Troventol-based composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to aerosol composition, suitable for application for treatment of bronchospasms and associated with them disorders, which contains therapeutically efficient amount of troventol, microground together with propellant and one or more pharmaceutically acceptable carrier. Composition preferably contains 40-640 mcg of troventol and carrier can be selected from surface-active substance, co-solvent, antioxidant and/or filling agent.

EFFECT: invention also relates to dosing inhalator which contains aerosol composition for treatment of bronchospasms and associated with them disorders.

22 cl, 6 tbl, 2 ex

 

The technical field

The invention relates to pharmaceutical compositions containing a therapeutically effective amount of administered by inhalation bronchodilatory agent, possibly in combination with one or more therapeutic agents for the treatment of bronchospasm and related disorders.

Background of invention and prior art

Asthma is described as a chronic disease that involves inflammation of the pulmonary tract and bronchial hypersensitivity, which lead to the clinical manifestation of obstruction of the lower Airways, which is usually irreversible. Pathophysiology of asthma or related disorders includes bronchostenosis arising due to spasm of bronchial smooth muscle and airway inflammation and edema of the mucosa. The treatment of asthma and other related disorders, as it is known, is carried out using β-2 agonists, also known as agonists of β-2 adrenergic receptors. Such agonists β-2 adrenergic receptors, are known to have bronchodilatators effect on patients, resulting in reduced symptoms of dyspnea. More specifically, as shown, agonists of β-2 adrenergic receptors increase the conductivity of the potassium channels to the cells of the muscles of the respiratory tract, causing hyperpolarization and relaxation of the membrane. β-2 adrenergic ptory short steps, such as salbutamol and terbutaline, are recommended for relief of chronic symptoms, while the long acting agents such as salmeterol, formoterol and bambuterol preferably used in combination with other medicines for long-term control of asthma.

Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease state characterized by the restriction of the airway that is not fully reversible. COPD (chronic obstructive pulmonary disease) is an umbrella term describing the lung disease associated with airway obstruction. The restriction of the airway is usually progressive and associated with abnormal inflammatory response of the lungs to toxic particles or gases that appear mainly when Smoking cigarettes.

Bronchodilating agents (bronchodilators) are a mainstay of treatment of patients with established chronic obstructive pulmonary disease (COPD), but currently the majority of patients use of β-agonists.

In the international application number PCT/ER/03533 described mortar compositions for use in an aerosol inhaler, containing the active substance, dispersant (propellant), including hydrofluroalkane (HFA), a co-solvent, is also low-volatile component to increase the mass median aerodynamic diameter (MMAD) of aerosol particles when the inhaler.

In the application WO 94/13262 proposed application of organic and inorganic acids as stabilizers, to prevent chemical decomposition of the active ingredient in the solution of aerosol containing HFAs. Among the used medicinal substances, which are described in many examples, the composition is ipratropium bromide.

In applications WO 96/32099, WO 96/32150, WO 96/32151 and WO 96/32345 described dosing inhalers for the introduction of various active ingredients in suspension in the dispersant, with the inner surface of the inhaler is fully or partially covered by one or more polymers of fluorocarbons, possibly in combination with AfterUpdate polymers.

However, some researchers have described the compositions that do not require the use of any surfactant or co-solvent. In the application WO 93/11743 described compositions comprising ftoruglevodorodnye or hydrogenous ftoruglevodorodnye dispersant in combination with salmeterol on the list, salbutamol, fluticasone propionate or beclomethasone dipropionate. In this application also describes compositions comprising ftoruglevodorodnye or hydrogen ftoruglevodorodnye as a dispersant, which do not contain any surfactants and can be used with almost any medication. However, such compositions are not suitable for certain is that drugs, in particular, for ipratropium bromide.

Troventol known from the Soviet patent No. 1532047.

This invention provides an active, effective and stable pharmaceutical compositions containing only troventol or troventol in combination with one or more therapeutic agents, preferably, the dosing inhaler.

The purpose of this invention to provide pharmaceutical compositions containing troventol and a pharmaceutically acceptable carrier or excipient and possibly one or more therapeutic agents.

Another objective of the present invention is to provide a method of producing pharmaceutical compositions containing troventol.

Another purpose of this invention is to provide a method of treatment of a mammal, such as people suffering from respiratory diseases and disorders, such as bronchial asthma and related disorders, the method includes the introduction of a therapeutically effective amount of the pharmaceutical composition according to the invention.

The invention

In accordance with this invention provides an aerosol composition suitable for the treatment of bronchospasm and related disorders, comprising a therapeutically effective amount of troventola, or one, or in combination with one of the several suitable therapeutic agents and one or more pharmaceutically acceptable carriers.

According to this invention also provides a method of preparation of the dosing inhaler containing an aerosol composition according to the invention, the method involves the following stages:

a) adding the active ingredients in the container;

b) adding a pharmaceutical carriers to the mixture under item (a);

C) the injection container with a metering valve and opening the container dispersant (propellant).

This invention also provides a method of treating a mammal, such as man, from respiratory diseases such as bronchial asthma, disorders resulting bronchostenosis, this method includes the introduction of a therapeutically effective amount of the pharmaceutical composition according to the invention.

Detailed description of the invention

This invention relates to troventola, anticholinergic substance. Troventol represents from the point of view of chemistry 8-azoniabicyclo[3.2.1]octane or 3-[2-(hydroxymethyl)-1-oxo-2-phenylmethoxy]-8,8-dimethylated. It is available in the form of a white microcrystalline powder, and by its nature has no smell.

