Combined aerosol preparation for treating respiratory diseases

FIELD: medicine.

SUBSTANCE: as active ingredients, a formulation contains fenoterol hydrobromide and ipratropium bromide monohydrate; the excipients are absolute ethanol, triethylcitrate, propellant 1,1,1,4 tetrafluoroethane (HFA-134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) and a pharmaceutically acceptable acid specified in hydrochloric, orthophosphoric and citric acids.

EFFECT: increasing the respirable fraction and obtaining an optimised particle release profile.

2 dwg, 6 ex

 

The invention relates to medicine and the pharmaceutical industry, relates to a composition and process for the preparation of highly effective pharmaceutical substances and excipients, to form an aerosol of fine particles with the aim of penetrating into the bronchi and alveoli of the lungs and treatment of diseases of the respiratory system.

In the treatment of bronchial asthma is an important factor in successful therapy is the delivery of a drug in aerosol form to the inflammation in the bronchi. In practice, the treatment of diseases of the respiratory tract are three main methods of forming aerosols. This medication under pressure and sprayed with excipients propellant, also known as metered aerosols, powders for inhalation, activated, usually by inhalation of the patient, and the solution or suspension is sprayed with a special device is a nebulizer. Each method has its own specific properties that make them preferable for use in different groups of patients, the site of application, weather conditions, etc., Common to these methods drugs should ensure the formation of an aerosol cloud with a particle size of not more than 10 μm, preferably not more than 5.0 μm. The presence of particles with a size less than 0.5 μm is useless, because they do not occludin who are in the lungs and excreted in the exhalation.

The level of technology

Advantages of aerosol drugs to treat respiratory diseases are their portability and ease of use.

Aerosol preparations for the treatment of respiratory organs are used with the middle 50 years of the last century. The first aerosol preparations consisted of a suspension of liquified gases - propellants. As propellants used chlorinated freon, inert and non-toxic compounds, however, as it turned out, having the property of destroying the ozone layer of the planet. Because of this their use has been banned and have been developed drugs with new propellants - hydrofluroalkane. The most acceptable of them are Tetrafluoroethane (propellant HFA-134a) and Heptafluoropropane (propellant HFA-227ea). The use of these propellants radically changed the production technology of aerosol preparations and compositions of the preparations themselves. To reduce the vapour pressure were used excipients. The most acceptable was ethyl alcohol. The use of ethanol allowed to obtain medications under pressure in the form of true solutions, and this in turn gave me the opportunity to resolve such a complex process technology, as the micronization powders, and allowed us to obtain inhalation steadily respirable fraction. For the formation of particles and is Rosalia inhalation with the most appropriate respirable size in the solution it is necessary to add auxiliary substances, selected from the group of biologically acceptable liquids. It should be heavy, low volatile liquid, preferably miscible with the propellant.

Famous U.S. patent 5348730, disclosing a method of producing an aerosol containing a dispersing agent, such as oleic acid, suspended in the propellant 1.1.1.2-Tetrafluoroethane. Finding the active component in the form of a suspension, not a solution, leads to the reduction of respirable fraction.

RF patent 2126248 C1 relates to a liquid pharmaceutical composition in the form of an aerosol. The composition comprises an active ingredient, at least one organic solvent, at least one partially fluorinated hydrocarbons as propellant and optionally at least one inorganic or organic acid. As a fluorinated hydrocarbon contains 1,1,1,2-Tetrafluoroethane, 1,1,1,2,3,3,3-Heptafluoropropane, as the organic solvent includes ethanol. Inorganic acid selected from the group comprising sulfuric acid, hydrochloric acid, nitric acid and phosphoric acid. Organic acids are selected from the group comprising ascorbic acid and citric acid. Active substance selected from the group comprising ipratropium in the form of bromide, oxitropium in the form of bromide, albuterol, metaproterenol, Tiotropium as brough the IDA and fenoterola. Introduction acid provides resistance to the destruction or decomposition of the active substance, but does not provide optimum spray cloud.

As the closest analogue of the claimed drug can be called a metered dose aerosol Berodual-N produced in the market the German company BOEHRINGER INGELHEIM PHARMA GmbH & Co. KG (http://grls.rosminzdrav.ru/Grls_View.aspx?idReg=5738&t=e93bdl55-f2cf-4a28-8d60-be22eedc0bl7) having the composition per dose:

Components

Ipratropium bromide monohydrate0,021 mcg
Fenoterola hydrobromide0,050 mcg
Ethanol absolute8,415 mg
Purified water0,799 mg
Citric acid0.001 mg
HFA-134aUp to 54 mg

To determine the respirable fraction use several devices described in pharmacopoeias. The most commonly used is an 8-stage Andersen impactor, which allows not only to determine the respirable fraction, but also to assess the profile of the distribution of particle sizes.

