Water-soluble films containing low-viscosity alginates

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a film containing as a film-forming agent an alginic acid salt with monovalent cation or mixed alginic acid salts containing at least one alginic acid salt with monovalent cation with 10% aqueous solution of the film-forming agent at temperature 20°C characterised by the viscosity of 100-1000 mPa-sec in accordance with the values measured at shear velocity 20 rpm with using a Brookfield viscometre equipped with a spindle No.2, as well as a method for making such film.

EFFECT: film is applicable for active ingredient delivery in a mammal's body and fast soluble while contacting with a wet surface.

18 cl, 2 tbl, 10 ex

 

The technical field

The present invention relates to a polymer film containing the alginate polymer, and to a method for producing such film. In addition, the invention relates to compositions in the form of alginate films containing at least one biologically active substance, such as a therapeutically active ingredient, and to a method for producing such compositions. In conclusion, the invention relates to the use of polymeric films containing alginate polymer, to obtain a medicinal product, as well as to the use of pharmaceutical film-forming composition based on a polymeric film containing alginate polymer, for treatment.

Prior art

Alginate is a salt of alginic acid is a linear polysaccharide synthesized in nature by brown algae (Phaeophyceae, mainly Laminaria). It usually consists of 100-3000 Monomeric residues, connected with each other in the flexible circuit. These balances are of two types, namely: β-(1→4)-linked residues of D-mannurone acid (M) and α-(1→4)-linked residues of L-guluronic acid (G), respectively. The remains are epimerase (residues D-mannurone acid after polymerization under the influence of enzymes into the remains of the L-guluronic acid) and differ only in position C5. About the NACO in the polymer chain, they lead to very different conformations; any two of the rest of D-mannurone acid connected4With1-diequatorial, while the connection between any two balance L-guluronic acid is1With4-biaxially communication, which is illustrated in formula I, described herein below.

Residues organized into blocks of identical or strictly alternating residues (for example, MMMMMM...GGGGGG... or GMGMGMGM...).

As counterions for negatively charged groups of alginates are various monovalent and polyvalent cations, for example, Na+To+, NH4+MD2+and CA2+.

Depending on various factors, such as the average length of the polymer chain, the polymer composition and cations present, the fluidity characteristics of alginates vary widely, from free flow (low viscosity) to stop dropping (high viscosity).

Alginates are applied in various fields, for example in the pharmaceutical and food products in which they are used, for example, as thickeners, stabilizers and geleobrazovanie. Their use in pharmaceutical compositions mentioned in several patents and patent applications. Thus, in U.S. patent No. 6923988, assigned company Lipocine, Inc., OPI is to see a solid pharmaceutical composition, designed for improved delivery of active ingredients. Mentioned that the pharmaceutical composition can contain alginate as a disintegrator.

In U.S. patent No. 6923981, assigned company Warner-Lambert Company, describe bystrorastvorimaya used oral film, intended for oral hygiene. Provides a list of film-forming agents, and, despite the mention in it of sodium alginate, the preferred States of pullulan, and no example alginate film is not given.

In U.S. patent No. 6656493 and 6740332, both of which were assigned to the company Wm. Wrigley Jr. Company, describe the edible film dosage form intended for oral hygiene. Film dosage forms contain at least three types of film forming agents, namely: maltodextrin, a hydrocolloid and a filler. The purpose of hydrocolloid are giving consistency and reducing fragility, and as examples of hydrocolloid mentioned alginates.

The patent application U.S. No. 20050013847, assigned company FMC Corporation, relates to delivery systems, including film of a homogeneous thermally reversible gel in which the gel film contains a film-forming amount of thermally reversible water-soluble alginate, and optionally, at least, the underwater representative choose from a plasticizer, a second film-forming agent, a filler and a pH regulator; and the active substance. The second film-forming agent, as approved, is optional, but all the examples show films containing at least two film-forming agent. Given as an example of a method of obtaining a gel-like film includes heating originaldatabase mixture to elevated temperature to obtain a homogeneous molten composition. The active substance is added either before or after receiving the molten composition, and then the molten composition containing the active substance is cooled and subjected to further processing. Mentioned that to modify the properties of dissolving dosage forms of the film may also contain additional components that can afford to get a solid dosage form capable of medicines immediate-release, release in the intestine or delayed release.

In U.S. patent No. 6709671, assigned company LTS Lohmann Therapie-Systeme AG, describe a single-layer film obtained from mucoadhesive composition, which contains at least one water-soluble polymer; a surfactant, individually or in combination, at IU is e, one representative selected from the group consisting of polysperma and plasticizer, or polisport and a plasticizer; and at least one cosmetic or pharmaceutical ingredient that is intended for application in the oral cavity.

There are many ways of delivery of active pharmaceutical ingredients (drugs) in the body (collectively called compositions), which depend on the type of medication and treatable disease. For example, compositions for oral administration such as tablets, capsules and lozenges; solutions of drugs in vials and pre-dialed syringes for injections; compositions for external use, such as bandages and ointments, and sprays for the nose. Also there are other methods of drug delivery, such as implanted pumps and compositions with delayed release, placed in the body. Select the composition will generally have a significant impact on therapeutic result of application of the drug, its side effects and the ease with which the patient will be able to apply the medicinal substance.

The most widely used dosage form is a tablet that you swallow to release the drug in the intestine. Tablets comprising the of the medicinal product, which mechanically compacted with a few additional elements, which give the tablet its structure and characteristics of delivery. Tablets should be swallowed with liquid, such as water, and some patients, such as children and elderly patients can encounter difficulties when swallowing.

The problem with tablets is used orally, is that many drugs can decompose during the passage through the acidic environment of the stomach. Upon receipt of the drug in the intestine, the drug is absorbed into the bloodstream through the portal vein leading to the liver, where a large proportion of active pharmaceutical ingredients in the metabolism usually becomes inactive chemical compounds under the influence of enzymes that would normally control the presence of foreign substances in food products, that is, there are so-called presystemic metabolism.

The result of these factors lead to a significant delay a positive therapeutic effect, which leads to the risk of side effects in the gastrointestinal tract, strengthen the need for the introduction of much larger quantities of the drug in comparison with what will be required, for example, in a direct injection process is and medicines into a vein.

Despite the fact that injections achieve rapid pharmacological effect and reduce the risk of side effects, injections are usually performed by qualified medical personnel in a medical center or hospital, which thus limits the convenience of this form of injection drugs.

Sprays for the nose can provide a quick start steps, but usually it is limited to local treatment of the respiratory tract. For States in which over long periods of time requires certain maintenance drugs, usually use other forms of compositions, such as long-acting drugs, patches or infusion device.

Summary of invention

The General purpose of the present invention is to provide a film which is adhesive with respect to the wet surface of the body of the mammal and in contact with the wet surface has a rapid dissolution.

Another General object of the invention is to provide a film that is easy to get and which to obtain the above-mentioned advantageous properties does not require the presence of additives, such as surfactants and disintegrators.