The molecular weight of this compound is 459,3 and the melting point is 253-255°C.

Bronchodilatory effect troventola is expressed in various methods of administration is intravenous, subcutaneous, oral or by inhalation. However, action is their medicine is stronger and longer lasting with the introduction of inhalation compared with other methods of introduction.

Compared with ipratropium troventol only causes mild mydriasis, and its effect on the secretion of the salivary glands and the muscles of the intestine is less pronounced, and it has no effect on holinoreaktivnye the Central nervous system. Troventol has weak peripheral n-cholinolytic properties, minor adrenolytic, antihistamines and antiserotonin action. Even at doses higher than the normal therapeutic dose, it is less harmful to the cardiovascular system and respiratory system. Atropine is one of anticholinergic drugs, but leads to some adverse reactions, some of which are dry mouth, difficulty swallowing, fever, constipation, blurred eyes, urinary retention in the elderly.

Dosing inhalers have been effective systems for oral and nasal delivery, which was widely used for the delivery of bronchodilatory and steroid compounds asthmatics, as well as for the delivery of other compounds, such as pentamidine and bronhorasshiryayushim anti-inflammatory drugs. Rapid onset of action of compounds that are entered this way, and no significant side effects have resulted in compositions that include a large number of compounds, for introducing this method.

Usually Leka the STV delivered to a patient using a dispersing system, usually includes one or more propellants, which have the corresponding vapor pressure and which is suitable for oral or nasal administration.

Accordingly, this invention provides aerosol formulations that contain two or more drugs in the form of particles that can be selected from appropriate combinations mentioned in this application, or can be selected from any other suitable drugs used in therapy using inhalers. Drugs, preferably presented in a form that is almost completely insoluble in the selected propellant.

Appropriate drugs can be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginalnomu drugs such as diltiazem, antiallergenic, such as kromoglikatom, ketotifen or nedocromil; anti-infective tools, such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracycline and pentamidine; antihistamines, such as methapyrilene; anti-inflammatory drugs, such as flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives drugs, such as noscapine; bronchodilatory tools, such as ephedrine, epinephrine, fenoterola, formoterol, izoprenalin, metaproterenol phenyl is frina, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutalina, isoetharine, tulobuterol, isoetharine, tulobuterol ortsiprenalina or (-)-amino-3,5-dichloro-[alpha]-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]- methyl]benzoimidazole; diuretics, such as amiloride; anticholinergics such as ipratropium, atropine or exotropia; hormones, such as cortisone, hydrocortisone or prednisolone; xantina, such as aminophylline, choline of theophyllinate, lysine of theophyllinate or theophylline; therapeutic proteins and peptides, for example, insulin or glucagon. For specialists in this area it is obvious that where it is appropriate, medications can be used in the form of salts (e.g. as alkali metal salts or amines or salts join acids) or as esters (e.g. lower alilovic esters) or in the form of a solvate (e.g., hydrates) to optimise the activity and/or stability of drugs and/or to minimize the solubility of the drug in the propellant.

Therefore, this invention provides a pharmaceutical composition comprising troventol, which does not cause side effects typical of atropine.

Thus, this invention provides a pharmaceutical composition comprising troventol and pharmaceutically acceptable novtel is or excipient and perhaps one or more other therapeutic agents.

This invention provides a composition containing troventol, preferably in the form of a composition in the dosing inhaler (MDI), which can be applied for the treatment of respiratory diseases. Containers for aerosol formulations typically include a container (tank or container)that connects to the valve. The valve contains a valve stem, through which are distributed structures. Typically, the valve contains a strip of rubber, designed for reciprocating motion of the valve stem, which prevents the leakage of propellant from the container. Dosing inhalers contain a valve that is designed to deliver a metered amount of the aerosol composition to the recipient at startup. Valves for MDIs available from manufacturers well known in the field of production of aerosols, for example, from Valois, France, Bespak pic, United Kingdom and 3M-Neotechnic Limited, United Kingdom.

The composition according to the invention is administered by inhalation to ensure effective local action and prevent unwanted systemic effects. A therapeutically effective dose troventola with the introduction by inhalation is preferably 40-640 mg. The composition according to the invention may also contain pharmaceutically acceptable excipients for the doctrine of suitable composition and may be obtained in the form of a composition for the dosing inhaler.

Aerosol composition according to the invention may include in addition to troventola one or more therapeutic agents, and at least one propellant, other pharmaceutically acceptable agents, such as co-solvents, antioxidants or surfactants.

The propellant according to this invention includes at least one propellant selected from the propellant 11 (DICHLORODIFLUOROMETHANE), propellant 12 (monitorthread), propellant 114 (dichlorotetrafluoroethane), 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227), or mixtures of two or more of such halogen-substituted hydrocarbons.

However, there were problems associated with stabilization of pharmaceutical aerosol formulations obtained by the application of a new class of propellants HFA. Pharmaceutical aerosol formulations are typically a solution or suspension. It is also possible to mix the suspension and some (possible traces) dissolved drugs, but this is usually not desirable. Some compositions in the form of solutions have the drawback consisting in the fact that the medicine contained in them, are more prone to decay. Further, there may be problems associated with the regulation of droplet size, which affects therapeutic profile. For this reason usually are preferred suspension.

