at least partially, the tobacco-containing substances liquid pharmaceutical composition according to any of claims 1-22,

b) introducing to the subject a liquid pharmaceutical composition containing nicotine in any form in accordance with any of claims 1-22, in the oral cavity of a subject, and

(C) allowing the nicotine in any form in the liquid pharmaceutical composition to be absorbed (absorbed) by the subject, mainly by buccal absorption.

Introduction the oral cavity is carried out by spraying, by instillation or backfilling using a pipette, preferably by spraying, most preferably by spraying under the tongue. The introduction is in the mouth, and not, for example, in the lungs and the and upper respiratory tract.

In one variant embodiment of the invention the specified nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-30 minutes.

Another variant embodiment of the invention leads to tmaxnicotine in venous blood of the subject after about 3-20 minutes.

In yet another variant embodiment of the invention the specified nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-15 minutes.

In the following variants of embodiment of the invention a method of delivering nicotine to a subject can include stage combinations, with at least one other method for obtaining reduction of the urge to smoke or use tobacco.

Liquid pharmaceutical composition can be used to obtain fast and/or long and/or complete reduction of the urge to smoke or use tobacco and/or to obtain a feeling of satisfaction from Smoking without Smoking, as will be described below.

Quick relief gives the subject a feeling of quick satisfaction of Smoking without Smoking.

One alternative embodiment of the invention reduces the urge to smoke or use of tobacco by achieving tmaxnicotine in venous blood of the subject after about 3-30 minutes by applying a liquid pharmaceutical composition according to the invention.

One following Ariant embodiment of the invention reduces the urge to smoke or use of tobacco by achieving t maxnicotine in venous blood of the subject after about 3-20 minutes by applying a liquid pharmaceutical composition according to the invention. Another variant embodiment of the invention reduces the urge to smoke or use of tobacco by achieving tmaxnicotine in venous blood of the subject after about 3-15 minutes by applying a liquid pharmaceutical composition according to the invention.

Termination (cancellation) of the urge to smoke or use tobacco

For some consumers, the goal may be the complete cessation of nicotine use, for various reasons, for example, health, economic, social or behavioural. It can be achieved by further reduction of the delivered quantity of nicotine in any form gradually over time. In specific embodiments, the embodiments of the invention, the method described above to obtain relief draught may, in addition, include the stage of reducing the amount of nicotine in the liquid pharmaceutical composition gradually over time, and/or the stage of reducing the frequency of introduction of the liquid pharmaceutical composition gradually over time, and/or stage of size reduction of the dose of the liquid pharmaceutical composition gradually over time, thus to achieve relief of craving for tobacco and/or to achieve seems like the possible satisfaction from Smoking. This method leads to the process of weaning gradually over time.

Different types of smokers reach sensations reduce thrust at different levels of nicotine in the plasma. This can, of course, affect the individual types of programs the introduction of the liquid pharmaceutical composition according to the invention. Different types of smokers include, for example, seekers peak or smokers who need the level of nicotine in plasma, constantly exceeding the level below which appear the withdrawal symptoms.

One strategy may be to reduce the frequency of introduction of the liquid pharmaceutical composition. Other variants of embodiments of the invention include varying doses of nicotine in a specified liquid pharmaceutical compositions, as well as the combination of the two embodiments.

System for delivery of nicotine and to facilitate traction

In accordance with the invention, a system for delivering nicotine in any form to a subject. This system includes a liquid pharmaceutical composition in accordance with the invention and at least one other means for obtaining reduction of the urge to smoke.

Another system according to the invention can be a system for obtaining reduction of the urge to smoke or use tobacco and/or maintain the feeling of satisfaction from Smoking from different companies. who I am without Smoking. This system includes a liquid pharmaceutical composition according to the invention and at least one way to reduce the urge to smoke or use tobacco. Other ways can be related or competing method selected from the group consisting of injection by means of chewing gum, nasal sprays, transdermal patches, inhalers, patches, tablets or parenteral methods, subcutaneous methods, intravenous methods, rectal methods, vaginal methods and techniques through the mucous membrane; or the use of tobacco.

In a specific embodiment, the embodiment of the invention, at least one method involves the introduction of nicotine.

The use of liquid pharmaceutical composition

Use a liquid pharmaceutical composition in accordance with the present invention to obtain a rapid and/or complete reduction of the urge to smoke and use tobacco or to provide the sensation of Smoking without Smoking, as described above.

The dose of nicotine is chosen so as to give the subject individual sensory perception and satisfaction with the action of nicotine in any form. The use of liquid pharmaceutical compositions may also be only used in accordance with the invention or a combination with other sredstvami ways, known in the field of abuse of drugs. In particular, the present invention can be used in combination with other means, as described above in the methods in the sections above.

This application can give a rapid decrease in the urge to smoke or use tobacco, by achieving tmaxnicotine in venous blood after about 3-20 minutes.

In a specific embodiment, the embodiment of the invention the use of a liquid pharmaceutical composition in accordance with the invention reduces the urge to smoke or use of tobacco by achieving tmaxnicotine in venous blood of the subject after about 3-15 minutes.

In accordance with the invention, the liquid pharmaceutical composition according to the invention is used for delivering nicotine in any form to a subject.

In one variant embodiment of the invention, the delivery of nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-30 minutes.

In another variant embodiment of the invention, the delivery of nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-20 minutes.

In yet another variant embodiment of the invention, the delivery of nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-15 minutes.

As clearly shown, and you shall be concluded from the figures, for example, in Fig. 4, shorter than tmaxthe faster the relief of traction, i.e. the urge to smoke.

EXAMPLES of VARIANTS of the EMBODIMENT of the INVENTION AND OBTAIN a LIQUID PHARMACEUTICAL COMPOSITION

The following examples are not limiting and are intended to illustrate the present invention. A person skilled in the art may apply alternatives and variations of the following examples within the present invention according to the following claims. Ingredients according to the following examples can be replaced with equivalent ingredients, preferably according to the above. The compositions of examples 2 and 3 were created for comparison purposes, as shown in Fig. 2.