Another additional objective invented the I is the provision of a film dosage forms, containing a biologically active substance, which may be therapeutic or non-therapeutic substance, where this film dosage form can be used to deliver biologically active substances to a mammal by applying a film of the dosage form on a damp surface such as a membrane mucous membrane of a mammal.

Another additional objective of the invention is the provision of pharmaceutical film-forming composition, which the patient will be easy and convenient to apply independently, which makes it possible to reduce the dosage of the active ingredient and, thus, reducing the potential side effects and which can create the desired pharmaceutical effect rapid and efficient manner.

Another objective of the present invention is to provide a film-forming pharmaceutical compositions containing one or more active ingredients, allowing you to bypass the emergence of presystemic metabolism of the active ingredient (ingredient).

Another objective of the present invention is to provide a pharmaceutical film-forming composition, enabling rapid onset of pharmacological action of one or more active ingredients.

Another objective of the invention for luchetta in providing pharmaceutical film-forming composition, making possible the introduction of active ingredients that are subject to degradation or destruction in the gastrointestinal tract.

Another additional object of the invention is to provide a pharmaceutical or non-pharmaceutical film-forming compositions which allow the easy introduction of ingredients with systemic and/or local activity, the patient is a mammal.

Still one other object of the invention is to provide a pharmaceutical or non-pharmaceutical film-forming composition, which firmly adheres to the mucous membrane of the oral cavity of the patient mammal to its dissolution, thus reducing the risk of loss, either intentional or unintentional, from the oral cavity of the patient.

Another objective of the invention is to provide a pharmaceutical or non-pharmaceutical film dosage forms containing active ingredients that are prone to fracture at elevated temperatures, such as temperatures, significantly exceeding room temperature.

An additional aim of the invention is the provision of pharmaceutical or non-pharmaceutical film dosage form can contain at least one active ingredient in high content.

Another goal of this izaberete the Oia is the provision of a method of producing a film, which can be used in pharmaceutical or non-pharmaceutical film-forming composition corresponding to the invention.

The present invention is based on the surprising discovery that the use of alginate composition proposed in the present invention, as the sole film-forming agent can be obtained a film which has adhesiveness with respect to the wet surface of the body of the mammal and in contact with the wet surface has the property of rapid dissolution.

It is very useful that the film of the invention is bioadhesives that means its adhesion to wet surfaces, such as mucous membrane or the cornea, preferably within seconds when applying the film on it.

In addition, in contact with a moist surface, such as the mucous membrane, the film of the invention is able to dissolve in less than a few minutes, for example within less than 2 minutes.

Thus, in accordance with one aspect of the invention features a film containing as the film-forming agent salt of alginic acid with a monovalent cation or a mixture of salts of alginic acid, containing at least one salt of alginic acid with a monovalent cation, and a 10%aqueous solution of the film is brazowego agent at a temperature of 20°C is characterized by a viscosity of 100-1000 MPa·s as measured, held at the shear rate of 20 rpm using Brookfield viscometer with spindle No. 2.

In one embodiment of the invention, the film contains at least one biologically active substance.

In accordance with another aspect of the invention features the use of a composition to obtain a film, where the composition contains one or more active ingredients and as a film-forming agent salt of alginic acid with a monovalent cation or a mixture of salts of alginic acid with a monovalent cation, characterized by the fact that a 10%aqueous solution of film-forming agent at a temperature of 20°C is characterized by a viscosity of 100-1000 MPa·S.

Applying a film-forming composition of the invention allows to obtain a film dosage form including a film containing a large amount of one or more active ingredients and possess an exceptionally desirable characteristics mentioned in the present description earlier. Thus, in accordance with another aspect of the invention features a film dosage form containing a biologically active ingredient, which can stick to the wet surface of the body of a mammal and in contact with the wet surface has the properties of fast dissolving.

In accordance with another aspect features a method of obtaining a film by obtaining a composition containing as the film-forming agent salt of alginic acid with a monovalent cation or a mixture of salts of alginic acid, containing at least one salt of alginic acid with a monovalent cation, and 10%aqueous solution of film-forming agent at a temperature of 20°C is characterized by a viscosity of 100-1000 MPa·s as measured, held at the shear rate of 20 rpm using Brookfield viscometer with spindle No. 2, distribution of the composition on a solid surface and ensure drying of the composition on the surface.

In General, once the composition of a salt of alginic acid of the invention will be dissolved, the viscosity of the alginate solution over time will change only very slightly. For example, the viscosity was measured as specified herein previously, within 10 minutes after the dissolution of the alginate.

In one embodiment of the method of the invention in the film-forming composition add at least one biologically active substance.

In accordance with another aspect of the offers is the use of the film of the invention for obtaining a medicinal product.

In accordance with another aspect of the invention provides a method of treating a mammal in need of such treatment, comprising introducing said mammal a pharmaceutical film-forming composition corresponding to the invention.

Other additional goals, aspects and implementations of the invention will become apparent after reading the subsequent description and the appended claims.

Detailed description of the invention

In accordance with one variant of the invention proposes alginate film based on film-forming composition containing alginate composition. Alginate composition used in accordance with the present invention, contains at least one salt of alginic acid with one or more monovalent cations, preferably selected from sodium, potassium and ammonium ions. Most preferably the alginate composition of the invention contains sodium alginate.

Alginate composition of the invention is characterized by a dynamic viscosity equal to 100 to 1000 MPa·s or 200-800 MPa·s, for example, 300 to 700 MPa·s as measured conducted for 10%aqueous solution at 20°C using a Brookfield viscometer LVF (from Brookfield Engineering Laboratories, Inc.) with spindle No. 2 at a speed add the ha 20 rpm

It should be noted that for the purposes of the present invention and in the absence of instructions to the other any interest amount is obtained by calculating the masses of the components. In other words, for example, 100 g of a 10%aqueous solution of alginate containing 10 g of alginate and 90 g of other components, including water.

Alginate composition of the invention preferably is characterized by the average content of guluronate (G) from 50 to 85%, preferably from 60 to 80%, most preferably from 65 to 75% (mass.), the average content of mannuronate (M) from 15 to 50%, preferably from 20 to 40%, most preferably from 25 to 35% (mass.) and an average molecular weight of 30,000 g/mol up to 90,000 g/mol, for example, from 35000 g/mol up to 85000 g/mol, such as from 40000 g/mol to 70000 g/mol, or from 40000 g/mol to 50000 g/mol.

Example alginate compositions intended for use in accordance with the present invention, the drug is Protanal® LFR 5/60 sold in company FMC BioPolymer. Protanal® LFR 5/60 is a low molecular weight (low viscosity) sodium alginate, extracted from the stem Laminaria hyperborea.

As an example of alginate, which can be mixed with alginate with a monovalent cation for modifying the viscosity of the alginate composition may be mentioned Protanal® LF 10/60. This sodium alginate sold by the company FMC BioPolymer, articulating the different percentage G/M 65-75/25-35, viscosity 20-70 according to the measurement to 1%aqueous solution at 20°C and at a shear rate of 20 rpm using Brookfield viscometer with spindle No. 2.

