Pharmaceutical composition for inhalation

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to dry powder-like pharmaceutical composition for inhalation and to method of its obtaining. Into composition of pharmaceutical composition included are two active ingredients, which represent salmeterol and fluticasone or their pharmaceutically acceptable salts, solvates or esters, two pharmaceutically acceptable excipients, which have value d50 respectively approximately 125-145 mcm and approximately 50-100 mcm and which represent mono- or disaccharides. Method of composition obtaining consists in formation of preliminary mixtures of each of active ingredients and each of pharmaceutically acceptable excipients and mixing two preliminary mixtures with obtaining with fraction of medication, with weight ratio of exipients in said two preliminary mixtures constituting from 1 to 5.

EFFECT: pharmaceutical composition is applied for treating asthma, COLD (chronic obstructive lung disease), allergies and infectious diseases.

6 cl, 7 dwg, 3 tbl, 3 ex

 

The technical field

The present invention relates to pharmaceutical compositions for inhalation. The invention additionally relates to a method for establishing the performance characteristics of such pharmaceutical compositions and the use of such compositions in the treatment of asthma, COPD (chronic obstructive pulmonary disease), allergies, infectious diseases and diseases of the cardiovascular system.

Prior art

Inhalation therapy pharmaceutical device for delivery, such as dry powder inhaler ("SLEEP"), typically used for delivery of predetermined doses of the pharmaceutical composition, and therefore the drug in the pulmonary system of the patient. Active connection must be inhalated. In order to have the ability to penetrate into the lungs, it must be represented as particles having a size from about 0.5 to 10 μm. Such particles can be obtained, for example, by micronisation, controlled deposition of suitable solvents or drying spray, if process conditions are selected, monitored, and enforced properly. In a typical SLEEP dose of the pharmaceutical composition is in the camera for aerosolization, where it undergoes the aerosolization and therefore dispersed to udihe the s particles in the air stream, created by the breath of the patient. Also in the field of technology it is well known that in order to settle in suitable areas of the lung, associated with local and/or systemic delivery of drugs dispersed particles should be of a suitable size.

Pulmonary system includes the upper respiratory tract, including the oropharynx and throat, and then the lower parts of the respiratory tract, which include the trachea followed by branching to the bronchi and bronchioles. The upper and lower parts of the respiratory tract are referred to as conductive Airways. Terminal bronchioles then divide into respiratory bronchioles, which then lead into the alveolar region, or deep parts of lungs.

It is well known that particles of drug deposited in specific areas of the pulmonary system based on aerodynamic particle size and flow rate of air, which they do. As a rule, with the average inhalation flow rates from 30 to 90 litres per minute particles having an aerodynamic diameter in the range from 0.5 to 3 μm, are suitable for systemic delivery, because these particles are selectively deposited deep in the lungs. As mentioned above, particles with aerodynamic diameter in the range from about 0.5 to 10 microns, suitable for local access is key in the lung.

Particles with aerodynamic diameter larger than 10 μm, as a rule, are deposited in the mouth, throat or upper respiratory tract, leading to only a small therapeutic benefit. Particles with aerodynamic diameter less than 0.5 μm, not deposited from the air flow in the lungs, and then fizzle out by the patient.

Thus, the size or diameter of the particles is critical for therapeutic effects of the pharmaceutical composition for inhalation. Attempts in this area included the use of excipients such as milled or micronized lactose for cultivation of medicinal product in a pharmaceutical composition, ensuring accurate dosing microgramme quantities of very strong drugs in milligramme dose with an acceptable degree of control. By controlling the ranges of particle sizes of the powders of excipients reported increased turnover, the ability to dispersion and aerosolization of dry powder compositions of the medicinal product.

In attempts to increase the aerodynamic properties (the ability to aerosolization and the ability to dispersion) of particles delivered to the selected area of the target light, recent efforts have led to the fact that we had to move away from the use of particles medicines crushed to desire the constituent size and then mixed with excipients media.

For example in accordance with WO 99/16419 compositions of the prior art containing crushed inhaled particles medications and large particles system excipientes media can give the opportunity to at least some particles of the drug had little contact with the major surface of the media and dismissed by inhalation, but a significant number of drugs were not able to break free from large particles of lactose, and deposited in the throat. To reduce unwanted deposition in the throat, WO 99/16419 disclosed microporous microparticles containing the drug, excipient (i.e. lactose) and surface-active substance.

