Composition, replacing tobacco (options), its preparation, the method of treating tobacco, a method of treating alzheimer's disease, parkinson's disease or ulcerative colitis

 

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. Describes the composition of these liquid crystals, or dispersions, or their predecessors, or secondary products containing nicotine and interstadial, or local analgesic, or combinations thereof, to reduce the local irritant effects of nicotine or masking the taste. Possible ways of introduction and administration include buccal introduction, including chewing gum, in which the recycled liquid crystals, their dispersion, or their predecessors, or secondary products, buccal adhesives, gels and pads using the liquid crystal, its variance or its predecessor, and aerosol for oral administration using the dispersion of these liquid crystals, their predshedstvennikov or secondary products, local injection in the form of adhesive pads and gels with the use of these liquid crystals, or their predecessors, or secondary products. Also described is a method of treatment of Alzheimer's disease, Parkinson's disease or ulcerative colitis. The invention does not cause side effects, bioavailable, it is convenient to use. 5 C. and 29 C.p. f-crystals, 6 ill., 5 table.

The invention relates to compositions containing nicotine, and methods of producing these compositions suitable for the treatment of medicines, preferably for the replacement of tobacco or refunds of tobacco and Smoking cessation.

The prior art Treatment through reimbursement of tobacco for Smoking cessation in the past was successful. Known compositions containing nicotine, designed to reduce the desire to use nicotine in subjects who wish to stop using tobacco products include, for example, described in U.S. patent 3845217 chewing compositions described in U.S. patent 4579858 viscous nasal drops, including nicotine, as described in the application Australia 664415 low viscosity containing nicotine compositions suitable for spraying into the nose, is described in U.S. patent 4920989 and 4953572 the data to spray in the mouth and for percutaneous administration of nicotine, and described in U.S. patent 4915950 manufacturing tools for percutaneous administration of nicotine. Several products based on the above-mentioned patents, are sold at the present time all over the world.

Well-known side effect of nicotine is local irritation, which depends on the concentration of nicotine. This harmful effect is particularly noticeable when the structures on the basis of nicotine applied locally, including through the introduction through the mucous membrane, including transbukkalno and nasal introduction and percutaneous introduction. The concentration of nicotine according to several of the above inventions and compilation of recipes is limited so harmful effect of causing or associated with local irritation. However, there are people who may seek to use doses of nicotine higher than the dose used in the famous formulation. In addition, chewing gum with nicotine can cause unpleasant side effects in addition to local irritation, such as dyspepsia and nausea. As for dyspepsia, increased bioavailability through the mucous membrane reduces indigestion and, therefore, local irritation caused by nicotine in the area of the mouth is local irritation in addition to sneezing and slezlivo. In the application of UK 2230439 described nicotine tablets with a shell or coating that contains a valid local oral analgesic, preferably eugenol. Although this source is not clear what the cause is introduced a local analgesic, reports a significant reduction burning sensation in the mouth that occurs when using conventional nicotine tablets. Nicotine composition in the form of tablets containing local analgesic described in the application Australia 662877, which States that the analgesic temporarily affects the taste buds, which, as indicated, reduces the desire to eat. Thus, although the application of the UK 2230439 proposed improvement in the reduction of local harmful effects caused by nicotine, contained in the tablets, there is still a need for reducing the side effects associated with local irritation caused by nicotine at all, including the above examples of methods of implementation and preparations of the invention or the products described in them.

In the patent EP 126751 B1 describes compositions with controlled release for introducing biologically active materials. According to the invention described in this patent, rozliczenie phase in contact with the liquid, constituting any part of the polar Department of the resulting thermodynamically stable phase. Liquid crystalline phase used according to the invention are preferably, but not exclusively to the group of cubic and hexagonal liquid crystalline phases. In the application WO 95/26715 described bioadhesive compositions comprising esters of fatty acids that form liquid crystals, preferably from the group of cubic and hexagonal liquid crystalline phases. In U.S. patent 5371109 described the use of L2phase consisting of a mixture of mono - and triglycerides and polar solvent as a composition for biologically active materials. The use of fatty acids in such mixtures, however, are not described. In U.S. patent 5531925 describes how to get the particles or their precursors, the above-mentioned liquid crystalline phases or their precursors with the structure reversion/inversion type II. In the application WO 97/13528 also described liquid crystal phase. Although in the last source in the description mentioned nicotine in a long list of drugs, the examples are not described in the preparative form, including nicotine.