The increase in the average molecular weight of the alginate composition of the polymer results in increased viscosity of the composition. The larger the viscosity, the smaller will be the resulting rate of release systems alginate matrices. The possibility of regulating the viscosity of the alginate composition by mixing any number of alginates, which are characterized by differing viscosities. You must realize that in the case of using the mixture of alginates not all alginates, taken separately, must will be characterized by a viscosity within the specified ranges. However, in order to be suitable when used for the purposes of the invention, the alginate mixture, resulting in the merger of more than one alginate substances should be such, which will be characterized by a viscosity within the above range.

Indeed, in the preferred case, the film-forming alginate composition on the basis of the invention, the result will be to produce a film with suitable d is I use characteristics of dissolution in contact with the wet surface, such as the membrane of the mucosa or the cornea. Characteristics of dissolution of the film have a strong influence on the delivery of any active ingredient included in the film, in the body curable patient. Through the use of bystrorastvorimaya film of the invention is the delivery of a certain amount of the active ingredient into the body curable patient can be provided in a short period of time, that is essentially the time of dissolution of the film, i.e. preferably less 2 minutes. This allows for the active ingredient in the body of the patient to obtain the desired concentration profile in a time-dependent, which makes it possible to obtain high peak concentration at a relatively lower total dose of the active ingredient in comparison with other forms of injection drugs.

In addition, the film-forming composition of the invention can contain any suitable drug use environment, such as one or more fillers or plasticizers. The plasticizer in his presence you can choose, for example, from polyethylene glycol, glycerol and sorbitol. The preferred plasticizer is sorbitol together with a small part of glycerin. Suitable for use number plastify the Torah is for example, from 10 to 85 g or from 30 to 70 g, for example, from 50 to 60 g of plasticizer per 100 g of alginate.

Filler, in his presence, may be, for example, microcrystalline cellulose. Suitable for use the amount of filler may range 0-20%, for example, 5-10% (mass.) of the total pharmaceutical composition. However, you must realize that a very advantageous characteristic of the invention is that, in addition to the alginate composition, other additives, such as fillers and plasticizers, which have an impact on the physical characteristics of the film, no matter what the content is not required, or requires a very low level of maintenance. This characteristic makes it possible inclusion in the film-forming composition of the invention, the active ingredient in high content. The active ingredient, in case of its presence in large numbers, in and of itself may contribute to the beneficial properties of the film, such as suitable for use surface properties.

The mechanical properties of the films of the invention are extremely satisfactory, in particular film is flexible, namely: it allows you to bend and fold without breaking and has very good tensile strength tensile.

Through the use of film-forming composition and on alginate-based, defined herein before, dosage form, corresponding to the invention, can be obtained in the form of a film containing one or more biologically active ingredients.

The terms "biologically active ingredient", "active ingredient", "active agent" and "biologically active substance" in this document are used vzaimozatmeniya way and imply the inclusion of any substance that has a desired biological activity or demonstrate the presence of desirable biological effect when administered to the patient is a mammal in accordance with the invention. Active ingredient/active ingredient may be, for example, a therapeutically active ingredient. There may be a biologically active ingredient, which, however, generally is not considered a pharmaceutical product, such as naturopathic medicine. As an example of non-pharmaceutical active ingredient may be mentioned stimulator or nutraceuticals, in the General case, the latter is defined as a substance that can be considered a food or part of food product and which provides medical care or is beneficial to health, including the prevention and treatment of disease. Other biologically active substances can do is be as therapeutic, and non-therapeutic use.

In accordance with the usage in this document, the term "wet surface" preferably denotes a surface characterized by humidity, preferably similar to the one that is usually moist mucous membrane or the cornea of the patient is a mammal, but also somewhat less wet surface, such as a detectable inside the ear.

Film dosage form corresponding to the invention, preferably has a thickness being from 0.1 to 2 mm, for example, from 0.2 to 1 mm, or from 0.2 to 0.6 mm, for example equal to 0.5 mm.

Standard dosage form can be any suitable for use surface area depending on the concentration of active ingredient in the film and suitable for use input dose. As an example, it can be noted that if necessary, the coating film in the oral cavity may be selected standard dosage form having a surface area of 1 cm2up to 10 cm2, while optionally applying a film on the eye may be preferred smaller surface area, such as from 0.04 cm2up to 1 cm2. Specialist in the relevant field of technology should have an idea about how to adapt the size and shape of the film standard drugs the military forms depending on such parameters, how to load film of the active ingredient (ingredient), the required dosage, the place of introduction into the organism of the patient is a mammal, and the like. In addition, you must realize that standard film dosage form can have any appropriate to use a shape corresponding to the injection of the active ingredient, for example, it may be rectangular, round, oblong, oval and the like.

Film dosage form of the invention may contain one or more active ingredients in a number that goes up to 85% (wt.) of the total dosage form, for example, up to 70% (mass.) or up to 60% (mass), such as greater than 20% (mass), or greater than 30% (mass), for example, more than 40% (mass). However, you must realize that it is also foreseen the possibility of the existence of the film dosage form of the invention, which is characterized by a very low content of active ingredient in the case of the desirability of this for any reason, for example, if necessary, delivery of the active ingredient at a very low dosage. Thus, in the case of prefer this version of the film dosage form can be characterized by a very low content of active ingredient, for example, comprising only 0,000001% (mass). The act of the main ingredients you can choose from among all active substances, known at the present time, and in the future from those that are currently unknown.

Thus, in accordance with one aspect of the invention provides a standard dosage form in film form having a selected surface area and thickness, and containing the active ingredient at the desired concentration.

The active ingredient, leaving soluble film dosage form of the invention, diffundere through interfacial surface will reach the underlying tissues and the bloodstream, which makes it possible not only local, but also systemic introduction of simultaneous essentially preventing the occurrence presystemic metabolism and digestion in the gastrointestinal tract.

In addition to the active ingredient (or ingredients) film dosage form of the invention may contain any physiologically (e.g., non-toxic when the level of addition) and/or pharmacologically acceptable additive, such as one or more flavor additives (additives, correcting the taste of the drug) and/or coloring additives. Examples of flavoring additives are sorbitol, peppermint, Supplement with orange, Supplement with a taste of cherry and cranberry extract. Examples of coloring agents are titanium dioxide and green or red food coloring.

On the dissolution rate of the film is influenced by the pH value of the film. In the General case in contact with the wet surface of the optimum dissolution rate shows a film characterized by a pH value of from 6 to 9, for example, from 8 to 9.

In addition, the time of dissolution of the film corresponding to the invention, in proportion to the film thickness and the concentration of all particles in the film.

Specialist in the relevant field of technology depending on the time of dissolution, desirable for this application will be able to choose to use the thickness of the film simply as a result of obtaining films, characterized by a certain range of different thicknesses, and for these films test at the time of dissolution.