In WO 03/024396 disclosed pharmaceutical composition comprising the fraction of drug particles with a mass median aerodynamic diameter of not more than approximately 10 microns; and at least 50% non respirable fraction excipient, where these are not respirable fraction excipient contains particles of excipient low density, having an aerodynamic diameter greater than approximately 10 microns and a geometric diameter greater than approximately 30 microns.

In the US 2005/175549 disclosed inhalation dry powder mixture containing effective amounts of two AFI, possibly together with a pharmaceutically admission is subject to the carrier. The media should be tonkodispersnoe crushed and may be selected from sugars, such as lactose. However, there is no indication of the use of different particle sizes for the respective media, and there is no indication that the attitude of the media in the composition can be used to determine specific characteristics of the inhalation mixture.

In the pharmaceutical compositions for inhalation with two or more than two active substances adjusting the aerodynamic diameter is problematic. The aerodynamic diameter of the composition is a parameter that determines how deep the particles penetrate into the respiratory tract: the smaller the particles penetrate deeper. Adjustment of the aerodynamic diameter inhalation of the composition necessary to ensure the penetration of the active ingredient in the desired part of the respiratory tract for full disclosure of its potential.

Especially with two or more than two active substances which should perhaps have different desired depth of penetration into the respiratory tract, the adjustment is very complicated due to the interactions of the excipients with the active substances and active substances with each other. When General methods of preparation of compositions for inhalation adjustment may not the be conducted in the right way, since the distribution of binding the active ingredients to excipientes media is very random.

Because there is a growing need for compositions for inhalation for use in combination therapy with two or more than two active agent, it is highly necessary to develop new compositions that provide directional introduction of various inhalation drugs the patient in a precise and uniform number.

Brief description of the invention

Thus, the present invention is to provide a pharmaceutical composition for inhalation containing more than one active ingredient, where the interaction between the various active ingredients significantly reduced. Another objective of the present invention is to provide a pharmaceutical composition of the above type for inhalation having improved stability, homogeneity and higher biological availability of the active ingredients. Another object of the invention is to provide a pharmaceutical composition, which gives the opportunity to reduce the amount of active agent in a single dose for a given treatment as compared with the compositions of the current level of technology. Another problem mentioned is carried out in to offer a pharmaceutical composition, giving the opportunity for a direct introduction it contains different active ingredients and for their delivery to the intended scope in the respiratory system of the patient in a predefined number. Another object of the invention is to provide a method of manufacturing these pharmaceutical compositions and a method of setting the operating characteristics of these available pharmaceutical compositions.

These tasks are solved by the independent claims. Preferred embodiments are specified in the dependent claims.

The present invention is based on a new approach for the preparation of pharmaceutical compositions and their performance characteristics and their application for inhalation therapy. Each of the different active ingredients are mixed in the method of pre-mixing with a suitable excipient. This method can include the various stages of mixing to ensure proper binding of the active ingredient with excipients carrier. The method of pre-mixing may vary depending on the active substance. The preliminary mixture is then mixed together in the main method of mixing, which includes different is the stage of mixing with lower intensity with obtaining a homogeneous mixture without breaking the binding at the stages of pre-mixing.

By using this approach can be achieved following unexpected effects.

The aerodynamic diameter of particles with one active substance can be adjusted independently of particles with different active substance. Thus, the introduction of each active substance in the respiratory tract can be adjusted properly. In addition, the active substance, to a lesser extent, interact with each other in the final composition, the stability of the composition is enhanced, easier to achieve homogeneity of the composition, increases the action of the active substance and a smaller amount of active ingredient required for the same steps as compared with conventional compositions.

Thus, the present invention allows to prepare a new composition for inhalation in combination therapy offers a way of establishing its characteristics.

Detailed description of the invention

In the first aspect of the present invention, a method for establishing the performance characteristics of a pharmaceutical composition for inhalation, at which stage:

a) providing at least two pre-mixes, each of which contains a mixture of active pharmaceutical ingredient and a suitable excipient;

b) mixing at least DV is x pre-mixes; and

C) introducing the mixture into a suitable device for delivery, is able to deliver a fraction of the drug in the pulmonary system of the patient,

wherein the mass ratio of the excipients in at least two pre-mixtures is from 1 to 5.

It was unexpectedly found that the characteristics of a pharmaceutical composition for inhalation, such as the fraction of fine particles (FTC) or dose of fine particles (DTC) corresponding API (active pharmaceutical ingredient), can be influenced by changing the mass relations of the excipients used in different pre-mixes, to a specific value. It is assumed that the mass ratio between the excipients used in different pre-mixtures comprising from 1 to 5 (including the values 1 and 5), ideal for fine adjustments FTC or dose of fine particles (DTC) active ingredients.