EXAMPLE 1

Obtain 1000 ml of the composition with 10 mg of nicotine/ml and a pH of about 8.5.

A mixture of 1

In chemical beaker containing 800 ml of water with a temperature of 90°C, was added 0.7 g of methylparahydroxybenzoate, acting as a preservative, and 0.3 g propilparagidroksibenzoat, acting as a preservative. The additive was dissolved under stirring for about 10 minutes. Then to the solution was added 10,45 g of sodium dihydrophosphate, acting as a buffer agent, and 0.5 g EDTA, acting as a chelating agent, and stirred for about 5 minutes. Then the solution was cooled to 30°under stirring.

SMEs

In chemical beaker containing 15.9 g of ethanol at room temperature, acts as a solvent, was added 0,045 g peppermint oil, acting as a flavoring. The liquid was stirred for 2 minutes.

The final mix

Mixture 2 was added under stirring in chemical beaker containing 150 ml of water. Was carefully added to 10 g of nicotine (base) chemical glass. Then, in chemical beaker was added a mixture of 1 and was stirred for 5 minutes. the pH of the final mixture was checked and brought to about pH 8.5 using sodium hydroxide (20%) and up to volume with water.

EXAMPLE 2

Obtain 1000 ml of the composition with 10 mg of nicotine/ml and a pH of about 7,0.

This example 2 differs from example 1 only by the pH value. The composition according to example 2 contains alkalizing buffer agent. This composition was needed as a comparison of Fig. 2.

A mixture of 1

In chemical beaker containing 800 ml of water with a temperature of 90°C, was added 0.7 g of methylparahydroxybenzoate, acting as a preservative, and 0.3 g propilparagidroksibenzoat, acting as a preservative. The additive was dissolved under stirring for about 10 minutes. Then to the solution was added 10,45 g of sodium dihydrophosphate, acting as a buffer agent, and 0.5 g EDTA, acting as a chelating agent, and stirred at those who tell about 5 minutes. Then the solution was cooled to 30°under stirring.

A mixture of 2

In chemical beaker containing 15.9 g of ethanol at room temperature, acts as a solvent, was added 0,045 g peppermint oil, acting as a flavoring. The liquid was stirred for 2 minutes.

The final mix

Mixture 2 was added under stirring in chemical beaker containing 150 ml of water. Was carefully added to 10 g of nicotine (base) chemical glass. Then, in chemical beaker was added a mixture of 1 and was stirred for 5 minutes. the pH of the final mixture was checked and brought to about pH 7.0 with hydrochloric acid to volume with water.

EXAMPLE 3

Obtain 1000 ml of the composition with 10 mg of nicotine/ml and about pH 6,0.

This example 3 differs from example 1 only the pH value. The composition according to example 3 contains alkalizing buffer agent. This composition was needed as a comparison of Fig. 2.

A mixture of 1

In chemical beaker containing 800 ml of water with a temperature of 90°C, was added 0.7 g of methylparahydroxybenzoate, acting as a preservative, and 0.3 g propilparagidroksibenzoat, acting as a preservative. The additive was dissolved under stirring for about 10 minutes. Then to the solution was added 10,45 g of sodium dihydrophosphate, acting as a buffer agent, and 0, g EDTA, acting as a chelating agent, and stirred for about 5 minutes. Then the solution was cooled to 30°under stirring.

A mixture of 2

In chemical beaker containing 15.9 g of ethanol at room temperature, acts as a solvent, was added 0,045 g peppermint oil, acting as a flavoring. The liquid was stirred for 2 minutes.

The final mix

Mixture 2 was added under stirring in chemical beaker containing 150 ml of water. Was carefully added to 10 g of nicotine (base) chemical glass. Then, in chemical beaker was added a mixture of 1 and was stirred for 5 minutes. the pH of the final mixture was checked and brought to about pH 6.0 with hydrochloric acid to volume with water.

EXAMPLE 4

Obtain 1000 ml of the composition from 17.5 mg nicotine/ml and a pH of about 9.0 to.

A mixture of 1

In chemical beaker containing 600 ml of water at room temperature, was added 12.0 g Synperonic®PE/F27, which poloxamers acting as a non-ionic surfactant. The additive was dissolved under stirring for about 20 minutes. Then the liquid was added 0.5 g EDTA, acting as a chelating agent, and 0.4 g of saccharin sodium, which acts as a sweetener, and stirred until then, until all ingredients are dissolved. Then added to 16.8 g g is drocarbons sodium, acting as a buffer agent, and the solution was stirred to obtain a clear solution.

A mixture of 2

In chemical beaker containing of 250.0 g of ethanol at room temperature, acts as a solvent, was added 0.7 g of methylparahydroxybenzoate, acting as a preservative and 0.3 g propilparagidroksibenzoat, acting as a preservative. The liquid was stirred until dissolved ingredients. Then added 5.0 g of peppermint oil, acting as a flavoring and 1.5 g of flavouring substances. The liquid was stirred to obtain a clear solution.

The final mix

Mixture 2 was carefully added to a mixture of 1 under stirring for about 1 minute. Then added to 17.5 g of nicotine (the Foundation) and the liquid was stirred for 2 minutes. the pH of the final mixture was checked and brought up to approximately a pH of 9.0 with hydrochloric acid. The final mixture was transferred into a volumetric flask of 1000 ml and made up to 1000 ml with water. In conclusion, I checked the pH of the solution, so he remained about a pH of 9.0.

EXAMPLE 5

Obtain 1000 ml of the composition with 14.3 mg nicotine/ml and a pH value of about 9.0 in.

A mixture of 1

In chemical beaker containing 600 ml of water at room temperature, was added to 20.0 g of Synperonic®PE/F27, which poloxamers acting as nonionic surface is but-active substance. The additive was dissolved under stirring for about 20 minutes. Then the liquid was added 2.0 g of Acesulfame K, acts as a sweetener, and stirred until then, until all ingredients are dissolved. Then added to 20.0 g of sodium bicarbonate, acting as a buffer agent, and the liquid was stirred to obtain a clear solution.