The active substance can be dissolved in the film forming solution and/or may not dissolve and be present in it, for example, forming an emulsion or suspension. For example, the active substance may be present in the form of a suspension of particles. In this case, as mentioned herein before, the time of dissolution will be somewhat greater due to the presence in the film of dispersed material.

Specialist in the relevant field of technology will be able to determine the desired thickness and surface area of standard dosage forms is depending on the content of the dispersed material and the desired time of dissolution, if necessary, by conducting simple tests.

In one embodiment of the invention features the film of the invention with printed text on it material or printed images, such as brand name, trade name, indication dosage, symbol and the like.

In one embodiment of the invention film dosage form is a pharmaceutical film-forming composition. In accordance with the usage in this document pharmaceutical film-forming composition" or "pharmaceutical film dosage form" and similar terms include the relevant invention compositions in the form of a film containing any of biologically active ingredients, as defined herein before, namely: any substance having the desired biological activity or demonstrate the presence of desirable biological effect when administered to the patient is a mammal, and where the substance is suitable for use in the treatment.

The present invention also relates to the use of pharmaceutical film-forming composition of the invention for treating, in particular for nicotine therapy and analgesic therapy.

In light of the description invented who I will become obvious very advantageous properties of pharmaceutical dosage forms of the invention for treatment of diseases, mentioned herein previously, as well as in the treatment of several other diseases that are easily imagine a specialist in the relevant field of technology.

It should be noted that the pharmaceutical film-forming composition corresponding to the invention can be administered orally, pernaselli, rectal, intrawaginalno surface, through wounds, ears and eyes of the patient. With the introduction of through the eye of a patient a pharmaceutical film-forming composition preferably is applied at the bottom of the eye cornea.

In the case of using film as a means of introducing active ingredient in the eye when she obvious advantages of a substitute, for example, eye drops or ointment. Indeed, eye drops may be difficult to enter, providing a uniform and accurate dosing. In addition, ointments or other semi-liquid dosage forms are often offered in packages such as tubes or bottles, which is characterized by a relatively short shelf life when stored after opening due to, for example, bacterial spoilage, so in many cases, the packaging must be disposed of even Neporozhniy. On the other hand, the dosage form of the invention is easy to use, providing accurate and controlled dosage, and you shall offer in packages with individual dosage, for example, in blister packs, in airtight envelopes or any other appropriate use, that will be obvious to a person skilled in the relevant field of technology.

The film of the invention can be used for delivery into the body of a wide range of substances and for a range of different purposes.

Since the film properties are adhesion and dissolution, passing quickly and completely in contact with a damp cloth, with the release, therefore, the substance in solution, the most obvious area of application will be the local shipping agents. Examples of local diseases are microbial infection in the upper respiratory tract and the genital tract, local inflammation in the muscles or joints, skin diseases such as psoriasis, wound healing or local pain relief.

However, the compounds released from the film, can also be absorbed and the surrounding tissue and additionally distributed in the rest of the body through the bloodstream. This concept is fast and efficient delivery into the bloodstream when the scarcity of side effects has been demonstrated for a variety of substances in a rectal substances. However, the use of rectal dosage forms are not widely distributed, possibly due to discomfort introduced the I and due to the existing tradition of using tablets for oral delivery.

The film can also be used for delivery of certain substances, which are slowly absorbed by the mucous membrane in the body, for example through the release of substances in the mouth for swallowing the purpose slow delivery in the digestive tract.

To illustrate the possibility of using shipping on film the basis for various diseases the following are a few examples.

The film can be used to treat diseases in the stomach, where the substances are delivered with the serum, and not from the stomach or as a result of absorption from the intestine and after passing through the liver. Ordinary diseases of the stomach, to be treated with the use of film delivery would be the symptoms associated with acidity, such as gastritis, ulcers, reflux or infection due to Helicobacter pylori. The types of substances that can be used include antimicrobial agents, receptor antagonists histamine-2 and proton pump inhibitor.

Because the film is able to deliver a substance without the need of ingesting water, as in the case of compressed tablets, the invention is very well suited for use with any medicinal substance, when disease patients makes them unable to swallow and/or save the medicinal substance in the body. obychnyj diseases include stroke, migraine, acute heart disease and patients with complicated cross in the digestive canal, sea sickness, nausea and other situations where water is not available or cannot be swallowed. Can be used many different types of substances, including substances that affect the Central nervous system, such as receptor antagonists serotonin tablets from sea-sickness, which does not require the appointment of a doctor, and various anti-inflammatory agents.

Another disease in which can be used film technology described in this application, is obesity. Indeed, patients suffering from obesity can be treated by surgery (removing parts of their stomach or intestines) in order to reduce the absorption of substances from the digestive tract. For delivery of medicinal substance in a film-like drugs, which exert their effect on the nervous system, history of gastrointestinal surgery, the patient is not affected. An example of the type of substance, the delivery of which can be ensured when using a film dosage forms, corresponding to the invention, is sibutramine.

One interesting group of substances includes peptides and proteins. Substances of this group cannot be easily ingested through the mouth to hit peshavaria the hydrated tract, because they will be digested under the influence of enzymes (proteases and peptidases), present in the stomach and intestines. However, peptides and specific protein can be absorbed after the release of the film through the mucous tissue, as opposed to the digestive tract mouth activity of peptidases small.

Because the film melts in your mouth, does not contain added sugars and should not proglatavetsa, she will be very well suitable for use in the oral treatment of diabetes. Examples suitable for use classes of substances are sulfonamide, biguanidine derivatives.

Patients are very well suited for film delivery substances, are the elderly and children. Both these groups of patients usually take the medicinal substance in a quantity greater than the average value, and are often unable to properly treat yourself. Older people often take drugs to sleep and due to diseases commonly associated with aging, such as dementia, Parkinson's disease, Alzheimer's disease, anxiety, depression, and lack of vitamins, nutrients and coenzymes. Classes of substances intended for this group of patients include drugs acting on TSN is, antimicrobial agents and low-molecular coenzymes.

In one embodiment of the invention features a method of obtaining a film, as film-forming agent containing a salt of alginic acid with a monovalent cation or a mixture of salts of alginic acid, containing at least one salt of alginic acid with a monovalent cation, and 10%aqueous solution of film-forming agent at a temperature of 20°C is characterized by a viscosity of 100-1000 MPa·s as measured, held at the shear rate of 20 rpm using Brookfield viscometer with spindle No. 2, as a result of obtaining the solution mentioned film-forming agent, the distribution of the solution on a solid surface and ensure drying of the solution on the surface.

For the distribution of a solution or composition on a solid surface solution or composition can simply be poured onto the surface and/or evenly over the surface to spread, for example, when using blades for glazing or similar equipment.