The compositions according to izobreteny may be obtained by dispersion of medicinal substance in the selected propellant in an appropriate container, for example, using ultrasound. The process is preferably carried out in anhydrous conditions, in order to avoid any harmful effects of moisture on the stability of the suspension.

The compositions according to the invention form a weakly flokulirovannym suspension when standing, but suddenly discovered that these suspensions can be easily redispersible under moderate stirring to obtain suspensions with excellent performance delivery, suitable for use in inhalers under pressure, even after prolonged storage. To minimize or, preferably, with the exception of the use of excipients, for example, surfactants, co-solvents, etc. in aerosol formulations according to the invention also preferably, as the compositions are obtained without taste and smell, less irritating and less toxic than conventional compositions.

In the suspensions according to the invention the particle size is usually adjusted at the time of receipt by the size of the solid particles of drug substance, typically by micronisation. However, when the suspended drug has sufficient solubility in the propellant, a process known as "Ostwald ripening", can lead to an increase of particle size. In addition, the particles may have a tendency to aggregation or adhesion to the parts of MDI, such as tank or valve. In addition, medication may be the feet is nciu to be absorbed by any not processed and/or not containing coating rubber components of the valve, especially during storage for a long time. In particular, preferably absorbed by the fine particles. The effect of Ostwald ripening and, especially, the deposition of medication can especially be noticed in the case of active drugs that are typically present in the compositions in small doses.

According to a preferred variant of the invention, the aerosol may contain a therapeutically effective amount of troventola with one or more therapeutic agents and/or propellant 11, or propellant 114, or a combination thereof, and/or propellant 12.

According to another preferred variant of this invention, the aerosol may contain a therapeutically effective amount of troventola with one or more therapeutic agents and/or propellant 11, or propellant 114, or a combination thereof, and/or propellant 12 with one or more surface-active substances.

Pharmaceutical aerosol formulations typically represent a suspension of drug substances, one or more liquid propellants, possibly sapropelite and possibly adjuvant, such as a solvent or surfactant, and/or other excipients. Aerosol composition is in the tank under pressure. The problems mentioned above were caused by the addition of one or more adjuvants, such as SP the mouths alkanes, dimethyl ether, surfactants (for example, including fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylated etc), and even ordinary chargerbulletin propellants in small quantities to minimize possible damage to the ozone layer.

Tried to enter various surface-active substances, such as oils, including corn oil, olive oil, cotton seed oil and sunflower oil, mineral oil type liquid paraffin, oleic acid, and phospholipids, such as lecithin or esters sorbitan and fatty acids, for example, sorbitan the oleate. Lecithin when used in the composition results in a fairly good quality suspensions.

Surfactant can be used in concentrations of from 0.001 to 100% by weight of the drug, preferably in a quantity of 1-50%, more preferably at a concentration of 5-30%. The concentration of the surfactants according to the invention may be equal to, for example, about 10%.

Preferably, each delivered from MDI dose was close to tolerable doses. Therefore, it is preferable that the composition was almost homogeneous at a dose during the run of the proportioning valve. It is preferable that the concentration of the suspension did not change EIT is sustained fashion during storage for a long time.

Thus, in compositions for inhalation is a very important particle size. The preferred particle size is in the range from 2 μm to 5 μm. It was also found that the particle size has a significant impact on the amount of active substance in the aerosol, which is delivered by inhalation.

One option medicines are mixed with propellant 11, or propellant 114, or their combination, the mixture was filled in containers, crimp them and loaded propellant 12. It was found that this method produces low doses of small particles. Then repeated the experiments, and when drugs and/or surfactant were crushed to particles with propellant 11, or propellant 114, or their combination with obtaining the suspension, then filled with a slurry tanks and loaded propellant 12. This led to dose with smaller particles compared to CFC aerosols, where not produced micromilieu described above. Therefore, micromelia can be done to obtain dose with smaller particles.

According to another variant of the present invention provides a method for obtaining aerosol composition according to the invention, the method includes: (a) adding drugs and/or surface-active substances together with propellant 11, or propellant 114, or their mixture (b) filling of the tank with the suspension; (C) the injection of a suitable valve, and (g) the loading of the propellant 12 through the valve.

According to another preferred variant of the present invention, the aerosol composition may contain a therapeutically effective amount of troventola together with one or more therapeutic agents and/or 1,1,1,2-Tetrafluoroethane (HFA 134a)or 1,1,1,2,3,3,3-heptapteridae (HFA 227), or their combination.

According to another aspect of the present invention provides a method of obtaining the above-mentioned composition of the aerosol, the method includes: (a) adding a therapeutically effective amount troventola together with one or more therapeutic agents in a container; (b) the injection metering valve in the container; (C) loading the container or 1,1,1,2-Tetrafluoroethane (HFA 134a)or 1,1,1,2,3,3,3-heptapteridae (HFA 227), or combinations thereof.

According to another preferred aspect of this invention, the aerosol composition may contain a therapeutically effective amount of troventola together with one or more therapeutic agents and/or 1,1,1,2-Tetrafluoroethane (HFA 134a)or 1,1,1,2,3,3,3-heptapteridae (HFA 227), or their combination and the co-solvent. In this case, the co-solvent preferably has a higher polarity than the propellant.

Typically, the co-solvent is contained in an amount of from 0.01 to 5% (by weight composition). Used with the solvent can be selected from the group of glycols, in particular, propylene glycol, polyethylene glycol and glycerin, or alcohols, such as ethanol. Usually the co-solvent is ethanol.