A mixture of 2

In chemical beaker containing 95,0 g of ethanol at room temperature, acts as a solvent, was added 3.5 g of peppermint oil, acting as a flavoring and 1.0 g of flavouring substances. The liquid was stirred to obtain a clear solution.

The final mix

Mixture 2 was carefully added to a mixture of 1 under stirring for about 1 minute. Then was added 14.3 g of nicotine (the Foundation) and the liquid was stirred for 2 minutes. the pH of the final mixture was checked and brought up to approximately a pH of 9.0 with hydrochloric acid. The final mixture was transferred into a volumetric flask of 1000 ml and made up to 1000 ml with water. In conclusion, I checked the pH of the solution, so he remained about a pH of 9.0.

The composition according to example 5 is the preferred composition.

EXAMPLE 6

Obtain 1000 ml of the composition with 14.3 mg nicotine/ml and a pH of about 9.0 to.

A mixture of 1

In chemical beaker containing 600 ml of water at room t is mperature, added to 20.0 g of Synperonic®PE/F27, which poloxamers acting as a non-ionic surfactant. The additive was dissolved under stirring for about 20 minutes. Then the liquid was added 0.2 g of benzalkonium chloride, which acts as a preservative, and 2.0 g of Acesulfame K, acts as a sweetener, and stirred until then, until all ingredients are dissolved. Then added to 20.0 g of sodium bicarbonate, acting as a buffer agent, and the liquid was stirred to obtain a clear solution.

A mixture of 2

In chemical beaker containing 95,0 g of ethanol at room temperature, acts as a solvent, was added 3.5 g of peppermint oil, acting as a flavoring and 1.0 g of flavouring substances. The liquid was stirred to obtain a clear solution.

The final mix

Mixture 2 was carefully added to a mixture of 1 under stirring for about 1 minute. Then was added 14.3 g of nicotine (the Foundation) and the liquid was stirred for 2 minutes. the pH of the final mixture was checked and brought up to approximately a pH of 9.0 with hydrochloric acid. The final mixture was transferred into a volumetric flask of 1000 ml and made up to 1000 ml with water. In conclusion, I checked the pH of the solution, so he remained about a pH of 9.0.

The composition according to example 6 is another before occhialini composition.

EXAMPLE 7

Obtain 1000 ml of the composition with 14.3 mg nicotine/ml and a pH of about 9.0 to.

A mixture of 1

In chemical beaker containing 600 ml of water at room temperature, was added to 20.0 g of Synperonic®PE/F27, which poloxamers acting as a non-ionic surfactant. The additive was dissolved under stirring for about 20 minutes. Then the liquid was added 0.5 g EDTA, acting as a chelating agent, and 2.0 g of Acesulfame K, acts as a sweetener, and stirred until then, until all ingredients are dissolved. Then added to 20.0 g of sodium bicarbonate, acting as a buffer agent, and the liquid was stirred to obtain a clear solution.

A mixture of 2

In chemical beaker containing 95,0 g of ethanol at room temperature, acts as a solvent, was added 0.7 g of methylparahydroxybenzoate, acting as a preservative and 0.3 g propilparagidroksibenzoat, acting as a preservative. The liquid was stirred until dissolved ingredients. Then added 3.5 g of peppermint oil, acting as a flavoring and 1.0 g of flavouring substances. The liquid was stirred to obtain a clear solution.

The final mix

Mixture 2 was carefully added to a mixture of 1 under stirring for about 1 minute. Then added p is IMEMO 2 ml of sodium hydroxide (50%) and 4 g of nicotine bitartrate. the pH of the final mixture was not allowed to fall below pH 8 by adding nicotine bitartrate. The preceding procedure to add sodium hydroxide and nicotine bitartrate was repeated until then, until you have added all of 40.7 g of nicotine bitartrate. the pH of the final mixture was brought to about pH of 9.0. The final mixture was transferred into a volumetric flask of 1000 ml and made up to 1000 ml with water. In conclusion, I checked the pH of the solution, so he remained about a pH of 9.0.

EXAMPLE 8

Obtain 1000 ml of the composition from 17.5 mg nicotine/ml and pH 10,94.

In chemical beaker containing 950 ml of water at room temperature, was added to 17.5 g of nicotine (the Foundation) under stirring for about 5 minutes. The volume was brought to 1000 ml by adding water. In conclusion, I checked the pH level.

EXAMPLE 9

Obtain 1000 ml of the composition from 17.5 mg nicotine/ml and pH 11,55.

In chemical beaker containing 950 ml of water at room temperature, was added 35 g of anhydrous sodium carbonate under stirring until complete dissolution. Then added to 17.5 g of nicotine (the Foundation) under stirring for about 5 minutes. The volume was brought to 1000 ml by adding water. In conclusion, I checked the pH level.

EXAMPLE 10

Obtain 1000 ml of the composition with 15,65 mg nicotine/ml and pH to 11.79.

In chemical beaker containing 950 ml of water at room temperature, was added the 158 g of sodium salt of glycine under stirring until complete dissolution. Then added 15,65 g of nicotine (the Foundation) under stirring for about 5 minutes. The volume was brought to 1000 ml by adding water. In conclusion, I checked the pH level.

EXAMPLE 11

Determination of buffer capacity

Way: 10.0 ml of the respective following solutions were titrated with 0.1 M HCl to a pH of 7.0. Determined the amount of 0.1 M HCl are needed to lower the pH from 9.0 to 8.0.

Definitions(1) sodium Bicarbonate (NaHCO3). MV: 84,0

(2) Dodecahydrate phosphate disodium (Na2HPO4·12H2O). MV: 358,1.

Ingredient per doseDKN0293DKN0294DKN0295DKN0296DKN0290DKN0291
Nicotine (mg/ml)10,010,010,0
NaHCO3(mg/ml)16,816,88,4
Na2HPO412H2O (mg/ml)71,635,871,6
Purified water to1 ml1 ml1 ml1 ml1 ml1 ml
The buffer capacity pH 9,0-8,0 (mEq/l)26,59,55015,84029

All solutions were brought to pH of 9.0, when necessary. Higher pH may cause irritation and corrosion, which can be harmful to tissues of the oral cavity.