Respirable fraction known drug determine the Lyali using the Andersen impactor, when the air flow rate of 28.3 l/min, when the transmission 4 l of air. We took the ratio of the mass of fine particles (2-7 cascades and filter) to the mass of all particles included in the impactor. For the drug, which does not contain a control particle size, it is 15-18%. Low values can be explained by the formation of a large number of small particles due to the lack of control particle size.

This is well illustrated by the plot of particles distribution fenoterol hydrobromide on the stages of the impactor (Fig.1).

Here along the axis of abscisses delayed values of the so-called "cutoff points" in microns, on the y - axis the percentage of the mass of drug deposited on the stages of the impactor. Draws the attention of a significant number of small, less than 0.5 micron particles, which do not provide a therapeutic effect, because mainly eliminated from the body during exhalation.

The present invention is to develop an effective stable inhalation composition for the treatment of asthma and chronic obstructive pulmonary disease. This problem is solved using the composition in the form of an aerosol spray containing as active components fenoterola hydrobromide and ipratropium bromide monohydrate, as auxiliary substances, ethyl alcohol absolute, triethylcitrate, propellant 1,1,1,4 Tetrafluoroethane (HFA-134a) or 1,1,1,2,3,3,3-Heptafluoropropane (HFA-227ea) and pharmaceutically who ramlau acid, selected from hydrochloric, phosphoric and citric acids in the following content of components in mg/dose:

Fenoterol hydrobromide0,025-0,100
Ipratropium bromide0,010-0,030
Monohydrate
pharmaceutically acceptable acid0,002-0,050
Triethylcitrate0,025-2,000
Ethanol anhydrous9,000-20,000
HFA-134a and/or
HFA-227eaUp to 54,000-65,000

Due to the instability of active substances in neutral medium, the drug should be acidified, therefore, when the test drug was administered acceptable acid.

Small therapeutic doses of active substances and low concentration in solution in the alcohol-propellant stipulate a specific role of regulator of particle sizes. Tests of a number of biologically inert compounds showed that the most promising compound is triethylcitrate.

Triethylcitrate (E 1505) - oily liquid, p is imeeetsja in the food and pharmaceutical industries, described in the European Pharmacopoeia, the acceptable daily intake of 20 mg/kg of body weight (Methodical recommendations on the safe use of excipients in medicinal products, Federal ncase, Minzdravsocrazvitia the Russian Federation, Moscow, 2004). T. O., security applications triethylcitrate no doubt.

It was found that the increase in the content of triethylcitrate the drug from zero to 0.25% increases respirable fraction 1.8 times, and the distribution profile has a maximum in the range from 1.5 to 2.0 μm. A further increase in the content of triethylcitrate to 1.0% has little effect on respirable fraction, but extends the distribution of the particles. Thus, managed to get the drug with an effective profile of the distribution of particles inhaled by patients. This is illustrated by the plot of the distribution for fenoterola hydrobromide (Fig.2).

Here also along the axis of abscisses delayed values of the so-called "cutoff points" in microns, on the y - axis the percentage of the masses. the drug deposited on the stages of the impactor.

As the propellant was used 1,1,1,4 of Tetrafluoroethane (HFA-134a) or 1,1,1,2,3,3,3-Heptafluoropropane (HFA-227ea). It should be noted that respirable fraction depends on a properly sized valve of the metering dispenser and their combinations.

The technical result is an increase respirable fraction up to 30% and optimum Professor the La particle distribution.

Preparation.

To obtain the product as possible for the two-stage and single-stage technologies.

In the first case, preparing the acid solution in ethyl alcohol absolute, it contains active substances control particle size-triethylcitrate, the solution is dispensed in aerosol containers, cylinders served by the metering valves and vacuumized, valves pressed. Then through the valve to the cylinders dosed propellant.

For single-stage technologies in the vessel-mixer, working under pressure, is preparing the acid solution in absolute ethanol, the solution is added to the active substance, the control of particle size and propellant, the solution is mixed. In aerosol containers placed metering valves, cylinders vacuumized, valves pressed. Dosing of a solution of active substance in the propellant takes place through the valve.

In both cases, the solutions are filtered through membrane filters with a pore size of 0.2 μm.

The invention is illustrated by examples, which cannot be construed as limitations on variations in the compositions. Given the number of components on a single dose of the drug. In the examples for fenoterola bromide selected dosage of 50 micrograms, for ipratropium bromide - 21 mcg.