According to a preferred aspect of this invention provides a method of obtaining the above composition, the method includes: (a) adding the drug in the container, (b) adding a co-solvent to the drugs and influence of ultrasound, (b) the injection metering valve in the container, (d) loading into the container or 1,1,1,2-Tetrafluoroethane (HFA 134a)or 1,1,1,2,3,3,3-heptapteridae (HFA 227), or combinations thereof.

According to another preferred variant, the composition of the aerosol may contain a therapeutically effective amount of troventola together with one or more therapeutic agents and/or 1,1,1,2-Tetrafluoroethane (HFA 134a)or 1,1,1,2,3,3,3-heptapteridae (HFA 227), or their combination, surfactant and the above-mentioned co-solvent.

Surface-active agent stabilizes the composition and contributes to the lubrication system of the valve in the inhaler. Surface-active agents may be selected from, for example, Polysorbate 20. Polysorbate 80, Myvacet 9-54, Myvacet 9-08, isopropylmyristate, oleic acid, Brij, ethyloleate, glyceryltrinitrate, glycerylmonostearate, glycerylmonostearate, glycerylmonostearate, glyceryl-monoricinoleate, cetyl alcohol, stearyl alcohol, atrperiod the deposits - chloride, block polymers, natural oils, polyvinylpyrrolidone, esters sorbitan and fatty acids, such as triolein sorbitan, polyethoxysiloxane esters sorbitan and fatty acids (for example, polyethoxysiloxane trioleate sorbitan), oleate of sorbisches, synthetic impotencehow (tritons), esters of ethylene oxide and the condensation products of op with formaldehyde, phosphatides, such as lecithin, polyethoxysiloxane fats, polyethoxysiloxane of oleomargarine and polyethoxylated fatty alcohols.

Surface-active agents are preferably used in amounts of 0.02 to 50% by weight troventola.

According to another aspect of the present invention provides a method of obtaining the above-described compositions, the method includes: (a) adding the drug in the container, (b) adding a co-solvent for the drug, as well as the solution of surface-active substances and the influence of ultrasound, (b) the injection metering valve in the container, (d) loading into the container or 1,1,1,2-Tetrafluoroethane (HFA 134a)or 1,1,1,2,3,3,3-heptapteridae (HFA 227), or combinations thereof.

According to another aspect of the present invention, the aerosol composition may contain a therapeutically effective amount of troventola, the filler and the above propellant. The filler acts as a carrier for drug delivery into the lungs. ispolnitel can be contained at a concentration of 10-500% by weight medication more preferably, in the range from 10 to 300%. The filler may be selected from a class of sugars, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol.

According to a preferred aspect of the invention provides a method of obtaining the above-described composition of the aerosol, which includes: (a) adding the active ingredients in the container, (b) adding a filler to the active ingredients, (b) the injection metering valve in the container, and (g) the loading of the propellant in the container.

According to a preferred aspect of this invention, the aerosol composition may contain at least one therapeutically effective isomer troventola, surfactant and/or 1,1,1,2-Tetrafluoroethane (HFA 134a)or 1,1,1,2,3,3,3-heptapteridae (HFA 227), or a combination of both. Surfactant can be selected from a class of salts of stearic acids, preferably the magnesium salt of stearic acid, or esters such as ascorbyl palmitate, isopropylmyristate, Tween 20, Tagat TO V, Myvacet and esters of tocopherol, preferably, it is isopropylmyristate. Surfactant is used at a concentration of from 0.01 to 5%.

According to the preferred is the SPECTA of the present invention also provides a method of obtaining the above-described composition of the aerosol, which includes: (a) adding the drug in the container, (b) adding thereto (a) a surfactant, (C) the injection metering valve in the container, (d) loading into the container or 1,1,1,2-Tetrafluoroethane (HFA 134a)or 1,1,1,2,3,3,3-heptapteridae (HFA 227), or combinations thereof.

The composition according to the invention can also contain antioxidants such as citric acid and benzylaniline.

This invention also provides a method of treatment of a mammal, such as man, respiratory diseases such as asthma, disorders, causing bronchostenosis, the method includes the introduction of a therapeutically effective amount of the pharmaceutical composition according to this invention.

The person skilled in the art it is obvious that you can make various substitutions and modifications of the invention described in this application, without leaving the scope of the invention. Therefore, it should be clear that although the present invention has been described in relation to preferred options and possible warning signs, experts can modify and change the General concepts described in this application, and also modifications and changes shall be considered as included in the scope of the invention.

The following examples are provided only to illustrate the invention and in no way is granicoat scope of this invention.

Example 1: an Inhaler with CFC.

A.

IngredientsQuantity/container
Troventol9.6 mg
Lecithin0,96 mg
Propellant 114.5 g
Propellant 1211.6 g

a) add troventol in the container

b) add the Propellant 11 and the solution of surface-active substances to troventola and treat the mixture with ultrasound,

C) perform the injection metering valve in the container and process ultrasound and

d) download the Propellant 12 through the valve.

Century

IngredientsQuantity/container
Troventol9.6 mg
Trioleate sorbitan2.4 mg
Propellant 114.5 g
Propellant 1211.6 g

a) add troventol in the container

b) add the Propellant 11 and actor surfactants to troventola and treat the mixture with ultrasound,

C) perform the injection metering valve in the container and process ultrasound and

d) download the Propellant 12 through the valve.

Example 2: HFA Inhaler with.

A.