Thus, until now, have not been described stable containing nicotianamine briefly mention this, never revealed as to obtain stable liquid-crystalline phases, including nicotine. Now it has been unexpectedly found that the combination of nicotine and fatty acids accelerates the formation of liquid crystals of the polar lipids. Therefore, it is now possible to obtain liquid crystals, including nicotine, are suitable in areas where controlled release.

The invention has Proposed a composition for therapeutic administration of nicotine. These compositions, including nicotine, reduce the harmful effects of nicotine related to local irritation or associated with the latter, due to the controlled release of nicotine by the joint introduction of interstatala or local analgesic or by any combination of these methods. The composition used for injection of nicotine. Further, these compositions are applied, without limiting the scope for nasal, buccal, pulmonary, and percutaneous methods of administration. Suitable are, without limitation, nasal sprays, buccal sprays, chewing gum, pills, cakes, pads for percutaneous or buccal injection, nasal gels, gels for transdermal or buccal introduction, plastisizer description pickguard for percutaneous introduction, the component of the invention can be characterized by the presence of very high doses, allowing for the use of overlays for percutaneous injection with a very small surface suitable for placement on the less visible parts of the body, such as behind the ear.

According to one aspect of the invention relates to compositions containing nicotine, which generally forms a liquid crystal phase or its precursor, comprising at least one amphiphilic lipid in an amount sufficient for the formation of this liquid crystalline phase. Variables that affect the formation of liquid crystalline phase of the precursor, preferably, are selected, without restriction, from the composition, temperature and pressure, or any combinations thereof, which may be carried out by specialists in the field of phase diagrams involving these variables. Changes in compositions preferably include those that occur when these compounds are in contact with fluid body and preferably are selected, without limitation, activities solvents and ionic activity, including change in the substances, for example, when washing the aqueous solution before or after the introduction of the predecessor section, where worked last. The formation of liquid crystalline phases, caused by temperature, preferably, without limitation occurs due to the temperature increase caused by contact with the body, preferably, but not exclusively, a man, moreover, these compositions are in contact with any part of the body that causes adaptation of the composition of the higher temperature at which is formed the other phase. Such phase transformations caused by the change in pressure can be applied, for example, in accordance with the phase diagram pressure - composition known or easily obtained by specialists in this field.

According to another aspect of the invention, it provides methods for producing dispersions, preferably colloidal dispersions, one or more liquid crystalline phases or their precursors containing nicotine and local analgesic or a combination of both. The specified predecessor preferably choose, without restrictions, from another liquid, solid phase, solution, or any other phase structure that can undergo phase parentline phase.

According to another aspect of the invention provides for compositions intended for receiving spontaneously formed dispersion liquid crystalline phases, in which the nicotine, one liquid acid and one monoglyceride present in proportions required for the formation of liquid crystalline phase when casting into contact with a polar solvent, preferably, without limitation, the water, which upon further dilution of the specified polar solvent or other polar solvent is converted into a stable colloidal dispersion liquid crystalline phase or its predecessor.

According to another aspect of the invention relates to a process for the preparation of liquid crystal compositions or their precursors containing at least one monoglyceride, at least one fatty acid and nicotine in which the nicotine and the specified fatty acid form a complex ion pair. The specified liquid crystal phase in, for example, buffered aqueous medium, such as saliva or mucus, causes a weakening of the complex nicotine - ion pair at a certain pH value, which leads to the release of nicotine adjustable by way of the liquid crystal is hearing the compositions, nicotine and local analgesic, prepared in solution, liquid phase or its precursor, in colloidal dispersions of one or more liquid crystalline phases or their predecessors.

The term "precursor" as used in the description and in the claims, refers to any composition according to this invention that when you change one or more variables in this way, as described in this invention, forms one or more liquid-crystalline phases containing nicotine.

The term "secondary product" used in the description and in the claims, refers to any received state, resulting according to this invention as the result of changes in the variables after the application of the present invention.

The term "nicotine" that is used in the description and in the claims, covers the base of the nicotine and its mono - and dication derivatives, resinat nicotine (see, for example, US 3845217) and complexes of nicotine.