16,8 mg/ml NaHCO3corresponds to 0.2 M

71,6 mg/ml of Na2HPO4·12H2O corresponds to 0.2 M

8,4 mg/ml NaHCO3corresponds to 0.1 M

to 35.8 mg/ml of Na2HPO4·12H2O corresponds to 0.1 M

The base nicotine has an alkalizing effect, but is too weak private buffer capacity. The buffer capacity of the composition reliably and sufficiently increases, when you add a buffering agent.

The above data clearly show that the present composition has a good buffer capacity, which provides the desired rapid absorption of nicotine through the mucous membrane.

Liquid pharmaceutical composition in accordance with the present invention may be administered with the use of suitable devices available on the market, for example, the spray device.

Analysis of nicotine

Analysis of the absorption of nicotine and the effect of the invention can be carried out in accordance with standard techniques known in this field, for example, using Biana is out for the determination of nicotine in the plasma of the subject.

The effects of the invention

Comparative tests were carried out as described above in the description of figures.

In Fig. 1 shows that when using liquid pharmaceutical compositions of the present invention, the level of nicotine in venous blood plasma increases significantly more quickly than when using Nicorette Microtab®. Nicorette Microtab®has the same pharmacokinetic profile, i.e. it is pharmacologically equivalent, as Nicorette Gum®all other chewing gum, currently available on the market. Chewing gum with nicotine currently represent about half of world sales of medicinal nicotine-containing products for Smoking cessation and similar indications.

In Fig. 2 shows that the higher pH of the liquid pharmaceutical compositions of the present invention, the faster the kinetics of absorption and higher concentration of nicotine in the plasma.

In Fig. 3 and 4 further shows that the composition of the present invention provides fast relief of traction, manifested by significantly more rapid reduction of the urge to smoke compared to the famous oral compositions of nicotine.

Use for therapy, treatment and production

The product liquid pharmaceutical compositions according to the invention can be used therapy. This therapy may be the treatment of a disease or medical condition selected from the group consisting of reducing tobacco use, cessation of tobacco use, other uses of tobacco, temporary abstinence when to stop using tobacco, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome and ulcerative colitis; and weight management.

Nicotine in any form may be used to obtain a liquid pharmaceutical composition according to the invention for the treatment of a disease or medical condition selected from the group consisting of reducing tobacco use, cessation of tobacco use, other uses of tobacco, temporary abstinence when to stop using tobacco, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome and ulcerative colitis; and weight management.

1. Liquid pharmaceutical composition containing nicotine in any form, characterized in that it is intended for introduction into the oral cavity an effective amount of nicotine by spraying, dripping or backfilling using a pipette, preferably by spraying, most preferably by spraying under the tongue, and the fact that she padmalochan by buffering and/or pH regulation in such a way that PR is the introduction to a subject the pH of the liquid in the oral cavity of the subject briefly increased from about 0.3 to about 4 pH units.

2. Liquid pharmaceutical composition according to claim 1, characterized in that it padmalochan by buffering and/or pH regulation so that when administered to a subject the pH of the liquid in the oral cavity of the subject is briefly increased to from about 0.5 to about 2.5 pH units.

3. Liquid pharmaceutical composition according to claim 1, characterized in that it padmalochan by buffering and/or pH regulation using one or more buffering agents selected from the group consisting of a carbonate, such as monocarbonate, bicarbonate or sekswitharpena; glycinate, phosphate, glycerol, acetate, gluconate or citrate of an alkali metal such as potassium or sodium, or ammonium, and mixtures thereof; and/or by using agents regulating the pH, such as agents selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide and calcium oxide; and/or by using forms of nicotine, at least partially regulating the pH.

4. Liquid pharmaceutical composition according to claim 1, where the nicotine in any form selected from the group consisting of nicotine in the form of a free base, salts of nicotine or a derivative of nicotine, and mixtures thereof.

5. Liquid pharmaceutical composition according to any one of claims 1 to 4, where the nicotine in any form selected from the group consisting of compounds include nicotine is or nicotine in any form non-covalent binding and mixtures thereof.

6. Liquid pharmaceutical composition according to claim 5, where the joint inclusion nicotine is a complex of a cyclodextrin, such as complex β-cyclodextrin.

7. Liquid pharmaceutical composition according to claim 4, where salt is nicotine is a salt formed in the form of tartrate, acid tartrate, citrate or malate.

8. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6 and 7, where the amount of nicotine in any form, be delivered at each introduction, is about 0.05 to 10 mg per nicotine in free base form.

9. Liquid pharmaceutical composition of claim 8, where the amount of nicotine in any form, be delivered at each introduction, is about 0.25 to 6 mg per nicotine in free base form.

10. Liquid pharmaceutical composition according to claim 9, where the amount of nicotine in any form, be delivered at each introduction, is about 0.5-4 mg per nicotine in free base form.

11. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6, 7, 9 and 10, where the liquid phase contains water.

12. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6, 7, 9 and 10, where the liquid phase contains alcohol, such as ethanol, glycerol, propylene glycol and polyethylene glycol, or mixtures thereof.

13. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6, 7, 9 and 10, where the liquid phase is to gain one or more lipids.

14. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6, 7, 9 and 10, where the liquid phase contains water and/or alcohol, such as ethanol, glycerol, propylene glycol and polyethylene glycol, and/or one or more lipids, or mixtures thereof.

15. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6, 7, 9 and 10, characterized in that it further comprises one or more flavoring and/or aromatic means such as a means selected from the group consisting of essential oils obtained by distillation, solvent extraction or cold pressed fresh or dried flowers, buds, leaves, stems, fruits, seeds, rind, bark or roots, such as peppermint oil, curly mint, eucalyptus, simalube, nyali, cloves, cardamom, cinnamon, bitter almond, coriander, cumin, ginger, juniper, orange, orange, lemon, grapefruit, Mandarin, bergamot, thyme, fennel and rosemary;

natural flavoring or flavoring funds, including diluted solutions of essential oils or concentrates of flavoring ingredients of natural origin, for example, fruits, berries, nuts, spices, mint, tobacco, cocoa, coffee, tea, vanilla, licorice, caramel, butterscotch, honey, wine, spirits and non-alcoholic beverages;

synthetic flavor and fragrance of funds, consisting of mixtures of helices is their substances, including hydrocarbons, alcohols, aldehydes, esters, ketones, ethers and oxides, mixed to obtain a natural taste, for example, fruits, berries, nuts, spices, mint, tobacco, cocoa, coffee, tea, vanilla, licorice, caramel, butterscotch, honey, wine, spirits and non-alcoholic beverages and mixtures thereof;

16. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6, 7, 9 and 10, characterized in that it further includes one or more stabilizing additives, such as additives selected from the group consisting of antioxidants, including vitamin E, i.e. Tocopherols, vitamin C, i.e. ascorbic acid and its salts, sodium pyrosulphite, equivalent, bottled hydroxyanisol; and preservatives, including parabens, benzalkonium chloride, chlorbutanol, benzyl alcohol, betaphenethylamine alcohol, chloride of cetylpyridinium; and chelating agents such as EDTA; and Galaev, such as propylgallate.

17. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6, 7, 9 and 10, characterized in that it further includes one or more additives selected from the group consisting of: thickeners, such as natural, semi-synthetic or synthetic polymers, such as starch and starch derivatives, cellulose and cellulose derivatives, polyethylene glycols and derivatives thereof, polyacrylates and polyvinyl complex and p is Ostia esters;

enhancers such as azone;

vitamins, such as vitamins C and E;

minerals such as fluoride, especially sodium fluoride, monitoroff sodium and fluoride tin;

anti-odor, such as zinc and cyclodextrins;

propellants, such as 1,1,2,2-Tetrafluoroethane (HFC-134a), optional liquefied, and 1,1,1,2,3,3,3-Heptafluoropropane (HFC-227), optional liquefied;

sweeteners, including one or more synthetic sweetening funds and/or natural sugars, such as sweeteners selected from the group consisting of artificial sweeteners, such as saccharin and its sodium and calcium salts, aspartame, Acesulfame and its potassium salt, thaumatin and glycyrrhizin;

polyhydric alcohols, such as sorbitol, xylitol, mannitol and glycerol, monosaccharides, including glucose (also called dextrose), fructose (also called levulose) and galactose;

disaccharides including sucrose, lactose (also called milk sugar) and maltose (also called malt sugar);

mixtures of sugars, including liquid glucose syrup, for example, hydrolysates of starch, containing a mixture of mainly dextrose, maltose, dextrin and water, syrup invert sugar, for example sucrose, inverted invertase containing a mixture of dextr the SHL, levulose and water; syrups high in sugar, such as molasses extracts, honey and malt; and mixtures thereof.

18. Liquid pharmaceutical composition according to any one of claims 1 to 4, 6, 7, 9 and 10, characterized in that one or more compounds liquid pharmaceutical compositions are dissolved in one or more surfactants and/or emulsifiers, such as nonionic, cationic, anionic or zwitter-ionic surfactants, including amphiphilic block copolymers, or mixtures thereof.

19. Liquid pharmaceutical composition according p, characterized in that one or more compounds liquid pharmaceutical compositions are dissolved in one or more surfactants selected from nonionic surfactants, including poloxamer, for example poly(oxypropylene)-poly(oksietilenom) block copolymers, alkalemia ethers of polyoxyethylene, polyoxyethylene derivatives of castor oil, esters of fatty acids and sorbitan of polyoxyethylene mono - and diglycerides and their esters, stearates of polyoxyethylene, polyglyceryl esters of fatty acids (including polyglycerylmethacrylate acid (PGPR)) and esters of sorbitol and fatty acids, cationic surfactants, including secondary, tertiary and Quaternary compounds and monia and cationic phospholipids, anionic surface-active substances, including salts of fatty acids, lactylate, especially stearylamine sodium and/or calcium, alkyl sulphates, alkyl sulphonates, ethanol and anionic phospholipids, such as phosphatidylserine, zwitter-ionic surfactants, including zwitter-ionic phospholipids, such as phosphatidylcholine and phosphatidylethanolamine, or mixtures thereof, preferably surfactants or their mixtures are non-ionic.

20. Liquid pharmaceutical composition according to any one of claims 1 to-4, 6, 7, 9, 10 and 19, characterized in that it comprises a base nicotine, acid sodium carbonate as a buffering agent, water acting as a solvent, ethanol acting as a co-solvent, poloxamer acting as a surfactant, EDTA, acting as a chelating agent, Acesulfame K, acting as a sweetener, optionally one or more preservatives and, optionally, one or more flavoring or flavoring agents.

21. The method of delivering nicotine in any form to a subject, including stage

a) introducing to the subject a liquid pharmaceutical composition according to any one of claims 1 to 20 in the oral cavity of a subject and

b) allowing the nicotine in any form in the liquid pharmaceutical composition to be absorbed into the systemic circulation, subje is the mainly by buccal absorption of nicotine.

22. The method according to item 21, where the absorption of the specified nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-30 minutes

23. The method according to item 22, where the absorption of the specified nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-20 minutes

24. The method according to item 22, where the absorption of the specified nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-15 minutes

25. The method of obtaining reduction of the urge to Smoking or other use of any substance containing tobacco, and/or provide feelings of satisfaction from Smoking without Smoking, including stage

a) replacing at least partially the substance containing tobacco, the liquid pharmaceutical composition according to any one of claims 1 to 20,

b) introducing to the subject a liquid pharmaceutical composition according to any one of claims 1 to 20 in the oral cavity of a subject and

c) allowing the nicotine in any form in the liquid pharmaceutical composition to be absorbed into the systemic circulation of the subject mainly by buccal absorption of nicotine.