IngredientsQuantity/container
Troventol9.6 mg
HFA 134a18,2 g
Troventol19,2 mg
HFA 134a18,2 g

add a medicine container

b) perform the injection metering valve in the container

C) load the container 1,1,1,2-Tetrafluoroethane (HFA 134a).

Century

IngredientsQuantity/container
Troventol9.6 mg
Abs. Alcohol 2%0,364 g
Lecithin 0,02%0,00192 mg
HFA 134a17,83 g

add a medicine container

b) add the alcohol and the solution of surface-active ve is estva to (a) and turn on the ultrasound

C) perform the injection metering valve in the container

d) load the container 1,1,1,2-Tetrafluoroethane (HFA 134a).

C.

IngredientsQuantity/container
Troventol9.6 mg
HFA 22720.6 g

add a medicine container

b) perform the injection metering valve in the container

C) load the container 1,1,1,2,3,3,3-heptapteridae (HFA 227).

1. The composition of the aerosol for the treatment of bronchospasm and related disorders, containing a therapeutically effective amount of troventola, propellant and one or more pharmaceutically acceptable carriers, wherein the troventola microtelco together with the propellant.

2. The aerosol composition according to claim 1, characterized in that the troventola contained in the number of 40-640 mg.

3. The aerosol composition according to claim 1, wherein the propellant is selected from the group consisting of propellant 11 (DICHLORODIFLUOROMETHANE), propellant 12 (monitorthread), propellant 114 (dichlorotetrafluoroethane), 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-Heptafluoropropane (HFA 227), or mixtures thereof.

4. The aerosol composition according to claim 1, characterized in that it additionally contains one or b is more other therapeutic agents.

5. The aerosol composition according to claim 4, characterized in that the above therapeutic agents selected from the group consisting of analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginalnomu drugs such as diltiazem, antiallergenic, such as kromoglikatom, ketotifen or nedocromil; anti-infective tools, such as cephalosporins, penicillins, streptomycin, sulfonamides, tetracycline and pentamidine; antihistamines, such as methapyrilene; anti-inflammatory drugs, such as flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives drugs, such as noscapine; bronchodilatory tools, such as ephedrine, epinephrine, fenoterola, formoterol, izoprenalin metaproterenol of phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutalina, isoetharine, tulobuterol, isoetharine, tulobuterol ortsiprenalina or (-)-amino-3,5-dichloro-[alpha]-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzene - methanol; diuretics, such as amiloride; anticholinergics such as ipratropium, atropine or exotropia; hormones, such as cortisone, hydrocortisone or prednisolone; xantina, such as aminophylline, choline of theophyllinate, lysine of theophyllinate or theophylline; and therapeutic proteins and peptides, for example the EP insulin or glucagon.

6. The aerosol composition according to claim 1, characterized in that said pharmaceutical carrier is selected from the group consisting of co-solvents, antioxidants, surfactants, surface-active agents and fillers used separately or in combination.

7. The aerosol composition according to claim 6, characterized in that it contains a surface-active agent selected from the group consisting of vegetable oils, such as corn oil, olive oil, cottonseed oil and sunflower oil; mineral oils such as liquid paraffin, oleic acid and phospholipids, such as lecithin or esters sorbitan and fatty acids such as oleate sorbitan, or mixtures of these substances.

8. The aerosol composition according to claim 7, characterized in that the surface-active agent is contained in an amount of from 0.001 to 100%, preferably in quantities of from 5 to 30%, based on the weight troventola.

9. The aerosol composition according to claim 6, characterized in that it contains a co-solvent selected from the group of glycols, such as propylene glycol, polyethylene glycol and glycerin, or from the group of alcohols, such as ethanol.

10. The aerosol composition according to claim 9, wherein the co-solvent is contained in an amount of from 0.01 to 5% based on the weight troventola.

11. The aerosol composition according to claim 6, characterized in that it contains a surface-active substance, you the security of Polysorbate 20, Polysorbate 80, Myvacet 9-54, Myvacet 9-08, isopropyl-myristate, oleic acid, Brij, ethyloleate, glyceryltrinitrate, glicerina-laurate, glycerylmonostearate, glycerylmonostearate, glicerina-ricinoleate, cetyl alcohol, stearyl alcohol, pyridinium-chloride, block polymers, natural oils, polyvinylpyrrolidone, esters sorbitan and fatty acids, such as triolein sorbitan, polyethoxysiloxane esters sorbitan and fatty acids (for example polyethoxysiloxane trioleate sorbitan), oleate of sorbisches, synthetic impotencehow (tritons), esters of ethylene oxide and the condensation products of op with formaldehyde, phosphatides, such as lecithin, polyethoxysiloxane fats, polyethoxysiloxane of oleomargarine and polyethoxylated fatty alcohols or mixtures of these substances.

12. The aerosol composition according to claim 6, characterized in that it contains a surface-active agent at a concentration of from 0.02 to 50% by weight of drug substance troventola.

13. The aerosol composition according to claim 6, characterized in that it contains a filler selected from the class saccharides, including monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran or mannitol.

14. The aerosol composition according to item 13, characterized in, is that it contains a filler in a concentration of 10-500% by weight troventola.

15. The aerosol composition according to claim 1, characterized in that it consists of troventola and HFA 134a or F 227.

16. The aerosol composition according to claim 1, characterized in that it contains troventol, lecithin and propellant.

17. The aerosol composition according to claim 1, characterized in that it contains troventol, ethanol in an amount of from 1 to 3% by weight of the composition; lecithin in an amount of from 0.01 to 0.1% by weight troventola and propellant.