Salt of nicotine, preferably, but not exclusively, include hydrochloride, nicotine, nicotine dihydrochloride, nicotine sulfate, monetarist nicotine, ditartrate nicotine zinc chloride-nicotine salicylate niloticano, but not exclusively, cotinine, myosin, anabasine, anatamy, nornicotine, beta nicotian, beta nornicotine and N-oxide of nicotine.

The term "liquid phase" used in the description and in the claims, means thermodynamically stable state of matter in which there is no short-range order and which is not truly crystalline, but which is characterized by long-range order, not as a liquid or amorphous.

The term "cubic liquid crystalline phase and cubic phase" used in this description and in the claims, mean isotropic liquid crystal phase, in which long-range order characterized one possible layout structures of cubic space groups, as shown by diffraction methods X-rays in combination with the study of phase diagrams, known to specialists in this field.

The terms "hexagonal liquid crystalline phase" or "hexagonal phase", as used herein, means an anisotropic liquid crystal phase, in which long-range order characterized, as shown by diffraction scattering method, a two-dimensional lattice.

The term "L2-phase" used in the description and in form long-range order, and is used as a synonym of the term "microemulsion".

The term "type", namely type I or type II or synonyms reverse (inverse) or conventional crystalline phase used in this description and the claims refer to the curvature of apolar - polar phase boundary, respectively, in accordance with the terminology currently used in the literature. Type phase is easily distinguished by the behavior of the phase when the number of polar components, such as dilution with water, when the phase type I will be diluted and transformed into another phase, for example in normal micelles, while the phase of type II will swell up to a certain point the water activity at which they will be in equilibrium with any additionally added polar components, such as water.

The term "adhesive" used in the description and in the claims, refers to the ability of the liquid crystal phase to change its state, for example, by absorption of polar components from the environmental point of use environment, causing further swelling phase, or causes the transformation phases. Specialists in this field will easily explain it as a consequence of the behavior of the phases of the systems is inimici and mass transfer, which leads to adhesion due to the driving force to achieve a close confrontation caused by its thermodynamic degree of freedom with the subsequent emergence of non-covalent bonds with the surface or place of use.

The term "state variables" used in the description and in the claims, refers to any variable parameters characterizing the behavior of the phase rule Gibb, known to specialists.

The term "thermodynamically stable" in this description and in the claims refers to physical composition, the stability of which in the sense of the integrity of its structure is limited only by chemical decomposition.

In this application such preferred surfactants which are capable of forming an ion pair or salt, thus contributing to the formation of liquid crystalline phases.

Description of figures Fig.1 shows a four-phase diagram of mixtures of oleic acid - nicotine (molar ratio 1:1) - monooleyl - water, illustrating the various physical phase state of mixtures of oleic acid - nicotine (molar ratio 1:1) - monooleyl - water, which can be used to implement the present invention. While L2phase 3, the solid crystalline form 4, cubic phase form 6 and the area of the three-phase dispersion 7. The definition phase using the technique of x-ray under a small angle and polarization microscopy was carried out according to T. Landh, J. Phys. Chem., 98, 8453-8467, 1994. Examples of the phase shift upon addition of an aqueous solution is shown as 8 and 9.

In Fig. 2 shows the in vitro release of nicotine over time (minutes) that occur in the test USP paddle dissolution (dissolution paddle stirrer). The composition of the samples are shown in table 1.

In Fig.3 shows the overlay for transbukkalno introduction laying the released drug, an optional cavity 2, a matrix with adjustable release 3 any liquid crystal composition according to the invention and a substrate 4.

In Fig. 4 shows the in vitro penetration of nicotine into the skin (the skin of the pig from the back) in time of liquid crystal phases, listed in table 2. The experiments were carried out in a diffusion cell Franz'a square diffusion 1.8 cm2. Experiments were performed at room temperature and the temperature of the phase of the receptor, 37oC. Samples weighing about 180 mg, shown in table 2, were applied to the skin. We used two control solution control solution 1 and 2, the reported examples of in vitro penetration (minutes) nicotine through the buccal epithelium of the pig. The compositions used liquid crystalline phases are shown in table 3. The experiments were carried out in a diffusion cell Franz'a square diffusion 1.8 cm2. Experiments were performed at room temperature and the temperature of the phase of the receptor, 37oC. On the buccal epithelium was applied approximately 55 mg samples given in table 3, which corresponded to the amount of nicotine/experience equal to 1 mg. Conditions of the experiments and the average number of infiltrated nicotine are shown in table 4.