Example 1

Fenoterola bromide 0,050 mg
Ipratropium bromide monohydrate0,021 mg
Citric acid0.005 mg
Triethylcitrate0,160 mg
Ethanol anhydrous16,000 mg
HFA-134aup to 65 mg

Results - respirable fraction 31,2%

Example 2

Fenoterola bromide0,050 mg
Ipratropium bromide monohydrate0,021 mg
Hydrochloric acid0.002 mg
Triethylcitrate0.030 mg
Ethanol anhydrous20,000 mg
HFA-134aup to 65 mg

Results - respirable fraction 17,6%

Example 3

Fenoterola bromide0,050 mg
Ipratropium bromide monohydrate 0,021 mg
Orthophosphoric acid0.002 mg
Triethylcitrate0,154 mg
Ethanol anhydrous20,000 mg
HFA-134aup to 65 mg

Results - respirable fraction 21,0%

Example 4

Fenoterola bromide0,050 mg
Ipratropium bromide monohydrate0,021 mg
Citric acid0.005 mg
Triethylcitrate0,350 mg
Ethanol anhydrous16,000 mg
HFA-134aup to 65 mg

The result is a respirable fraction of 27.5%

Example 5

Fenoterola bromide0,050 mg
Ipratropium bromide monohydrate0,021 mg
Citric acid0.005 mg
Triethylcitrate0,700 mg
Ethanol anhydrous16,000 mg
HFA-134aup to 65 mg

The result is a respirable fraction of 25.6%

Example 6

Fenoterola bromide0,050 mg
Ipratropium bromide monohydrate0,021 mg
Citric acid0.005 mg
Ethanol anhydrous16,000 mg
HFA-134aup to 65 mg

The result is a respirable fraction of 15.4%

Thus, the developed and the new stable during storage form of combined drug ipratropium fenoterola and bromide hydrobromide in the form of an aerosol metered, which eliminates the disadvantages of the known forms and effectively used in therapeutic practice for the treatment of diseases of the respiratory system.

Inhalation composition in the form of an aerosol for the treatment of asthma and chronic obstructive pulmonary disease, comprising as active components fenoterola hydrobromide and iprtr the Pius bromide monohydrate and excipients, characterized in that the quality of excipients contains ethyl alcohol absolute, triethylcitrate, propellant 1,1,1,4 Tetrafluoroethane (HFA-134a) or 1,1,1,2,3,3,3-Heptafluoropropane (HFA-227ea) and pharmaceutically acceptable acid selected from hydrochloric, phosphoric and citric acids in the following content of components in mg/dose:

Fenoterol hydrobromide0,025-0,100
Ipratropium bromide0,010-0,030
Monohydrate
pharmaceutically acceptable acid0,002-0,050
Triethylcitrate0,025-2,000
Ethanol anhydrous9,000-20,000
HFA-134a and/or
HFA-227eaup to 54,000-65,000



 

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Novel methods // 2484821

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41 cl, 2 tbl, 7 ex

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22 cl, 22 ex

FIELD: chemistry.

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16 cl, 1 tbl, 46 ex

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32 cl, 111 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 2,5 substituted arylsulphonamides of formula (Ia) or to their pharmaceutically acceptable salts, solvates, hydrates, stereoisomers or tautomers, where X represents S, SO or SO2; Y and Z represents (i) Y represents NR5; and Z represents =O, CO2R6 or C1-6alkyl; or (ii) Y represents CH2, CHF, CHCH3, O, S or SO2; and Z represents hydrogen or C1-6alkyl; R1 and R2 each independently represents halogen, C1-6alkyl or C1-6 halogenalkyl; R3 represents CN or NO2; R4 represents hydrogen or C1-6alkyl; R5 represents hydrogen or C1-6alkyl; and R6 represents hydrogen or C1-6alkyl. Invention also relates to compounds of formula (I) and (II), values of radicals of which are given in the invention formula, specific compounds, pharmaceutical composition based on compound of formula

,

and

,

method of modulating CCR3 activity.

EFFECT: obtained are novel compounds, possessing useful biological properties.

18 cl, 1 tbl, 3 ex

FIELD: medicine.

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EFFECT: method enables relieving signs of the allergic inflammation and a severity of RSV-infection by inhibiting anti-inflammatory murine il-5 gene and inhibiting the RSV virus replication.