Film dosage form of the present invention and containing at least one active ingredient, can be obtained, for example, as a result of dissolution of the active ingredient (ingredients) in the appropriate use of the solvent; optionally regulate the Finance pH of a solution of the active ingredient (ingredients) increase to approximately neutral or alkaline pH values; optional add plasticizer and microcrystalline cellulose, or any other suitable for use physiologically and/or pharmaceutically acceptable additives; adding the composition of the alginate salt, 10%aqueous solution which is at a temperature of 20°C is characterized by a viscosity of 100-1000 MPa·s as measured, held at the shear rate of 20 rpm using Brookfield viscometer with spindle No. 2; and processing solution thereby to obtain a film.

The solvent suitable for use in the dissolution of the active ingredient (ingredient)may, for example, be water or alcohol, for example methanol, ethanol, n-propanol, isopropanol or tert-butanol. Depending on the solubility and stability of the active ingredient (ingredients) and the pH of its solution can be adjusted, leading to 6-10, for example, 8-10 or 8-9. This purpose can be used any pH controller, which is compatible with the intended use case and with other ingredients of the composition, for example, suitable for use bufferarray system, an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, sodium bicarbonate, and the like.

In one embodiment of the method for obtaining a film dosage forms, corresponding to the invention and sod rzasa, at least one active ingredient, the active ingredient (the ingredients) and alginate (alginates) simply dissolved together in a suitable for use with solvent or mixture of solvents, and the solution is processed to obtain a film and provide drying.

In yet another variant implementation of the active ingredient to the alginate solution was added to obtain an emulsion or suspension of the active ingredient in the alginate solution.

In one additional embodiment, the implementation of the film-forming composition of the invention may contain both dissolved and undissolved active ingredients. As an example, we can say that the film-forming composition of the invention may contain a combination of active ingredient dissolved in alginate solution, and the active ingredient suspended in the solution.

After distribution of the film-forming composition, optionally containing any active ingredient, on a hard surface composition on the surface allow to dry. Dry film dosage form corresponding to the invention preferably contains a homogeneous dispersion solubilizing or suspensions of the active ingredients (ingredient). This contributes to the very best delivery Akti is the main ingredient over a damp surface, to which the film is stuck. Thus, when bonding to wet surfaces of the body, such as mucous membrane or the cornea, the film will quickly dissolve, and when dissolved film at the interface between the film and the wet surface will quickly establish the concentration gradient of the active ingredient, ensuring the occurrence of diffusion of the active ingredient through this interfacial surface. Thus, the active ingredient will be absorbed, leaving the film as the dissolution of the latter.

In one embodiment, the implementation of active ingredient applied to the film of the invention after receiving the film, where the film may contain or may not contain another active ingredient. Thus, the active ingredient can be applied, for example, in the form of a spray spray on dry or wet film. The active ingredient in the film can also be applied in powder form. Furthermore, the same way you can apply and flavoring.

Obtaining a dry film may include the stage of applying the solution on a substrate and drying the wet film. The drying is preferably performed at room temperature, for example, 17-25°C in normal atmosphere over a period of time ranging, for example, at 10 o'clock. Drying can also take the ü in a dry atmosphere or under pressure, less than atmospheric. If nepodvijnosti active ingredient (ingredient) thermal decomposition drying can be accelerated by increasing the temperature, such as 35°C.

After that, the thus obtained film can be given appropriate size and shape so as a result of cutting down or cutting out.

Optional to receive the film from the solution may remove any air bubbles, for example, as a result of moderate heating or using a vacuum.

Film dosage form corresponding to the present invention, achieves, for example, the following advantages:

- xGex is reproducible;

- no plasticizer or filler;

film can be folded and winded in a roll without any risk of adhesion, cracking or breaking;

film has very good surface tensile strength (at break) tensile;

in the film you can include a relatively large amount of the active ingredient(ingredient);

for the method of obtaining does not require any heat treatment;

active ingredient (ingredients) quickly become participants in the metabolism without any destruction in the stomach, what is who doing what you can use low doses and the emergence of a less pronounced negative side effects, thus, the diaper can be used regardless of the meal;

- when used in the oral cavity the risk of vyplevyvaniya the film is low, because the film sticks to the mucous membrane in the oral cavity;

after oral or transbukkalno the introduction of any residue in the oral cavity remains;

the tape is easy to print the text or number;

film you can rank in the millimeter scale and cut to obtain the desired length and shape (e.g. round, oval, square, rectangular and the like);

- the dose easily can be individually adapted for each patient;

- there is no need for a coating of sugar or any other coating that makes production simpler and less costly; and

film does not contain lactose (which may cause allergic reactions) and gelatin.

The following case studies should be seen merely as illustrations, and not any restrictions the rest of the description. It seems that without further development on the basis of the description in this document specialist in the relevant field of technology will be able to use the present invention in its fullest extent. All publications cited in the present who eat the document, in their entirety by reference are included in this document.

The phrase "contains/contains" means

"includes/include the following, but is not limited to only this." Thus, can be included and other ingredients.

Information confirming the possibility of carrying out the invention

EXAMPLE 1

Film dosage form, corresponding to the invention, obtained using the following ingredients:

12 g of sodium alginate, corresponding to the drug Protanal® LFR 5/60, characterized by a viscosity of 300 to 700 MPa·s (10%aqueous solution and at a temperature of 20°C;

80 grams of distilled water;

3 g sorbitol;

2 g of glycerol;

2 g of cranberry extract;

- 1 drop green food coloring;

- sodium hydroxide;

5 g of paracetamol as active pharmaceutical ingredient).

Active pharmaceutical ingredient mixed with water and held the regulation of pH, bringing its value to about 8 to 8.5 with aqueous NaOH. Added plasticizers, flavoring and coloring additives. Then to the above aqueous solution at room temperature in small portions was added Protanal® LFR 5/60 and stirring is carried out until, has not yet received the homogeneous solution.

The solution was applied on ispolzuemuyu as substrate glass plate, with a surface area of 900 cm2using spatulas for application intended for the coating of the wet film. The thickness drove up to 0.8-1 mm. Film was dried for about 12 hours at room temperature under atmospheric pressure, which led to an approximately 30%loss of film thickness.

The surface area of the obtained film was 900 cm2. These films can be obtained by standard pharmaceutical form suitable for use by size. As an example, we can say that standard film dosage form having a surface area of 6 cm2contains approximately 33 mg of paracetamol.

When placed in the oral cavity in the sky film standard dosage form almost immediately stuck to it and was dissolved for 1.5 minutes without saving any residue.

EXAMPLE 2

Acting in General as in example 1, the film dosage form, corresponding to the invention, obtained using the following ingredients:

12 g of sodium alginate, corresponding to the drug Protanal® LFR 5/60, characterized by a viscosity of 300 to 700 MPa·s (10%aqueous solution and at a temperature of 20°C;

80 grams of distilled water;

3 g sorbitol;

2 g of glycerol;

2 g of cranberry extract;

- 1 drop see the Yong food coloring;

- sodium hydroxide;

12 g of paracetamol as active pharmaceutical ingredient). Film standard dosage form having a surface area of 6 cm2contains approximately 80 mg of paracetamol.