In Fig.6 shows the in vitro release of nicotine over time (minutes) of liquid crystalline phases in chewing gum with appropriate excipients known to specialists in this field. Sample 1 is shown by a line with diamonds corresponds to the commercially available Nicorette, 2 mg, manufactured by Pharmacia & decision Upjohn. The composition of sample 2, shown by the line with squares, and sample 3, is shown by a line with triangles, shown in example 8. The experiments were conducted as described in U.S. patent 5087424.

Detailed description of the invention the composition of the invention include active drug substance, preferably nicotine. More specifically, the compositions contain nicotine, which is part of gbes restrictions, colloidal dispersions of these liquid crystalline phases, their predecessors or secondary products. The present invention particularly includes compositions with controlled release formulations of biologically active compound is preferably, but not exclusively, nicotine, in cubic liquid crystalline phases of type I and II, the hexagonal liquid crystalline phases of type I and II, intermediate liquid crystalline phases of type I and II and lamellar phases, in all cases, regardless of the spatial arrangement of groups and predecessors or secondary products of these liquid crystalline phases, including any phase or mixture of phases, borrowed during the application of this composition by so called changes or changes in the form of changes in the physical or chemical nature, affecting one or more variable parameters that define the system.

Phase precursors or secondary products include, therefore, in addition to the above-mentioned liquid crystal phase any phase that is not characterized as a liquid crystal phase, including, without limitation, the solid phase, the phase of the micellar solutions of type I and II, stage races is p>

It is preferable to use the liquid crystal compounds, their precursors and secondary products to replace tobacco, Smoking cessation, and instead of Smoking. More specifically, these liquid crystal compounds, their precursors and secondary products useful in the treatment of these conditions when used alone or in suitable devices known to experts in the field of drugs and dosage forms, when percutaneous introduction or through the mucous membrane.

The above liquid crystal compounds, their precursors and secondary products can be entered in plasters, pads, chewing gum, tablets, and other forms used in combination with the above liquid crystal compounds, their precursors and secondary products. More specifically, the above-mentioned liquid crystal compounds, their precursors and secondary products are preferably used in the form of transdermal dosage forms of nicotine, and buccal dosage forms of nicotine or in combination with them. More preferably, these liquid crystal compounds, their precursors and secondary products are used to literally call the lingual tablets and pads, including dosage forms used to replace wet or chewing tobacco. The above liquid crystal compounds, their precursors and secondary products are used for coating bulk carrier, preferably but not exclusively of inert nature. It is most preferable to apply the coating on the granules or powder of starch or other polymer.

In the formulation above dispersed liquid crystal compounds, their precursors and secondary products containing biologically active substance preferably but not exclusively, the nicotine liquid crystal phase, its predecessors or secondary products, preferably selected without limitation from colloidal particles suitable for nasal spray or drops, or spray or drops for oral administration. Dispersed liquid crystal compounds, their precursors and secondary products preferably are selected, without limitation, from the group of cubic liquid crystalline phases of type I and II, the hexagonal liquid crystalline phases of type I and II, intermediate liquid crystalline phases of type I and II and lamellar phases, in all cases, regardless prostranstvenoe any other phase or their mixture, borrowed during application of the composition when the change or changes caused by changes in the physical or chemical nature, affecting one or more variable parameters characterizing the system. A stable dispersion of the above mentioned liquid crystal phase, or a mixture of phases, or their predecessors, or secondary products are easily derived by different methods fragmentation, known to specialists. Preferred is the spontaneous formation of stable colloidal dispersions of the above-mentioned liquid crystal phase, or a mixture of phases, or their predecessors. The above-mentioned colloidal compositions of the above-mentioned liquid crystalline phases or their precursors and secondary products containing nicotine, can be used for the manufacture of nasal and buccal/sublingual dosage forms in the form of droplets and aerosols and aerosol dosage forms for administration to the lungs or other forms used in combination or in conjunction with the above liquid crystal compounds, their precursors or secondary products. More specifically, these liquid crystal compounds, their predecessors or secondary products predpochtitelney or in combination with these dosage forms.