18. The composition of the aerosol for the treatment of bronchospasm and related disorders, containing troventol in the number of 40-640 mg, propellant, a surfactant and co-solvent, characterized in that the troventola microtelco together with the propellant.

19. The composition of aerosol p, wherein the surfactant is a lecithin, oleic acid or trioleate sorbitan.

20. The composition of aerosol p, wherein the co-solvent is an ethanol.

21. The composition of aerosol PP-20, characterized in that it contains troventol in the number of 40-640 mg, propellant, which is a R 11, R 12, R 114, HFA 134a or HFA 227 or a mixture thereof; a co-solvent in an amount of 0.01-5% by weight troventola; a surfactant in an amount of 0.001 to 100% by weight troventola and the second active substance.

22. Dosing inhaler containing an aerosol composition for the treatment of bronchospasm and related races is troist according to any one of claims 1 to 21.



 

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19 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neonatology, and can be used for prevention of development of severe forms of bronchopulmonary dysplasia (BPD) in preterm newborn babies. For this purpose, in child of 3-4 days old presence of at least two of five criteria is detected: 1) gestation age <32 weeks, 2) performing artificial lung ventilation (ALV) for not less than 3 days or application of respiratory support with positive pressure in respiratory ways through nasal catheters, 3) dependence on oxygen in concentration more than 21% for not less than 3 days, 4) presence of symptoms of respiratory failure (RF) for more than 3 days, 5) X-ray changes in form of interstitial edema, nodose-reticular network, increased pneumatisation, homogenous shadows without hyperinflation. In case if at least two of said criteria are present, nebuliser treatment with budesonide is administered; if child had symptoms of moderate severe or severe RF, simultaneously inhalations with berodual or atrovent are carried out; in case of impossibility to disconnect child from ALV apparatus, aminofylline is added. On the 14-th day of life repeated examination is performed. From 14 to 28 day of life inhalations with budesonide are continued, in case of RF is absent; in case of RF of I-III degree - inhalations with budesonide with addition of berodual or atrovent, in case of impossibility to disconnect child from ALV apparatus, dexamethasone is applied.

EFFECT: invention contributes to efficient prevention of development of severe BPD in children of risk group due to differentiated administration of drug therapy.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to treating male patients suffering bronchial asthma early acquired androgen deficiency. That is ensured by a singular therapy 10 mg once a day combined with andriol 40 mg twice a day in the morning and in the evening. The therapeutic course makes 2 months.

EFFECT: potentiation of a bronchodilating effect of singular with no side effects.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medications and deals with combination of R,R-glycopyrrolate or its physiologically acceptable salts and montelukast in effective amount for treatment of respiratory diseases, selected from group, which includes allergic rhinitis, bronchial asthma, chronic obstructive lung diseases and common cold. Also described are pharmaceutical composition for treatment of respiratory diseases, which contains R,R-glycopyrrolate or its physiologically acceptable salts and montelukast in effective amount, and application of R,R-glycopyrrolate or its physiologically acceptable salts and montelukast or its physiologically acceptable salts in effective amount for preparation of pharmaceutical composition.

EFFECT: claimed combination inhibits release of IL-2 synergically.

15 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmacology, and concerns the application of compounds of formulae for preparing a drug for reducing high pulmonary pressure, treating acute and chronic pulmonary diseases, such as respiratory distress syndrome, acute pulmonary injury, acute respiratory distress syndrome, and treating COPD.

EFFECT: invention provides higher clinical effectiveness.

7 cl, 1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel optically active phenylthanolamine compounds of formula (I) having a (-)-configuration, or pharmaceutically acceptable salts thereof, which have β2-receptor agonist effect and can be used to treat asthma or bronchitis. In formula (I) R1 is H or halogen; R2 is CF3, CN or halogen; R3 is a straight or branched alkyl, having 1-6 carbon atoms or a cycloalkyl having 3-6 carbon atoms.

EFFECT: high efficiency of using the agents.

9 cl, 1 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: compounds of the invention exhibit properties of β2- adrenoreceptor agonists. In formula (I) , R1 represents hydrogen; each R2, R3, R4, R5, R4' and R5' independently represents hydrogen or C1-C6alkyd; e is equal to 0 or 1; A represents C(O); D represents oxygen or sulphur; m is equal to an integer 0 to 3; n is equal to an integer 0 to 3; R6 represents the group -(X)p-Y-(Z)q-R10; each X and Z independently represents C1-C6akylene group; each p and q is independently equal to 0 or 1; Y represents a bond, oxygen, CH2 or NR9; R7a and R7b independently represent hydrogen or C1-C6alkyl; R9 represents C1-C6alkyl; R10 represents hydrogen or saturated or unsaturated 6-members ring system optionally containing at least one ring heteroatom, chosen of nitrogen. And this ring system is optionally substituted by C1-C6alkoxycarbonyl; R7 represents 6-12-members aromatic ring system which is optionally substituted by halogen, trifluoromethyl, hydroxyl, C1-C6alkyl, C1-C6alkoxy or NH2; provided R6 does not represent hydrogen or unsubsituted C1-C6alkyl group. Also, the invention refers to methods for producing compounds of formula (I), to a pharmaceutical composition exhibiting properties of β2- adrenoreceptor agonists containing the compound of formula (I) as an active ingredient, to application of the compound of formula (I) in preparing a drug, to a combination containing the compound of formula (I) and one or more agents.