In that case, if you use more than two pre-mixtures, the ratio equal to 1-5, reflects the mass ratio of the mass of the largest excipient in one pre-mixture to the mass of the smallest excipient in another preliminary mixture.

On the operational characteristics of the composition can additionally be affected by the use of mixing with high shear and/or low the m shear at the stage a) and/or b). As you can see in example 3, can also be included in the conditions under which use both types of mixing.

In accordance with a preferred embodiment of excipient used in a variety of pre-mixtures, is the same or different. In that case, if the excipients are different, they may differ chemically and/or different particle size. In the latter case, for the preferred embodiment, the d50 value for the individual excipients differ by more than 10%, preferably more than 15%, most preferably more than 20%.

Thus, in accordance with an aspect of the present invention proposed pharmaceutical composition for inhalation containing fraction medicines at least two active pharmaceutical ingredients and at least two pharmaceutically acceptable excipients, where the active pharmaceutical ingredients associated with these excipients, and where each active ingredient associated with different excipients, in which the d50 value for the individual excipients differ by more than 10%, preferably more than 15%, most preferably more than 20%.

The value of d50 is also known as the median diameter or median value of the particle diameter, and represents the value of the diameter is RA particles in the event, when the cumulative percentage distribution reaches 50%. He is one of the important parameters representing characteristics of the particles. For example, if d50 is 5 μm, 50% of the particles exceeds 5 μm, and 50% less than 5 microns.

The present invention contains at least two different forms of active pharmaceutical agents independently associated with at least two excipients. That is, the invention also covers cases in which three or more than three active agent are combined in a single pharmaceutical composition. But in standard cases, the usual number of active agents is two or at most three active agent.

Used in this document, the term "associated" refers to any type of reversible binding between the individual particles of active agents and excipients. It includes binding by ionic bond, covalent bond, or more weak links, such as hydrogen bridge of communication and van der Waals forces.

Previously used the term "different" means that the particle size (d50 value) of different excipients as described above. This does not necessarily mean that the excipients must chemically differ, although this is not excluded by this definition.

As described above, in a preferred embodiment of the present image is the shadow value of d50 for the individual excipients differ by more than 10%. It was unexpectedly found that the positive effects of the present invention, in particular smaller interaction between the individual active ingredients with each other in the final composition, to improve stability of the composition, the better the homogeneity of the composition and, importantly, that the action of the active substance increases, and a smaller amount of active ingredient required for the same steps as compared with conventional compositions can be achieved in that case, if the value of d50 for the individual excipients differ by more than 10%.

As can be seen in Table 1 and in accordance with any results, by the fact that they provide (and mixed) pre-mixed with excipients, for which d50 differ by more than 10%, can affect the fraction of fine particles (hereinafter also referred to as PTC) for each API, in this final case to reduce.

Active ingredient, is presented in the compositions of the present invention, fundamentally can represent any desired pharmaceutically active compound, which can be entered by inhalation dry powders. In order to active the connection was inhalation, that is able to penetrate into the lung, it must be represented as particles having an average maximum diameter of approximately 10 μm, n is the sample, approximately 1 to 10 μm and preferably from about 1 to 6 μm. Such particles can be obtained using methods known in themselves, for example, by grinding, the controlled deposition of a suitable solvent (for example even from supercritical carbon dioxide) or by spray drying, if process conditions are selected appropriately, monitored, and enforced. Used in this document, the term "fine particle" means a particle having an average size of 5 microns or less.

In accordance with the preferred embodiment at least two of the active ingredient is independently selected from the group consisting of active ingredients suitable for inhalation, preferably analgesics, antiallergic, antibiotic, anti-infective, antihistamines, anti-inflammatory, antitussive agents, bronchodilators, anticholinergic drugs, hormones, xantina, vaccines, therapeutic proteins, peptides and combinations thereof, more preferably of albuterol, beclomethasone, budesonide, carmoterol, ciclesonide, fenoterola, fluticasone, formoterol, indacaterol, ipratropium, mometasone, salbutamol, salmeterola, Tiotropium and their pharmaceutically acceptable salts or solvate.