The composition of the invention contains nicotine and preferably, but not exclusively, local topical analgesic. Such compositions include topical local analgesic is selected, without limitation, of the following substances: benzyl alcohol, benzocaine, chlorbutanol, chloroprocaine, clove, eugenol, lidocaine hydrochloride lidocaine mepiwakaina, phenol, prilocaine, procaine, tetracaine, hydrochloride tetracaine, salicylic alcohol, or a mixture thereof. It is preferable to get these songs in solution or the above-mentioned liquid crystal composition of these phases, their predecessors or secondary products and their colloidal dispersions. These compositions are characterized by reduced side effects related to local irritation caused by the action of nicotine on the blocking of peripheral pain receptors, which otherwise would have been occupied by nicotine.

Specifically, the composition of the invention include one or more surfactants, preferably, without limitation, one or more polar lipids selected from the non-limiting group of glycolipids, phospholipids, monoglycerides and diglycerides or mixtures thereof, preferably the floor is asasa in equilibrium with any factor, characterized by variable state parameter.

More specifically, the composition of the invention include one or more biologically active substances, preferably nicotine, one or more monoglycerides, preferably, but without limitation, selected from the group consisting of esters of glycerol and palmitoleic acid, oleic acid, linoleic acid, linoleinovoy and arachidonic acids. The most preferred ester of glycerol and oleic acid. Optional components in addition to conventional pharmaceutical excipients include, without limitation, one or more fatty acids selected without limitation from the group stearic acid, palmitic acid, oleic acid, linoleic acid, linoleinovoy acid, arachidonic acid, one or more polar solvents, such as aqueous solutions, glycerin or propylene glycol or mixtures thereof, one or more local analgesics taken in quantities providing education composition, forming or capable of forming a liquid crystal phase changing any of the variables of state - of composition, temperature and pressure, or combinations thereof. Also included usually ispolzuemyi such components can be added, without going beyond the scope of this invention.

Forms of embodiment, technology and methods of manufacturing the compositions according to the invention are illustrated below by examples, not limiting the invention.

Example 1.

Monooleate glycerin, oleic acid, nicotine, pure glycerin and water in the following quantities: Component Weight. % Monooleate glycerol - 45 Oleic acid - 10 Nicotine - Glycerin 10 - 10
Phosphate buffer (pH 7.0) - 15
mix at room temperature. The above composition can be prepared in different ways.

One way is as follows. Hard monooleate glycerin add oleic acid and give the mixture to form a solution, which is added nicotine. To the thus obtained solution was added glycerin and give the mixture to form a solution, to which water is added with the formation of the cubic liquid crystalline phase.

This composition according to the invention is suitable for replacement of tobacco, Smoking cessation, and instead of Smoking that is carried out by various methods. The composition in the form of adhesive gel is applied directly on the buccal mucosa, through which is introduced the nicotine. The composition is melted and poured on the pad shown in Fig.N.

Example 2.

The compositions listed in table 1 were obtained twice as described in example 1 and in vitro release of nicotine in phosphate buffer (pH 7.0) of the compositions was determined using a commercially available detection devices dissolution according to USP. The results are shown in Fig.2.

It is easy to see that the resulting composition with a controlled rate of release. Important factors are the ratio of nicotine: oleic acid and water content. Thus, this invention can be used to control the speed of release of nicotine.

Example 3.

Monooleate glycerin, oleic acid, benzyl alcohol, nicotine and water are mixed in the following amounts:
Component Weight. %
Monooleate glycerin - 8
Oleic acid - 4
Benzyl alcohol - 4
Nicotine - 4
Water - 80
The above composition can be obtained in different ways. One way is the following. Hard monooleate glycerin add oleic acid and benzyl alcohol and give the mixture to form a solution, which is added nicotine. To the thus obtained solution was added water and allow mixture to form a hexagonal liquid crystal phase type I.

Example 4.