EXAMPLE 3

Film dosage form, corresponding to the invention, obtained using the following ingredients:

12 g of sodium alginate, corresponding to the drug Protanal® LFR 5/60, characterized by a viscosity of 300 to 700 MPa·s (10%aqueous solution and at a temperature of 20°C;

80 grams of distilled water;

3 g sorbitol;

2 g of glycerol;

2 g of cranberry extract;

- 1 drop of green food coloring;

6 g of ibuprofen as an active pharmaceutical ingredient)dissolved in ethanol.

Ibuprofen was dissolved in a small volume of ethanol, and the solution was stirred with water, which in result led to the deposition of crystals of ibuprofen. Added plasticizers, flavoring and coloring additives. After that, at room temperature in small portions was added Protanal® LFR 5/60 and stirring is carried out until, has not yet received a homogenous milky-white suspension of crystals of ibuprofen.

The suspension was applied on the substrate glass plate having a surface area of 900 cm2using the blades on the I buttering, designed for applying a wet film. The thickness regulating drove up to 0.8-1 mm. Film was dried for about 12 hours at room temperature under atmospheric pressure, which led to an approximately 30%loss of film thickness.

The surface area of the obtained film was 900 cm2. These films can be obtained by standard pharmaceutical form suitable for use by size. As an example, we can say that standard film dosage form having a surface area of 6 cm2contains approximately 40 mg of ibuprofen.

When placed in the oral cavity in the sky film standard dosage form almost immediately stuck to it and was dissolved for 1.5 minutes without saving any residue.

EXAMPLE 4

Acting in General as in example 1, but using to regulate the pH of the film-forming composition aqueous bicarbonate buffer film dosage form, corresponding to the invention, obtained using the following ingredients:

12 g of sodium alginate, corresponding to the drug Protanal® LFR 5/60, characterized by a viscosity of 300 to 700 MPa·s (10%aqueous solution and at a temperature of 20°C;

- 80 g-based buffer aqueous solution of sodium bicarbonate at pH 8-8,5;

3 g is the orbit;

2 g of glycerol;

2 g of cranberry extract;

- 1 drop of green food coloring;

- sodium bicarbonate;

5 g of acetylsalicylic acid (active pharmaceutical ingredient).

Film standard dosage form having a surface area of 6 cm2contains approximately 33 mg of acetylsalicylic acid.

EXAMPLE 5

Acting in General as in example 1, the film dosage form, corresponding to the invention, obtained using the following ingredients:

12 g of sodium alginate, corresponding to the drug Protanal® LFR 5/60, characterized by a viscosity of 300 to 700 MPa·s (10%aqueous solution and at a temperature of 20°C;

80 grams of distilled water;

2 g of cranberry extract;

- 1 drop of green food coloring;

- sodium hydroxide;

12 g of paracetamol as active pharmaceutical ingredient). Film standard dosage form having a surface area of 6 cm2contains approximately 80 mg of paracetamol.

The film obtained without the use of plasticizer, is more fragile, but in contact with the wet surface dissolves very quickly.

EXAMPLE 6

Film dosage form, corresponding to the invention, obtained using the following ingredients:

1 g of sodium alginate, appropriate drug Protanal® LFR 5/60, characterized by a viscosity of 300 to 700 MPa·s (10%aqueous solution and at a temperature of 20°C;

- 80 g-based buffer aqueous solution of potassium phosphate at pH 8.5, 0.1 mol/l;

2 g of glycerol;

3 g sorbitol;

- 5.5 g of nicotine bitartrate (as a biologically active ingredient). The active ingredient was mixed with the buffer. Added glycerin and sorbitol.

Then, to the thus obtained aqueous solution at room temperature in small portions was added Protanal® LFR 5/60 and stirring is carried out until, has not yet received the homogeneous solution.

The solution was applied on the substrate glass plate having a surface area of 1200 cm2using spatulas for application intended for the coating of the wet film. The thickness of the wet film, adjusting, brought up to approximately 0.3 mm, the Film was dried for about 12 hours at room temperature under atmospheric pressure, which led to an approximately 30%loss of film thickness.

These films are characterized by a dry film thickness of approximately 0.2 mm, cut out the standard dosage form having a surface area of 3 cm2.

When placed in the oral cavity in the sky film standard dosage form practice is automatic immediately stuck to it and was dissolved for 1.5 minutes without saving any residue.

EXAMPLE 7

When using the same film-forming composition and method as in example 6, was obtained film containing nicotine bitartrate and characterized by the thickness of the wet film of approximately 0.15 mm, and a dry film thickness equal to approximately 0.1 mm Standard dosage form having a surface area of 3 cm2when placed in the oral cavity was dissolved in 45 seconds without saving any residue.

EXAMPLE 8

Acting in General as in example 1, the film dosage form, corresponding to the invention, obtained using the following ingredients:

to 11 g of sodium alginate, corresponding to the drug Protanal® LFR 5/60, characterized by a viscosity of 300 to 700 MPa·s (10%aqueous solution and at a temperature of 20°C;

80 grams of distilled water;

3 g sorbitol;

2 g of glycerol;

6 g of paracetamol as active pharmaceutical ingredient).

Received and subjected to testing at the time of dissolution in contact with the wet surface of the palate in the oral cavity film, characterized by different thickness of dry films. The results are presented in table 1, herein below.

Table 1
The time of dissolution depending on the dry film thickness for films of the invention
Approximate dry film thickness (mm)The time of dissolution (seconds)
<0.05 mm1-2
0,05-0,1 mm5-8
0.1-0.15 mm10-12
0,15-0,3Approximately 20

The same film was also obtained by adding flavoring oil of peppermint. Flavoring effectively masked the taste of paracetamol without providing significant effect at the time of dissolution of the film.

In the General case, delivery of the active ingredient using film dosage forms, corresponding to the invention, surprisingly, is more effective in comparison with, for example, pharmaceutical forms for oral administration. As an example, we can say that standard film dosage form containing the active ingredient and is shown as an example in this document earlier, demonstrates the presence of the desired therapeutic effect when conducting delivery with its help, for example, for prologo patient person and when the content of an active ingredient in a quantity relevant only share, which is usually administered by mouth in order to achieve the same level of therapeutic effect, such as pain.

EXAMPLE 9

The film obtained using the alginate, which is characterized by a viscosity corresponding to the invention, were compared with films obtained from the use of alginates, not relevant to the invention.

Used the following ingredients:

to 11 g of alginate a, b or C (as defined in table 1, below);

3 g of glycerin;

4 grams of sorbitol;

- 80 g of distilled water.

Got an aqueous solution of glycerin and sorbitol, and with careful stirring by means of rotating blades in the lower part of stirred tank was added to the alginate. The solution was stirred to homogeneity while adding as necessary additional quantity of water.

The solution was applied on the substrate glass plate having a surface area of 900 cm2using spatulas for application intended for the coating of the wet film. The film thickness by adjusting drove up to 1 mm. Film was dried for about 12 hours at room temperature under atmospheric pressure. The characteristics of the films obtained using alginate And, In The S, respectively, are presented in table 2.