In the case of compositions that Moderato least one pharmaceutically active ingredient in the form of a pharmaceutically acceptable salt, this salt may be selected from salts of chloride, bromide, iodide, nitrate, carbonate, sulfate, methyl sulfate, phosphate, acetate, benzoate, bansilalpet, fumarata, malonate, tartrate, succinate, citrate, lactate, gluconate, glutamate, edentate, nelfinavir, pamoate, Pantothenate or hydroxynaphthoate. It can also be represented in the form of a pharmaceutically acceptable complex ester such as acetate, propionate, phosphate, succinate or etabonate.

The number of active compounds in the compositions obtained in accordance with the invention, may be varied within wide ranges and depends largely on the respective active compounds, and to some extent also from the used powder inhaler. Typically, the concentration of the active compound may range from about 0.1 to 10 wt.%, in particular from about 0.1 to 5 wt.% based on the weight of the entire composition. You may also can be desirable to a higher or lower concentration, where, however, sometimes there are concentrations of active compound is less than 0.001 wt.% or less than 0.01 wt.%.

Basically fit all excipients (or carriers), commonly used in dry powder compositions, for example, a suitable mono - or disaccharides, such as glucose, lactose, lactose monohydrate, sucrose or trehalose is, sugar alcohols such as mannitol or xylitol, polylactic acid or cyclodextrin, glucose, trehalose, and in particular lactose monohydrate.

However, the preferred excipients selected from the group consisting of sugars and saccharides, preferably lactose, having a purity of inhalation, more preferably alpha-lactose monohydrate in the form of crystalline lactose, powdered lactose or micronized lactose.

Excipient preferably provided in the composition according to the invention with a particle size that is not suitable for inhalation. However, the particles of the medium, on the other hand, should not be too large, since the latter may have an adverse effect on FTC. Thus, in the preferred embodiment the fraction of the drug composition contains two excipient having a d50 value about 125-145 μm and approximately 50-100 microns.

If desired, in addition to pengalaman particles of excipient composition may also contain a proportion of inhalation particles excipient; for example, in addition to the relatively coarse particles of the carrier-monohydrate lactose composition may contain a proportion, for example from 0.1 to 10 wt.% micronized lactose monohydrate, which may be, for example, the particle diameter is a maximum of 10 μm, a CR is doctitle most 5 μm, for at least 50% of the particles.

Among the most preferred excipients present commercially available monohydrate, alpha-lactose that has pharmaceutical quality. Preferred excipients having a d50 value of approximately 185-215 (coarse lactose)having a d50 value of approximately 125-145 µm (fine lactose), and having a d50 value of 50-100 μm (superrecovery lactose). Thus, the combination of such excipients (coarse, fine and superrecovery lactose) blagoprijatno can be used in the present invention, since the value of d50 for them differs by more than 10%.

Share excipient substances in the compositions according to the invention can vary within a wide range depending on cultivation required or desired for a particular active ingredient. Typically, the share of excipient substances to the total fraction of the medicinal product may be, for example, from about 80 to 99.9 wt.%, where, however, a higher or lower share can also be beneficial depending on the active ingredient.

In yet another embodiment the pharmaceutical composition is prepared by mixing at least two pre-mixes, each of which contains one active ingredient and one excipient. It is especially important to realize izobreteny is, because the composition of pre-mixes ensures that each individual active ingredient is associated with its own specific excipients.

Described dry powder composition can be used in all conventional dry powder inhalers. They are particularly favorable for use in mnogochasovykh dry powder inhalers that contain a reservoir for powder.

In another aspect the present invention relates to a method for producing a pharmaceutical composition for inhalation containing fraction of the medicinal product, as defined above, at which stage:

a) providing at least two active ingredients and at least two pharmaceutically acceptable excipients, where the d50 value for the individual excipients differ by more than 10%, preferably more than 15%, most preferably more than 20%;

b) education pre-mixes for each of the active ingredients and each of the active excipients;

C) mixing at least two pre-mixes with receiving a fraction of the medicinal product; and

g) introducing a fraction of the drug in a suitable device for delivery that can deliver the specified fraction of the drug in the pulmonary system of the patient.

As stated above, in this method, at least two of the active ingredient is preferably selected from the group consisting of active ingredients suitable for inhalation, preferably analgesics, antiallergic, antibiotic, anti-infective, antihistamines, anti-inflammatory, antitussive agents, bronchodilators, anticholinergic drugs, hormones, xantina, vaccines, therapeutic proteins, peptides and combinations thereof, more preferably of albuterol, beclomethasone, budesonide, carmoterol, ciclesonide, fenoterola, fluticasone, formoterol, indacaterol, ipratropium, mometasone, salbutamol, salmeterola, Tiotropium and their pharmaceutically acceptable salts or solvate.