Monooleate glycerin, oleic acid, benzocaine and nicotine mixed in the following amounts:
Component Weight. %
Monooleate glycerol - 2
Oleic acid - 1
Benzocaine - 1
Nicotine - 1
Water - 95
The above composition can be obtained in different ways. One way is the following. Hard monooleate glycerin add oleic acid and nicotine and give the mixture to form a solution, to which is added benzocaine and allow it to dissolve. To the thus obtained solution was added one-fifth of the amount of water indicated in the table, and give the mixture to form a hexagonal liquid crystalline phase of type I, to which the remaining water is added, after which spontaneously forms a stable colloidal dispersion. This composition according to the invention can be used to replace tobacco, replacement and Smoking cessation various metadata device for nasal administration of nicotine. For a similar purpose it can be provided in the form of droplets or aerosol for oral administration. In addition, it forms a liquid aerosols and is used in standard devices, which are known to experts in this field, working with particle size in the colloidal region, suitable for the introduction of nicotine into the lungs through the mucous membrane of the lungs.

Example 5.

Benzyl alcohol and nicotine mixed with formation of a solution, to which water is added to obtain the composition of the following composition:
Component Weight. %
Nicotine - 1
Benzyl alcohol - 1
Water - 98
The above composition can be obtained in different ways, it can be added as optional components, such as stabilizers, buffering agents, sweeteners and flavorings. The composition may be introduced into the nasal mucous membrane by means of a metered dose inhaler with feeding, such as described in U.S. patent 4579858, to replace tobacco, termination and replacement area. In addition, the composition can be applied in aerosol form for oral administration by injection of a solution directly into the mouth and mucous membranes.

Example 6.

The compositions listed in table 2, are given as a description of the arrangements specified in the description of the shape.

It is obvious that the invention can be applied for the controlled injection of nicotine through the skin.

Example 7.

The compositions listed in table 3 were obtained as described in example 1 and tested for in vitro injection of nicotine in the buccal epithelium of pigs to determine the permeability of nicotine.

The results are shown in Fig. 5 and table 4 show the mean values of penetration of nicotine. The experiment described in the explanation of table 4.

It is easy to appreciate that this invention provides a controlled release of nicotine and adjustable absorption through buccal epithelium of pigs in vitro.

Example 8.

Composition composition (see table. 5) may be mixed with the base chewing gum and optional flavorings in the following amounts:
Component Weight. %
Liquid-phase composition 2 or 3 above. - 2
The basis of chewing gum (Dreyco) - 77
Powder sorbitol - 15
The solution of sorbitol (70%) - 4
Flavors - 2
and can be recycled with getting chewing gum known methods. In vitro release of nicotine from the chewing gum as defined in accordance with U.S. patent 5087424 shown in Fig.6 together with the corresponding figure for 2 mg controlled by the rate of release of nicotine. It is clear that it is possible to use precursors described liquid crystalline phases, in which the change occurs if the change of variables selected from the chemical composition, preferably water activity, body temperature, or a combination of these parameters.

Further aspects of the present invention seen in Fig.1.

In Fig. 1 shows a triangular diagram used to illustrate the phase behavior of a four-part system consisting of oleic acid, nicotine, monooleate glycerin and water. In Fig.1 shows an example (not limiting the invention) conduct phase at a molar ratio of oleic acid: nicotine, which is 1:1. Can be applied to other relationships.

This diagram shows some of the physical phases formed at different compositions shown in the diagram. These phases can be, for example, enriched water one dimensional lamellar liquid crystal phase 1, hexagonal (type II) liquid-phase 2, Svobodnaya liquid phase 3, the solid crystalline phase 4, depleted water one dimensional lamellar liquid crystal phase 5 and a three-dimensional cubic liquid crystalline phase 6 (type II).

This Fig is to saliva or any other fluid in the body, changes the physical state of the composition towards the corner where there was water, along the line 8. Thus, when exposed to large amounts of water free flowing viscosity of the fluid composition increases as soon as it becomes hexagonal liquid crystalline state of the type II and then passes in the multiphase region (not shown in figure 1), so in the end go in the three-phase region, in which the cubic liquid crystalline phase coexisting with lamellar phase 1 in accordance with the composition indicated along the line 8. In this three-phase region of the cubic liquid crystalline phase 6 easily dispersed and forms small particles surrounded by a lamellar phase 1.

As is well known to specialists in this field, the adhesion to such surfaces, such as mucous membrane in the mouth, is significantly increased due to absorption of water and consistent changes in the physical state, as seen along the line 8 in Fig. 1.