Table 2
AlginateCommercial nameViscosity∗Film characteristicsThe dry film thickness(mm)The time of dissolution (min)
And (according to invention)Protanal® LFR 5/60<10∗∗Good wettability, adhesiveness with respect to the membrane of the mucosa in the oral cavity~0,3<2
In (mismatch invention)Protanal® LF120 M20-70∗∗∗Poor wettability, the lack of adhesiveness with respect to the membrane of the mucosa in the oral cavity~0,318-21
With (mismatch invention)Protanal® LF200 M70-150∗∗∗Poor wettability, the lack of adhesiveness to otnosheniy to the membrane of the mucosa in the oral cavity ~0,3>20
∗ The dimension for a 1%-aqueous solution at a shear rate of 20 rpm using Brookfield viscometer with spindle No. 2.
∗∗ Accordance viscosity 300-700 MPa·s (10%aqueous solution.
∗∗∗ Accordance viscosity greater than 1000 MPa·s (10%aqueous solution.

EXAMPLE 10

Five compounds for various therapeutic applications and different chemical nature chose to study whether to include them in the film dosage form while maintaining the properties of the delivery (the structural integrity of the film, strong adhesion to the mucous membranes, rapid dissolution in wet conditions, the release of substances when dissolved).

Agent 1: paracetamol (N-acetyl-p-aminophenol or 4'-hydroxyacetanilide)

pKa of 9.5 Mw 151,2

Only slight solubility in water

Agent 2: acetylsalicylic acid; 2-acetoxybenzoic acid

pKa3,5,Mw 180,16

1 g/100 g of water

Agent 3: ibuprofen; n-isobutylketone acid

pKa of 4.8 Mw 206,29

Negligible solubility in water

Substance 4: nicotine; (S)-3-(1-methyl-2-pyrrolidinyl)pyridine

pKa8,5,Mw 162,23

The liquid, with elevena water

Substance 5: lidocaine; diethylaminoacetate-2,6-xylidide

pKa of 7.9, Mw 234,34

Salt of hydrochloric acid dissolved in water

As you can see on chemical formulas, these compounds vary in size, value, pKa, solubility in water, the type of ring systems, availability of basic (amine groups) and acidic (carboxyl) groups (all substances demonstrated fully protonated) and other characteristics.

Paracetamol, nicotine and lidocaine are characterized by high values of pKa of 7.9 to 9.5. Ibuprofen and acetylsalicylic acid are characterized by low values of pKa of 3.5 to 4.8.

PKa value demonstrate that the first three substances are basic, while the latter two compounds are acidic. Paracetamol and ibuprofen, as reported, are characterized by only a slight solubility in water, and basic and acidic substances must be in environments with low or high pH value.

Despite considerable variability in the physical properties given in the different solubility characteristics of these substances, they can all be successfully used for composing film dosage forms, corresponding to the invention, storing each positive properties,which indicates the suitability of the film dosage forms of the invention, regardless of the pKa value of the active substance, included in them. Thus, in General, substances that are characterized by values of pKa from about 1 to 14, such as from 2 to 12 or 3 to 10, for example, from 3.5 to 9.5, can be used for composing using film technology inventions.

1. Bioadhesive film containing as the film-forming agent salt of alginic acid with a monovalent cation or a mixture of salts of alginic acid, comprising at least one salt of alginic acid with a monovalent cation, and film-forming agent contains an average of 50-85% (wt./wt.) guluronate and 15-50% (wt./wt.) mannuronate, has an average molecular weight of from 30000 to 90000 g/mol, and its 10%aqueous solution at 20°C has a viscosity of 100-1000 MPa·s, measured using Brookfield viscometer with spindle No. 2 at the shear rate of 20 rpm

2. The film according to claim 1 in which the monovalent cation selected from PA+To+and NH4+.

3. The film according to claim 1, in which the salt of alginic acid with a monovalent cation contains from 25 to 35% (wt./wt.) beta-D-mannuronate.

4. The film according to claim 1, in which the salt of alginic acid with a monovalent cation contains from 65 to 75% (wt./wt.) alpha-D-guluronate.

5. The film according to claim 1, containing a plasticizer or a filler.

6. The film according to claim 1, having a thickness of from 0.1 up to 2 mm.

7. The film according to claim 1, which is in contact with the wet surface is dissolved within less than 2 minutes

8. Dosage form containing film according to any one of claims 1 to 7, and biologically and/or therapeutically active substance in a concentration of from 0.000001% to 85% (wt./wt.) of the total weight of the composition.

9. Dosage form of claim 8, in which the concentration of the active substance is from 30 to 80% (wt./wt.) of the total weight of the composition.

10. A method of manufacturing bioadhesive film by obtaining a composition containing as the film-forming agent salt of alginic acid with a monovalent cation or a mixture of salts of alginic acid, comprising at least one salt of alginic acid with a monovalent cation, and film-forming agent contains an average of 50-85% (wt./wt.) guluronate and 15-50% (wt./wt.) mannuronate, has an average molecular weight of from 30000 to 90000 g/mol, and its 10%aqueous solution at 20°C has a viscosity of 100-1000 MPa·s, measured using Brookfield viscometer with spindle No. 2 at the shear rate of 20 rpm; distribution EOI composition on a solid surface and ensure drying of the specified composition on the surface.

11. The method according to claim 10, in which monovalent cation selected from PA+, K+and NH4+.

12. The method according to claim 10, in which the salt of alginic acid which you monovalent cation contains from 25 to 35% (wt./wt.) beta-D-mannuronate.

13. The method according to claim 10, in which the salt of alginic acid with a monovalent cation contains from 65 to 75% (wt./wt.) alpha-D-guluronate.

14. The method according to claim 10, in which the composition comprises a plasticizer or a filler.

15. The method according to claim 10, in which the composition comprises a biologically and/or therapeutically active substance in a concentration of from 0.000001% to 85% (wt./wt.) of the total weight of the composition.

16. The method according to item 15, in which the specified concentration of the active substance is from 30 to 80% (wt./wt.) of the total weight of the composition.

17. The method according to item 15 or 16, including the production of dosage forms with ed.

18. The method of therapeutic effects on the body of a mammal, comprising an introduction to the specified mammal, the dosage form according to any one of p or 9.



 

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FIELD: medicine, pharmaceutics.

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25 cl, 3 tbl, 7 ex

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35 cl, 1 dwg, 8 ex

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2 ex

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SUBSTANCE: invention relates to azabenzothiophenyl compounds of formula I

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11 cl, 12 ex

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3 tbl

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2 tbl

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15 cl, 8 tbl, 22 ex

FIELD: chemistry.

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10 cl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly using an aqueous extract of tobacco leaves for preparing an agent for treating tobacco dependence. Using an aqueous solution of the aqueous extract of tobacco leaves or a lyophilizate of the aqueous extract of tobacco leaves in sterile water for preparing the agent in the form of injections for treating tobacco dependence wherein said solution have the certain content of a dry substance. A kit for treating tobacco dependence comprising a syringe, a sterile water bottle and the lyophilizate of the aqueous extract of tobacco leaves.