2 cl, 17 dwg, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new phenylpyrimidone derivatives of formula I possessing the properties of a phosphodiesterase type 5 (PDE5) inhibitor. The compounds of formula I can be used for treating various vascular disorders, such as erectile dysfunction, pulmonary arterial hypertension, etc. In formula each R1 and R2 independently means H; C1-C10alkyl; halogen; CF3; CN; OR5; NR6R7; NHCOR8; aryl; or C1-C4alkyl optionally substituted by OR5; Z means OR3; R3 means C1-C6alkyl or C1-C3alkyl, substituted by C1-C3alkoxy group; R4 means SO2NR6R7; NR9R10, providing NR9R10 is other than NH2; COR11; OR12; or R4 means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH and C1-C6 alkyl; or R4 means 5- or 6-merous cyclic monosaccharide group; R5 means C1-C6alkyl; C1-C4alkyl optionally substituted by C1-C4alkoxy group; each R6 and R7 independently means H, OH, C1-C6alkyl, C1-C6alkoxy group, C3-C6alkenyl, C3-C6cycloalkyl, adamantyl, C3-C8lactamyl, aryl, Het or (CH2CH2O)jH, wherein j is 1-3; or each R6 and R7 independently means C1-C6alkyl, optionally substituted by OH, C1-C4alkoxy group, SO3H, SO2NR13R14, SO2R16, NR13R14, aryl, Het or 5-6-merous heterocyclyl; or each R6 and R7 independently means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of C1-C6 alkyl and C1-C6alkyl substituted by hydroxyl; or R6 and R7 together with a nitrogen atom attached whereto form 5-7-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH, COOR8, (CH2CH2O)jH, wherein j is 1-3, C1-C4alkoxy group, Het and C1-C6alkyl substituted by aryl; or R6 and R7 together with a nitrogen atom attached whereto form a glucosyl amino group, an amino acid residue, a residue of an amino acid ester or an amino amide residue. The other radical values are specified in the patent claim.

EFFECT: invention refers to pharmaceutical compositions based on the above compounds, using them, methods for preparing the compounds, and intermediate products.

18 cl, 2 tbl, 224 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and the pharmaceutical industry and describes a pharmaceutical inhaled medication for treatment of bronchial asthma and chronic obstructive lung disease, containing micronised tiotropium bromide as an active substance, and which contains as a carrier lactose with the average particle size of 120-200 mcm, sodium benzoate, sieved with a bulk density within the range of 0.30-0.50 g/cm3 and sodium benzoate micronised with the average particle size of 0.5-10 mcm with a specified content of components per a dose of medication.

EFFECT: invention provides higher percent of a respirable fraction of the active substance and, therefore, higher pharmacological activity.

3 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an agent for preventing and/or treating an allergic disease selected from pollinosis, allergic rhinitis, allergic conjunctivitis, atopic dermatitis and asthma, which is a low-molecular polysulphated hyaluronic acid derivative.

EFFECT: obtaining a low-molecular polysulphated hyaluronic acid derivative.

15 cl, 103 dwg, 17 tbl, 55 ex

FIELD: medicine.

SUBSTANCE: invention refers to methods of treating a patient suffering from severe and uncontrolled asthma which involve pulmonary administration of a glucocorticoid in the form of a vapour-phase nebulised aerosol in a combination with oral administration of a glucocorticoid. According to one of the declared methods, the nebulised aerosol is administered by inhalation at no more than 20 l/min rate in the total inhalation volume of at least 0.4 l of the vapour phase; t administration of the nebulised aerosol is preceded by administering no more than 150 ml of aerosol-free air. The glucocorticoid is administered in a daily dose of no more than 40 mg of prednisolone and an equivalent dose of another glucocorticoid. The other method of treating the patient involves pulmonary administration of the glucocorticoid in an amount of 400 to 4,000 mcg with using a nebuliser which is used to administer the glucocorticoid aerosol into the lower portion of the lungs at excessive pressure of 40 mbar or less that leads to deposition of more than 200 mcg of the glucocorticoid in the lower portion of the lungs. What is also declared is a method of treating the patient which involves pulmonary administration of the glucocorticoid in the amount of 400 to 4,000 mcg with the aerosol administered by inhalation consisting of three pre-specified periods wherein after the third period, the patient is advised to stop inhaling and exhale; the presented treatment leads to deposition of more than 200 microgram of the glucocorticoid in the lower portion of the lungs.

EFFECT: invention provides improved deposition of the inhaled glucocorticoid in the lower portion of the lungs, min 30% less consumption of oral glucocorticoids and fewer oropharyngeal side effects.

16 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and the pharmaceutical industry and describes a pharmaceutical inhaled medication for treatment of bronchial asthma and chronic obstructive lung disease, containing micronised tiotropium bromide as an active substance, and which contains as a carrier lactose with the average particle size of 120-200 mcm, sodium benzoate, sieved with a bulk density within the range of 0.30-0.50 g/cm3 and sodium benzoate micronised with the average particle size of 0.5-10 mcm with a specified content of components per a dose of medication.

EFFECT: invention provides higher percent of a respirable fraction of the active substance and, therefore, higher pharmacological activity.

3 cl, 10 ex

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