26. The method according A.25, where the specified absorption of nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-30 minutes

27. The method according to p, where the specified absorption of nicotine in any form leads to t maxnicotine in venous blood of the subject after about 3-20 minutes

28. The method according to p, where the specified absorption of nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-15 minutes

29. The method according to any of PP-28, where the introduction of the subject a liquid pharmaceutical composition is carried out by spraying, dripping or backfilling using a pipette, preferably by spraying, most preferably by spraying under the tongue.

30. The method of obtaining reduction of the urge to Smoking or other use of the substance containing tobacco, and/or provide feelings of satisfaction from Smoking without Smoking, where the method according to p-29 used in combination with one or more other methods for obtaining reduction of the urge to Smoking or other use of the substance containing tobacco, and/or the feeling of satisfaction of Smoking without Smoking.

31. The method according to item 30, where the one or more other methods selected from the group consisting of injection by means of chewing gum, nasal sprays, transdermal patches, inhalers, patches, tablets and parenteral means or ways subcutaneous means or ways intravenous means or ways rectal means or ways, vaginal means or ways and means or ways of introducing chere is C the mucous membrane; or use tobacco.

32. The method according to p with one or more other methods include the introduction of nicotine.

33. A system for delivering nicotine in any form to a subject, comprising a liquid pharmaceutical composition according to any one of claims 1 to 20 and at least one other means for delivering nicotine in any form to a subject.

34. System for obtaining reduction of the urge to smoke or use tobacco and/or maintain the feeling of satisfaction from Smoking without Smoking, comprising a liquid pharmaceutical composition according to any one of claims 1 to 20 and at least one other means for obtaining reduction of the urge to smoke or use tobacco.

35. System according to any one of p and 34, where at least one other substance selected from the group consisting of injection by means of chewing gum, nasal sprays, transdermal patches, inhalers, patches, tablets and parenteral means or ways subcutaneous means or ways intravenous means or ways rectal means or ways, vaginal means or ways and means or methods of introduction through the mucous membrane; or the use of tobacco.

36. System p, where, at least, a different tool includes the introduction of nicotine.

37. The use of liquid pharmaceutical composition according to any one of claims 1 to 20 for receiving the Oia rapid and/or complete reduction of the urge to smoke or use tobacco and/or maintain the feeling of satisfaction of Smoking without Smoking.

38. The application of clause 37, where the reduction of the urge to smoke or use of tobacco by achieving tmaxnicotine in venous blood of the subject after about 3-30 minutes

39. The application of § 38, where the reduction of the urge to smoke or use of tobacco by achieving tmaxnicotine in venous blood of the subject after about 3-20 minutes

40. The application of § 38, where the reduction of the urge to smoke or use of tobacco by achieving tmaxnicotine in venous blood of the subject after about 3-15 minutes

41. The use according to any one of p-40, where the delivery of nicotine in any form leads to tmaxnicotine in venous blood of the subject after about 3-30 min, preferably about 3-20 min, and most preferably about 3-15 minutes

42. The method of producing a liquid pharmaceutical composition according to any one of claims 1 to 22, which includes stages:

a) obtaining a first mixture containing a first solvent, at least one buffering agent and/or other means of regulating the pH and nicotine in any form,

b) adding the first component to the specified first mixture, and the specified first optional components are initially dissolved,

c) obtaining one or more second(s) of the mixture(s)containing one or more second Rast is aricela and second components, which may contain nicotine in any form,

d) mixing the first mixture and one or more second(s) of the mixture(s) to the final mixture with the optional addition of one or more additional(s) solvent(s) and adding nicotine in any form,

(e) regulating the pH of the final mixture.

43. The method according to § 42, where the mixing is carried out at a temperature from about room temperature to about 95°C.

44. The method according to any of PP and 43, where the nicotine in any form selected from the group consisting of nicotine in the form of a free base, salts of nicotine-derived nicotine, such as a connection of inclusion of nicotine or nicotine in any form non-covalent binding; and mixtures thereof.

45. The method according to any of PP and 43, where the buffering and/or pH regulation is carried out by use of one or more buffering agents selected from the group consisting of a carbonate, such as monocarbonate, bicarbonate or sekswitharpena; glycinate, phosphate, glycerol, acetate, gluconate or citrate of an alkali metal such as potassium or sodium, or ammonium, and mixtures thereof; and/or by applying agents regulating the pH, such as agents selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide and calcium oxide; and/or through the application forms nicot is on, at least partially regulating the pH.

46. The method according to any of PP and 43, where the first solvent, and optionally one or more second(s) solvent(s) selected from water and/or alcohol, such as ethanol, glycerol, propylene glycol and polyethylene glycol, and/or one or more lipids, and mixtures thereof.

47. The method according to any of PP and 43, where the first and second components are selected from one or more flavoring and/or aromatic means such as a means selected from the group consisting of essential oils obtained by distillation, solvent extraction or cold pressed fresh or dried flowers, buds, leaves, stems, fruits, seeds, rind, bark or roots, for example, peppermint oil, curly mint, eucalyptus, simalube, nyali, cloves, cardamom, cinnamon, bitter almond, coriander, cumin, ginger, juniper orange , orange, lemon, grapefruit, Mandarin, bergamot, thyme, fennel and rosemary;

natural taste and fragrance of funds, including diluted solutions of essential oils or concentrates of flavoring ingredients of natural origin, for example, fruits, berries, nuts, spices, mint, tobacco, cocoa, coffee, tea, vanilla, licorice, caramel, butterscotch, honey, wine, spirits and non-alcoholic beverages;

synthetic flavoring and aromatizing the funds, consisting of mixtures of chemicals, including hydrocarbons, alcohols, aldehydes, esters, ketones, ethers and oxides, mixed to obtain a natural taste, for example, fruits, berries, nuts, spices, mint, tobacco, cocoa, coffee, tea, vanilla, licorice, caramel, butterscotch, honey, wine, spirits and soft drinks; and mixtures thereof;

one or more stabilizing additives, such as additives selected from the group consisting of antioxidants, including vitamin E, i.e. Tocopherols, vitamin C, i.e. ascorbic acid and its salts, sodium pyrosulphite, equivalent, bottled hydroxyanisol; and preservatives, including parabens, benzalkonium chloride, chlorbutanol, benzyl alcohol, beta-phenethyl alcohol, chloride of cetylpyridinium; and chelating agents such as EDTA; and Galaev, such as propylgallate;