EFFECT: improved properties of the composition.

27 cl, 2 tbl, 32 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical product for treatment of respiratory disease, which contains combinations: a) first active ingredient, representing compound of general formula , where m equals 0, 1 or 2; each R1 independently represents halogen or cyano; R2 represents hydrogen atom or methyl; R3 represents C1-C4alkyl; and R4 represents hydrogen or halogen; or its pharmaceutically acceptable salt; and (b) second active ingredient, which represents glucocorticosteroid. Invention also relates to application of product by any of ii.1-15, to method of respiratory disease treatment, to set, as well as pharmaceutical composition.

EFFECT: obtaining of novel pharmaceutical product for treatment of respiratory disease.

35 cl, 5 ex, 1 dwg

FIELD: medicine.

SUBSTANCE: inhalation of the nonsteroidal anti-inflammatory drug lysine acetylsalicylate with using a nebuliser applicable in inhaling therapy for treating chronic obstructive pulmonary disease or emphysema is offered.

EFFECT: such introduction have a beneficial effect on patient's cough, as well as improves respiratory function (reduces intensity of bronchial obstruction symptoms) since the preparation is absorbed and accumulated more by the pulmonary structures involved by the disease.

4 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 6-substituted isoquinolone derivatives of formula

or , or stereoisomeric forms and/or pharmaceutically acceptable salts thereof, where R2 denotes H or (C1-C6)alkyl; R3, R4 and R5 denote H; R6 and R6' independently denote H, (C1-C8)alkyl, (C1-C6)alkylene-R', (C1-C6)alkylene-C(O)O-(C1-C6)alkyl, C(O)-(C1-C6)alkylene-R', or R6 and R6', together with a N atom with which they are bonded form a (C5-C6)heterocyclyl group in which one or more carbon atoms can be substituted with 1, 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms or a combination of different heteroatoms; R7 denotes H, halogen, (C1-C6)alkyl; R8 denotes H; n equals 1; m equals 1, 2, 3, 4 or 5, and L denotes O or O-(C1-C6)alkylene; where, R' denotes (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl; where in residues R6 and R6' alkyl or alkylene can optionally be substituted one or more times with COOH groups; and where in residues R6 and R6' (C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times with suitable groups independently selected from a group comprising CONH2 and (C1-C6)alkyl; where if m equals 3, R6 cannot denote H; where if m equals 3 and R6 denotes (C1-C8)alkyl, then the alkyl is substituted once or more times, preferably one to three times, with a COOH group. The invention also relates to use of the compound of formula (I) and a medicinal agent based on the disclosed compounds.

EFFECT: novel isoquinolone derivatives which inhibit Rho-kinase and/or Rho-kinase mediated phosphorylation of the myosin light-chain phosphate.

31 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new benzimidazole derivatives of general formula (I) or to its pharmacologically acceptable salts wherein R1 represents a C6-aryl group which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), or a heterocyclic group which represents pyridyl, dihydrobenzofuranyl, 1,3-benzodioxolyl, tetrahydropyranyl, tetrahydrofuranyl which can be substituted by 1-3 groups optionally specified in a group of substitutes (a), R2 represents a C1-C6 alkyl group, R3 represents a C6-aryl group which can be substituted by 1-2 groups optionally specified in a group of substitutes (a), Q represents a group represented by formula =CH-, or a nitrogen atom and a group of substitutes (a) represents a group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a carboxyl group, a C2-C7 alkylcarbonyl group, a C2-C7 alkoxycarbonyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, an amino group, a 4-morpholinyl group and a di-C1-C6 alkyl)amino group. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I), to a PPARγ activator/modulator based on the compound of formula (I), to using the compound of formula (I), to a method of reducing blood glucose, to a method of activating PPARγ, a method of treating and/or preventing said pathological conditions.

EFFECT: there are produced new benzimidazole derivatives showing PPARγ modulatory activity.

41 cl, 2 dwg, 6 tbl, 76 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (1): R1 means haloalkyl containing 1-6 fluorine atoms; R2 means C1-C6alkyl or halogen; R3 means -L-NR4R5, -X-NR-C(O)R8 or -X-NR-C(O)NR4R5 wherein L means -X-C(O), -(CR2)j, -O(CR2)1-4 or and X means (CR2)j or [C(R)(CR2OR)]; R4 and R5 independently mean H, C1-C6alkyl, halogen-substituted C1-C6alkyl, hydroxy group-substituted C1-C6alkyl, or (CR2)k-R6; R8 independently means (CR2)k-R6 or C1-C6alkyl, or halogen-substituted C1-C6alkyl; R7 means H; alternatively, R4 and R5 together with N atom in each NR4 R5 form a 4-7-member heterocyclic ring containing 1 -2 heteroatoms independently specified in N and O substituted by 0-3 groups R11; R11 means R8, (CR2)k-OR7, CO2R7, (CR2)k-C(O)-(CR2)k-R8, (CR2)kC(O)NR7R7 or (CR2)kS(O)1-2R8; each R means H or C1-C6alkyl; each k is equal to 0-6; and j and m are independently equal to 0-4; provided R1 does not mean trifluoromethoxygroup, provided R3 means C(O)NH2, C(O)NR12R13; wherein R12 and R13 together form piperazinyl; the values of the radical R6 are presented in the patent claim. The invention also refers to the pharmaceutical composition containing said compounds.