Similar solid crystalline phase with composition along the line 9 passes through successive changes of physical States in the acquisition or addition of water, as shown along the line 9, and finally enters visheupomyanutoi phases to replace tobacco or Smoking cessation. However, experts in this field is the obvious use of these phases for the treatment of other conditions, such as Alzheimer's disease, Parkinson's disease and ulcerative colitis, for which it is known therapeutic effect of nicotine.


Claims

1. The composition, the replacement for tobacco that contains nicotine and local analgesic or a mixture of local analgesics to reduce local irritation associated with nicotine, as well as one or more monoglycerides.

2. The composition, the replacement for tobacco that contains nicotine, one or more polar lipids and one or more anionic surfactants in quantities sufficient for the formation of liquid crystalline phase, or its predecessor, or a secondary product when placed in a polar solvent.

3. The composition according to p. 2, wherein the polar solvent is an aqueous solution, glycerin, or propylene glycol, or a mixture.

4. The composition according to p. 2, characterized in that the liquid crystal phase, or its predecessor, or a secondary product represents any phase of the following: a cubic liquid crystalline phase is from phase type I or type II and lamellar phases, in all cases, regardless of the spatial distribution of groups and predecessors or secondary products against these liquid crystal phases, including any phase or a mixture, due to the use composition when you change the physical or chemical nature, affecting one or more variable parameters that define the system, the solid phase, the phase of the micellar solution type I type II phase solution of the two-layer type including a phase porous material ( phase3), phase L2, microemulsions and true solutions.

5. The composition according to p. 2, characterized in that one or more polar lipids are monoglycerides.

6. The composition according to p. 2, characterized in that one or more anionic surfactants are fatty acids.

7. The composition according to p. 6, characterized in that one or more fatty acids selected from the group consisting of stearic acid, palmitic acid, oleic acid, linoleic acid, linoleinovoy acid and arachidonic acid.

8. The composition according to p. 7, wherein the fatty acid is an oleic acid.

9. The composition according to p. 2, featuring the position under item 1 or 9, characterized in that the local analgesic or local analgesics selected from benzyl alcohol, benzocaine, chlorbutanol, chloroprocaine, clove, eugenol, lidocaine hydrochloride lidocaine mepiwakaina, phenol, prilocaine, procaine, tetracaine, hydrochloride tetracaine and salicylic alcohol or combinations thereof.

11. The composition according to p. 10, characterized in that the local analgesic is benzocaine.

12. The composition according to p. 11, characterized in that the local analgesic represents benzyl alcohol.

13. The composition according to p. 1 or 5, characterized in that one or more monoglycerides selected from the group consisting of esters of glycerol and palmitic acid, oleic acid, linoleic acid, linoleinovoy and arachidonic acids.

14. The composition according to p. 1 or 5, wherein the monoglyceride is monoolefinic.

15. The composition according to p. 1 or 5, wherein the monoglyceride is monolinoleate.

16. Composition under item 1 or 2, characterized in that further comprises a pharmaceutically acceptable additive for use as a medicine.

17. The composition according to p. 16, wherein the pharmaceutically acceptable additive is selected from Osetia under item 16 or 17, intended for the treatment of Alzheimer's disease, Parkinson's disease or ulcerative colitis.

19. The composition according to p. 16 or 17, intended for nasal, buccal, percutaneous introduction or for introduction via the mucous membranes or into the lungs.

20. The composition according to p. 16 or 17, which is intended for insertion into a nasal spray or gel, buccal spray, chewing gum, pills, cakes, skin pads, adhesive or gel buccal lining, adhesive, or gel, or aerosol, or for introduction into the lungs.

21. The composition according to p. 16 or 17, designed for percutaneous introduction for the human ears.

22. A method of obtaining a composition that replaces tobacco, comprising a mixture of nicotine and one or more polar lipids and one or more anionic surfactants in quantities sufficient for the formation of liquid crystalline phase, or its predecessor, or a secondary product when placed in a polar solvent.

23. The method according to p. 22, wherein the one or more polar lipids are monoglycerides.

24. The method according to p. 22, characterized in that one or more anionic surfactants presray from the group consisting of stearic acid, palmitic acid, oleic acid, linoleinovoy acid, linoleic acid and arachidonic acid.