one or more additives selected from the group consisting of:

thickeners such as natural, semi-synthetic or synthetic polymers, such as starch and starch derivatives, cellulose and cellulose derivatives, polyethylene glycols and derivatives thereof, polyacrylates and polyvinyl complex and ethers;

enhancers such as azone;

vitamins, such as vitamins C and E;

minerals such as fluoride, especially sodium fluoride,monitoroff sodium and fluoride tin;

anti-odor, such as zinc and cyclodextrins; propellants, such as 1,1,2,2-Tetrafluoroethane (HFC-134a), optional liquefied, and 1,1,1,2,3,3,3-Heptafluoropropane (HFC-227), optional liquefied; sweeteners, including one or more synthetic sweetening funds and/or natural sugars, such as sweeteners selected from the group consisting of:

artificial sweeteners, such as saccharin and its sodium and calcium salts, aspartame, Acesulfame and its potassium salt, thaumatin and glycyrrhizin;

polyhydric alcohols, such as sorbitol, xylitol, mannitol and glycerol, monosaccharides, including glucose (also called dextrose), fructose (also called levulose) and galactose;

disaccharides including sucrose, lactose (also called milk sugar) and maltose (also called malt sugar);

mixtures of sugars, including liquid glucose syrup, for example, hydrolysates of starch, containing a mixture of mainly dextrose, maltose, dextrin and water, syrup invert sugar, for example sucrose, inverted invertase containing a mixture of dextrose, levulose and water; syrups high in sugar, such as molasses extracts, honey and malt; and mixtures thereof.

48. The method according to any of PP and 43, where the first and/or second components are races who varenymi one or more surfactants and/or emulsifiers, such as nonionic, cationic, anionic or zwitter-ionic surfactants, including amphiphilic block copolymers or mixtures thereof, preferably where one or more surfactant selected from nonionic surfactants, including poloxamer, for example poly(oxypropylene)-poly(oksietilenom) block copolymers, alkalemia ethers of polyoxyethylene, polyoxyethylene derivatives of castor oil, esters of fatty acids and sorbitan of polyoxyethylene mono - and diglycerides and their esters, stearates of polyoxyethylene, polyglyceryl esters of fatty acids (including polyglycerylmethacrylate acid (PGPR)) and esters of sorbitol and fatty acids, cationic surfactants, including secondary, tertiary and Quaternary ammonium compounds and cationic phospholipids, anionic surface-active substances, including salts of fatty acids, lactylate, especially stearylamine sodium and/or calcium, alkyl sulphates, alkyl sulphonates, ethanol and anionic phospholipids, such as phosphatidylserine, zwitter-ionic surfactants, including zwitter-ionic phospholipids, such as phosphatidylcholine and phosphatidylethanolamine, or mixtures thereof, and most preferably surface-active agents or mixtures thereof are non-ionic.

49. Liquid pharmaceutical composition according to any one of claims 1 to 20 for use in therapy.

50. Liquid pharmaceutical composition according to § 49, where therapy is a treatment of a disease selected from the group consisting of addiction to tobacco or nicotine, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis; and weight management.

51. The use of nicotine in any form to obtain a liquid pharmaceutical composition according to any one of claims 1 to 20 for the treatment of diseases selected from the group consisting of addiction to tobacco or nicotine, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerative colitis; and weight management.



 

Same patents:

FIELD: medicine, pharmacy.

SUBSTANCE: invention represents a pharmaceutical tablet comprising a core and bound envelope wherein (a) core comprises solid particles of water-soluble dye dispersed in matrix, and (b) envelope comprises hellanic gum. Due to the presence of water-soluble dye in the tablet core it shows spotted shape that provides easy recognition of the tablet. The tablet is useful for peroral and intraoral administration.

EFFECT: improved and valuable properties of tablet.

30 cl, 6 ex

FIELD: organic chemistry, medicine, narcology, pharmacy.

SUBSTANCE: invention relates to a sustained-release medicinal formulation designated for reducing abuse to nicotine. The medicinal formulation comprises 5,8,14-triazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,5,7,9-pentaene or its pharmaceutically acceptable salt that is administrated in patient at the rate less 6 mg/h that corresponds to at least 0.1 mg of indicated compound for 24 h. Also, invention relates to the sustained-release medicinal formulation comprising low dose of indicated medicinal substance. Method for using involves oral administration of the sustained-release medicinal formulation at the first stage for period from about 1 day to about 30 days followed by administration the sustained-release medicinal formulation at the second stage. Invention provides reducing abuse for nicotine and simultaneous decreasing appearance of nausea frequency as adverse effect.

EFFECT: valuable medicinal properties of composition.

10 cl, 13 ex

FIELD: medicine.

SUBSTANCE: method involves delivering nicotine to patient organism and administering medicament by smearing internal surface of superior and inferior nasal passage part. Treatment is carried out with cigarette consumption being retained. Smell receptor canal blocker like rapid sodium canal blocker lidocaine is used as the medicament. Its aerosol is introduced immediately before smoking action as single jet in each nasal passage. Medicament introduction is localized with epithelial smell receptor cells arrangement.

EFFECT: enhanced effectiveness of treatment.

2 cl, 2 tbl

FIELD: medicine, narcology, pharmacy.

SUBSTANCE: invention proposes applying the following agonists of gamma-aminobutyric acid receptors of B-type: β-(4-chlorophenyl)-GABA (Baclofen), 3-aminopropyl(methyl)-phosphinic acid, 3-aminopropylphosphinic acid, Y-amino-β-4-(4-chlorophenyl)-nitropropane or their salts, esters, ethers, complexes and their corresponding isomers used in treatment of nicotine dependence. Invention provides the selective suppression of smoking addiction and effect on behavior indices causing the abuse relapse and with absence of symptoms typical in nicotine dependence.

EFFECT: valuable properties of compounds.