EFFECT: producing new 5-(4-(halogenalkoxy)phenyl)pyrimidin-2-amine derivatives showing c-kit, PDGFRα, PDGFRβ kinase inhibitory activity, optionally in the form of isomers or pharmaceutically acceptable salts.

12 cl, 77 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel crystalline forms of tiotropium bromide, characterised by X-ray powder diffraction pattern XRD, having peaks at approximately 20.2, 26.5, 28.0 and 31.2±0.2 degrees 2-theta and at approximately 20.9, 21.1, 21.4 and 34.43±0.2 degrees 2-theta. The invention also relates to methods of producing said forms and pharmaceutical compositions having anticholinergic activity, based on said compounds.

EFFECT: novel more stable forms of tiotropium bromide which can be used in medicine to treat asthma or chronic obstructive pulmonary disease are obtained.

22 cl, 16 dwg, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,3-substituted pyrazine sulphonamides of formula (I), use thereof in treating allergic diseases, inflammatory dermatosis, immonological disorders and neurodegenerative disorders, as well as pharmaceutical compositions, having CRTH2 receptor inhibiting action and inhibiting chemoattractant receptor, homologous to the molecule expressed on T-helpers 2. in general formula .

A is selected from a group consisting of

, n denotes an integer independently selected from 0, 1, 2, 3 or 4; m equals 1 or 2; B is selected from a group consisting of phenyl or piperazinyl; R1 denotes hydrogen; R2 denotes phenyl, where R2 is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl; R3 is selected from a group consisting of (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, where each of said (C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl is optionally substituted with one or more substitutes selected from a group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, heteroaryl, aryl, thioalkoxy and thioalkyl, or where said aryl, heteroaryl, (C1-C6)alkylaryl, (C1-C6)alkylheteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl can be condensed with one or more aryl, heteroaryl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl groups and can be substituted with one or more substitutes selected from a group consisting of (C1-C6)alkyl, alkoxy, aryl, heteroaryl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, nitro, sulphoxy, sulphonyl, sulphonamide and trihaloalkyl; R7 is selected from a group consisting of hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl, heteroaryl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, carboxyl, cyano, amino and hydroxy; aryl is selected from phenyl or naphthyl; and heteroaryl is selected from pyridyl, indolyl, 3H-indolyl, benzimidazolyl, quinolizinyl.

EFFECT: high efficiency of using the compounds.

4 cl, 10 dwg, 46 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of formula I where: R1 represents a group selected from among -CH2OH, -NH(CO)H while R2 represents a hydrogen atom or R1, together with R2, forms group -NH-C(O)-CH=CH- where the nitrogen atom is bonded to the carbon atom in the phenyl ring whereto R1 is bonded, the carbon atom bonded to the carbon atom in the phenyl ring whereto R2 is bonded; R3a and R3b are independently selected from the group consisting of hydrogen atoms and C1-4alkyl groups; X and Y are independently selected from the group consisting of an ordinary bond and an oxygen atom; n, m and q (each) independently have a value selected from among 0, 1, 2 and 3; p has a value selected from among 1, 2 and 3; R4 and R5 are independently selected from the group consisting of hydrogen atoms, a halogen atoms, C1-4alcoxy, -CONH2, -NHCONH2, -SR7, -SO2R7 where R7 represents C3-4cycloalkyl; R6 is selected from the group consisting of hydrogen atoms, a halogen atoms, C1-4 alkyl and C1-4alcoxy or its pharmaceutically acceptable salt or a stereoisomer thereof. Additionally, the invention relates to a pharmaceutical composition based on the compound with formula I and to a method for β2-adrenergic receptor activity modulation.

EFFECT: produced are new 4-(2-amino-1-hydroxiethyl) phenol derivatives possessing the activity of β2-adrenergic receptor antagonists.

22 cl, 32 ex

FIELD: chemistry.

SUBSTANCE: claim describes novel vinylogous acid derivatives of formula , in which ring A is as defined in claim 1, R1 denotes hydrogen, C1-C6-alkyl or -NR'R", -( C0-C6-alkylene)-NR'R'', where R' and R" are independently selected from a group comprising hydrogen, C1-C6-alkyl, formyl, C1-C6-alkylcarbonyl; R2, R2' and R2" independently denote hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy group; R3 denotes phenyl; R4 denotes hydrogen, C1-C6-alkyl, optionally substituted phenyl or phenyl- C1-C6-alkyl, R5 denotes hydrogen or C1-C6-alkyl; as well as physiologically acceptable salts thereof.

EFFECT: compounds inhibit chymase and can be used as medicinal agents.

15 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound - 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride of formula I showing antispasmodic and bronchial spasmolytic activity.

EFFECT: invention extends the range of antispasmodic and bronchial spasmolytic low-toxic agents.

3 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula l

in the form of a salt wherein W means a group of formula and A means acetate or xinafoate, as well as to based pharmaceutical compositions which may be used for treating the diseases accompanied by bronchospasms.

EFFECT: what is offered is a new effective bronchial spasmolytic.

7 cl, 23 ex, 4 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to ophthalmology. A pharmaceutical composition is applicable in ophthalmology and contains the non-steroid anti-inflammatory drug indometacin and a phospholipid agent of the nanoparticle size 10-30 nm herbal phosphatidylcholine, maltose in the following proportions, wt %: phosphatidylcholine 20-43, maltose 55-78, indometacin 2-8. The indometacin and soya phospholipid composition represents a lyophilised powder.

EFFECT: invention provides prolonged storage stability of the composition.

2 dwg, 1 ex

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