26. The method according to p. 25, wherein the fatty acid is an oleic acid.

27. The method according to p. 23, wherein the monoglyceride is monoolefinic.

28. The method according to p. 23, wherein the monoglyceride is monolinolein.

29. The method according to p. 22, characterized in that the add and mix with other ingredients local analgesic or a mixture of local analgesics.

30. The method according to p. 29, characterized in that the local analgesic or local analgesics selected from benzyl alcohol, benzocaine, chlorbutanol, chloroprocaine, clove, eugenol, lidocaine hydrochloride lidocaine mepiwakaina, phenol, prilocaine, procaine, tetracaine, hydrochloride tetracaine and salicylic alcohol or mixtures thereof.

31. The method according to p. 30, characterized in that the local analgesic is a benzocaine.

32. The method according to p. 30, characterized in that the local analgesic represents benzyl alcohol.

33. Method of treating tobacco comprising introducing the composition of PP. 1-21.

34. A method for the treatment of Bo is .1-21.

 

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The invention relates to medicine, specifically to medicines on the basis of herbal remedies designed to treat tobacco

The invention relates to medicine, namely, neurology, and for the treatment of acute and chronic cerebral insufficiency, as well as neurodegenerative diseases

The invention relates to new substituted the isoxazoles of General formulas I, II, III, IV, V, where R1selected from lower alkyl, carboxyamide, alkoxycarbonyl, aminocarbonyl, aminocarbonylmethyl and so on; R2choose from alkylsulfonyl, hydroxysulfonic and aminosulfonyl; R3selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from alkyl, cyano, halogenoalkane, hydroxyalkyl and so on; provided that R2is aminosulfonyl, if R2- substituted phenyl radical is in the 3-position isoxazol; R4selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyethyl and so on; R5selected from methyl, hydroxy and amino; R6selected from phenyl or 6-membered heterocycle containing one nitrogen atom, and phenyl may be optionally substituted by one or more radicals independently selected from lower alkylsulfonyl, lower alkyl, cyano, lower halogenoalkane and so on; R7selected from lower alkyl, hydroxyl, carboxyl, halogen, lower carboxyl and so on; R8represents one or more radicals and so on

The invention relates to medicine, namely, neurology, and relates to means for the treatment of dyscirculatory encephalopathy

The invention relates to medicine, namely, neurology

The invention relates to medicine, specifically to means of therapy dementia

The invention relates to pharmacology and medicine, in particular to a method of treatment of Alzheimer's disease and pharmaceutical compositions on the basis of climinal for treatment

The invention relates to medicine and relates to pharmaceutically acceptable compositions for inhibition of nitric oxide synthase in a mammal, which comprises a mercapto - or selenoprotein and a pharmaceutically acceptable carrier, methods of inhibition of nitric oxide synthase selectively inhibiting the inducible isoform of the nitric oxide synthase, and treatment of various conditions, where appropriate inhibition of biosynthesis of nitric oxide by injecting the mammal mercapto - or selenoproteins in pure form or in pharmaceutically acceptable media
The invention relates to an improved process for the preparation of derivatives of 3-phenyl-4-aminobutanoic acid, in particular 3-carboethoxy-4-phenylpyrrolidine-2, which is that the diethyl ether of benzylidenemalonate acid interacts with nitromethane in the presence of an alkaline catalyst - ethylate sodium or potassium in the environment methyl, ethyl or isopropyl alcohol, the resulting product hydronaut when the hydrogen pressure to 4.9 ATM using palladium or Nickel catalyst in the environment methyl, ethyl or isopropyl alcohol or acetic acid

The invention relates to imidazole derivative of General formula I, where n=0 or 1, R1is hydrogen, alkyl, R2is hydrogen or R2and R3form a double bond, R3is hydrogen, alkyl, R4is hydrogen, alkyl, hydroxy-group, alkoxy, R5is hydrogen or alkyl, or R4and R5form a carboxyl group, R6, R7, R8is hydrogen, alkyl, hydroxy-group, alkoxy, hydroxyalkyl, halogen, X-CHR9-(CHR10)m-, m = 0 or 1, R9and R10is hydrogen or alkyl

The invention relates to medicine, and is intended for the treatment of inflammatory diseases of different etiology
The invention relates to medicine, namely to dentistry
The invention relates to dentistry, concerns the creation of a medical adhesive tapes for fixing laminar prostheses and method of their preparation
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