9 cl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazol-3-carboxamide or its salt for manufacturing a medicinal agent used for treatment of nicotine dependence and/or symptoms of nicotine withdrawal syndrome and a method for help in ceasing using tobacco. The claimed compound is known as antagonist of central cannabinoid receptors and agent used for treatment of disorders associated with using psychoactive substances. Indicated compounds are effective with respect to complete or partial tobacco abstinence with elimination of attenuation of nicotine withdrawal syndrome and patients show reduced weight loss or its absence.

EFFECT: valuable medicinal properties of antagonist.

3 cl, 5 ex

The invention relates to medicine, namely to section narcology, and can be used for the treatment of tobacco

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

The invention relates to medicine, to compositions containing polar lipid composition on the basis of nicotine in liquid crystals and colloidal dispersions and their predecessors or secondary products, which are in contact with fluid body and/or under the influence of body temperature into liquid crystals, or a mixture of liquid crystals, which acts as a matrix with controlled release of nicotine, suitable for Smoking cessation and/or replacement area

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to phenoxyphenylalkane sulfonates of the general formula (I): wherein R3 means alkyl group comprising from 4 to 7 carbon atoms and this group can be substituted from one to some times with fluorine or chlorine atom; A means oxygen atom or NH-group. Also, invention describes a method for preparing compounds of the formula (I) and medicinal agent based on thereof. Compounds can be used in treatment of pain syndromes and neurodegenerative diseases.

EFFECT: valuable medicinal properties of compounds.

7 cl, 3 tbl, 30 ex

FIELD: medicine, neurology, in particular treatment of disseminated sclerosis.

SUBSTANCE: complex therapy includes plasma exchange, interferonotherapy, administration of copaxon, cytostatics, symptomatic and bracing agents, and cyclosporin A. Administration of steroids is excluded. Additionally ceruloplasmine intravenously drop-by-drop in dose of 100 mg and cerebrolysate intramuscularly in dose of 10 ml for 10 days are administered. Claimed method provides stable remission up to 12 months for 89.2 % of patients.

EFFECT: decreased invalidisation due to reconstitution of regulatory relationship between nervous and immune systems.

1 ex, 1 tbl

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition stimulating adenosine receptors and comprising one or some compounds of the formula (I) and new compounds of the formula (II) . The composition provides the effective modulation of the adenosine system.

EFFECT: valuable properties of modulators.

12 cl, 541 ex

FIELD: organic chemistry, neurology, medicine.

SUBSTANCE: invention relates to a new medicinal agent used in treatment of feeble-mindedness comprising a derivative of 2-aryl-8-oxodihydropurine, namely, a derivative of 2-aryl-8-oxodihydropurine that comprises acetamide group at position 7 or 9 of purine ring. Invention proposes compounds of formulae (Ia) and (Ib) wherein radicals X1, Y1, R12, R13, R22, R23, R32, R42 and R43 have the corresponding values, or their pharmaceutically acceptable acid-additive salt. Also, invention proposes using compounds of the formulae (Ia) and (Ib) or their pharmaceutically acceptable acid-additive salt for preparing a medicinal agent used in treatment or prophylaxis of feeble-mindedness wherein feeble-mindedness represents deterioration of the teaching process, dysmnesia, dysmnesia-based disorientation, mental dysfunction, Alzheimer's disease, cerebrovascular feeble-mindedness and/or senile feeble-mindedness, and in treatment or prophylaxis of higher cerebral dysfunction. Invention provides the development of a medicinal preparation for prophylaxis or treatment of feeble-mindedness symptoms associated with diseases that can induce feeble-mindedness and higher cerebral dysfunction.

EFFECT: valuable medicinal properties of agents.

12 cl, 3 tbl, 5 ex

FIELD: medicine, neurology, therapy, pharmacy.

SUBSTANCE: invention relates to pharmaceutical preparations used in treatment of neurological disorders. Preparations comprise eicosapentaenoic acid and arachidonic acid and shoes at least 90% of purity and taken as components of the preparation in the ratio from 1:1 to 20:1. Also, invention relates to methods for treatment of neurological disorders. Invention discloses the positive effect of the preparation on pathological neurodegenerative process. Invention provides the combined using eicosapentaenic and arachidonic acids in treatment of neurological disorders.

EFFECT: valuable medicinal properties of preparation.

11 cl, 3 tbl, 1 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: claimed method includes blending of active base and auxiliary ingredients to form tablet corn, representing composition of sugar powder, monocrystalline cellulose, vinylpyrrolidone and calcium stearate; humidifying of obtained mixture; drying of obtained granules; dry granulation through granulator with standardized holes; pelletization of standardized granules to produce tablet corn; and coating. Mixture is humidified with 5-7 % starch mucilage in starch mucilage/humidifying mixture mass ratio of 1:25-30, wherein mixture is blending with starch mucilage for homogeneous distribution wet in whole mass.

EFFECT: tablets with increased hardness and enhanced pharmacological activity.

2 cl, 2 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a new agent with expressed selective activity with respect to central muscarinic acetylcholine receptors belonging to subtype M1. Agent represents 1-phenyl-1-(1'-methylcyclopentyl)-4-piperidino-2-butyne-1-ol hydrochloride of the formula (1) known early as low toxic cholinolytic. Agent expands a set of ligands used in research of mechanisms of the central nervous system function. Agent shows high capacity for penetration through blood-brain barrier, low toxicity and high effectiveness.

EFFECT: valuable medicinal properties of agent.

1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

FIELD: pharmaceutical industry.

SUBSTANCE: invention provides composition containing 0.1-0.5% nicotinic acid, 0.01-0.05% olifen-containing preparation, 0.5-1 mln ME interferon, and solvent. Use of this composition allows interferon dose to be lowered in single time administration cases. Bioavailability and residence time in system bloodstream of preparation are increased. In addition, liver first passage effect is avoided as well as accompanying unfavorable reactions resulting in changed preparation structure. Preparation also alleviates inflammatory phenomena in focuses of primary virus contact with microorganism cells.

EFFECT: expanded therapeutical possibilities.

5 cl, 3 dwg, 3 tbl, 3 ex

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