EFFECT: aqueous extract of tobacco leaves and kit are effective for treating tobacco dependence.

8 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention related to chemical-pharmaceutical and cosmetic industry, and deals with lamellar form of delivery, dissolving or decomposing in water medium, for release of, at least, one medicinal or cosmetically acting substance into hole or cavity in body, including polymer matrix in form of hardened foam with spaces or cavities, as well as, at least, one medicinal or cosmetic active substance, characterised by the fact, that matrix polymer is represented by grafted copolymer of polyvinyl alcohol and polyethylene glycol, which consists on 75% from polyvinyl alcohol and on 25% from polyethylene glycol. Also described are methods of said medicinal forms manufacturing.

EFFECT: elaboration of lamellar form of medication delivery.

6 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a pharmaceutical oral formulation for nicotine or its derivative delivery to a subject by means of oral mucosa absorption, containing nicotine where the above-stated oral formulation is buffered with at least tromethanole.

EFFECT: what is presented is the method of oral nicotine delivery for reduction of craving to smoke or use tobacco, and also the methods for preparing the oral formulation, applying the oral formulation for nicotine uptake in the subject's mouth and applying nicotine for making the oral formulation for treating tobacco or nicotine dependence.

57 cl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and chemical-pharmaceutical industry, particularly a water-soluble film which disintegrates in a mouth for active agent delivery. The disintegrating film contains at least one water-soluble polymer and one active agent. The present invention also offers methods for making the disintegrating oral film and applying the disintegrating film for oral of an effective dose of the active agent for absorption through an oral mucosa. According to certain versions, the disintegrating film contains at least one water-soluble polymer and one active nicotine.

EFFECT: making the water-soluble film which disintegrates in the mouth for the active agent delivery.

7 cl, 10 ex, 2 dwg

FIELD: medicine.

SUBSTANCE: invention refers to a chewing gum containing (a) an interior which contains a first flavouring agent which is mint; (b) at least one active pharmaceutical ingredient (API) in the interior and/or in one or more coatings; (c) at least one internal polymer film coating of the interior containing at least one second flavouring agent selected from a group consisting of citrus, cinnamon, berries or mixed fruit; and (d) at least one external solid coating of the latter internal polymer film coating. The preferential API is nicotine.

EFFECT: invention provides a prolonged effect of the flavouring agents, predominance of the flavouring agents in the coating in the interior, avoidance of problems of chemical or pharmaceutical incompatibility of the medicine in the interior and the flavouring agents in the coatings, and higher control of medicine release.

19 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and its application for prevention and treatment of abuse with psychoactive substances and dependence on psychoactive substances, which contains compound of formula (R)-2-{3-[1-(acenaphthene-1-yl)pyperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl} -N-methyl acetamide or its pharmaceutically acceptable salt as active ingredient.

EFFECT: compound, which is agonist and has highly selective affinity to ORL-1 receptors, possesses effects of reduction of intensity of alcohol abstinence symptoms and suppression of surplus intake of alcohol and other psychoactive substances.

18 cl, 1 tbl, 8 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to certain N-alkylcarbonylaminoacid esters of formula where R1 independently represents hydrogen or methyl; R2 independently represents alkyl C1-C2 and R3 independently represents alkyl C1-C4, offered in the present invention, as well as to compositions and therapies with using the declared compounds.

EFFECT: preparing new compounds which effect on sensory processes.

27 cl, 7 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, namely to development of a product reducing craving for smoking. The product represents a tablet (or sweet, or fruit pastille), containing powdered seeds of Hindu lotus (Nelumbo nucifera Gaertn), a dry extract of grape stems, sorbite (isomalt), aromatiser "Prunes", aromatiser "Hazelnut", sweetener aspartame, calcium stearate and aerosil.

EFFECT: product facilitates getting out of tobacco smoking, eliminates the accumulated hazardous substances from the body, exhibits an immediate positive effect, including in heavy smokers, with no severe distressful getting out of the habit and excessive strength of will efforts.

4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to dosage forms containing an active amount of pharmacologically acceptable Buproprion salt - Bupropion Hydrobromide, as well as to the administration of such dosage forms in treating one or more conditions of patients wherein the administration of Bupropion or its pharmacologically acceptable salt is allowed.

EFFECT: Bupropion Hydrobromide dosage forms exhibit with higher stability in comparison with the dosage forms containing Bupropion Hydrochloride that is proven by smaller reduction of activity of the compositions when stored for 3 or 6 months minimum under the forced conditions at 40°C and relative humidity 75%.

81 cl, 69 dwg, 73 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula: ,

where R1 is selected from a group consisting of cycloalkyl which is unsubstituted or substituted with hydroxy or lower alkoxy, lower hydroxylalkyl, lower hydroxyhalogenalkyl, -CH2-CR9R10-cycloalkyl; R9 is hydrogen or lower alkyl; R10 is hydrogen, hydroxy or lower alkoxy; R2 is hydrogen; X is O or NR14; R14 is hydrogen or lower alkyl; R3 is selected from a group consisting of lower alkyl, cycloalkyl, lower cycloalkylalkyl, lower alkoxyalkyl, lower halogenalkyl, lower carbamoylalkyl, lower phenylalkyl, lower heterocyclylalkyl, where the heterocyclyl is a saturated 4- or 5-member ring containing one or two oxygen atoms, lower heteroarylalkyl, where the heteroaryl group is unsubstituted or mono- or disubstituted with a halogen, and phenyl which is unsubstituted or mono- or disubstituted with a halogen; or R3 and R14 together with a nitrogen atom to which they are bonded form an N-heterocyclic ring selected from pyrrolidinyl, piperidinyl or azepanyl; R4 and R8 independently denote hydrogen or halogen; R5 and R7 are independently selected from a group consisting of hydrogen, halogen, lower halogenalkyl, lower halogen, alkoxy and cyano; R6 is selected from a group consisting of hydrogen, halogen, lower halogenalkyl, lower halogen alkoxy and cyano; and pharmaceutically acceptable salts thereof, as well as to a pharmaceutical composition based on said compounds, which has CB1 modulating activity.

EFFECT: novel compounds which can be used to treat and prevent diseases associated with modulation of CB1 receptors, such as obesity, are obtained and described.

23 cl, 153 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely an adhesive preparation for percutaneous introduction of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctate[b]pyridine (compound A). The preparation contains an adhesive layer formed on one base surface wherein the adhesive layer contains (1) the compound A or its physiologically acceptable salt formed by salt addition, and (2) an acryl adhesive, or (1) the compound A or its physiologically acceptable salt formed by salt addition, (2) the acryl adhesive and (3) a permeability enhancing agent.

EFFECT: preparation inhibits metabolite generation and continuously maintains the blood drug concentration.

19 cl, 7 tbl, 1 dwg, 63 ex

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