Similarly, the excipients are preferably selected from the group consisting of Sugars and saccharides, preferably lactose quality for inhalation, preferably alpha-lactose monohydrate in the form of crystalline lactose, powdered lactose or micronized lactose.

In another aspect the present invention relates to pharmaceutical compositions for inhalation, which is prepared using the above method. This pharmaceutical composition is preferably takes the form of an inhaler, more preferably form the delivery devices containing fraction medicinal means is a and one or more than one auxiliary agent, capable of delivering a specified fraction of the drug in the pulmonary system of the patient.

The preferred form of such device for delivery is a dry powder inhaler (IPN). The drug in these inhalers is in the form of a dry powder that must be inhalieren. There is no device or gas to promote powder. Commercially available examples is marketed under the trademark icons Rotadisk®, Diskhaler®, Diskus®or Turbohaler®.

In another aspect the invention relates to the use of the above pharmaceutical compositions for the treatment of asthma, chronic obstructive pulmonary disease (COPD), allergies, infectious diseases and diseases of the cardiovascular system.

The present invention is further illustrated with Graphics and Examples. The following additional examples illustrate the invention but, of course, should not be construed as limiting the scope of invention.

Description of Figures

Figure 1 shows detailed information about the main method of mixing according to the present invention.

Figure 2-7 demonstrate a dose of fine particles (DTC) in the compositions in accordance with table 2.

Examples

Example 1:

Table 1: Examples of compositions

The composition was mixed ACC is accordance with the methods, described in figure 1.

The results:

Table 1
Lactose in the pre-mixture 1Lactose in the pre-mixture 2FTC AFI 1FTC AFI 2
Composition 1Lactose (D50=72 µm)Lactose (D50=72 µm)47,7%42,7%
Composition 2Lactose (D50=135 µm)Lactose (D50=72 µm)26,3%36,8%
Composition 3Lactose (D50=135 µm)Lactose (D50=95 µm)20,8%20,3%

Also, Figure 1 illustrates how the mixing of the present invention to obtain a composition for use in the treatment of asthma.

In Composition 1 used the same excipients, in both pre-mixes. In Compositions 2 and 3 used excipients having a d50 value differs by more than 10%. Impact on FTC both used the AFI's noteworthy. Whereas the values FTC for Composition 1 are 47,7 and 42.7 percent, respectively, they are significantly reduced in Compositions 2 and 3. Thus, FTC is reduced, thereby improving pharmaceutical characteristics of Compositions 2 and 3 compared to Composition 1.

Example 2: the Proportion of lactose in the preliminary mixture

Results: see Figure 2-7

Table 2
The amount of lactose in each of the preliminary mixture is modified in order to carry out fine adjustment of the schedule change performance/results for each composition with special emphasis on the functionality of the first dose.
Preliminary mixture SalXPreliminary mixture FluP
DoseThe proportion of lactose (SalX/FluP)SalX [%]Lactose [%]FluP [%]Lactose [%]
4,80,9281,01,47 16,8
110/47,52,50,9270,01,4727,6
1,50,92to 58.11,4739,5
the 4.70,9778,93,3316,8
250/502,80,9770,53,3325,2
1,50,97to 58.13,3337,6
4,50,9774,97,3316,8
550/501,70,97to 58.17,3333,6
/td> 1,00,9745,87,3345,9

Conclusion:

By adjusting the proportion of lactose in the preliminary mixtures during the method of mixing the profile DTC/results can be accurately adjusted. In example 2, by reducing the dose of lactose DTC increased, especially at the beginning of the life cycle of the device, when it is much smaller in comparison with the remaining part of the life cycle of the device. Thanks to this subtle correction of the overall functionality of the composition is improved.

Example 3: Method of pre-mixing

Table 3 summarizes the results FTC for compositions made with or without prior mixing.

Table 3
The method of mixingMixerFTC AFI 1FTC AFI 2
Stage 1Stage 2Stage 3
Preliminary mixture AFI 1Prewar the tion mixture AFI 2 Pre-mixLow shear Low shear High shear30,5%36,7%
The lack of pre-mixHigh shearing force42,7%46,4%
Both AFI pre-mixed togetherAdditional lactoseHigh shearing force44,6%49,2%
Pre-mix only AFI 1Adding AFI 2 and lactoseLow shear High shearto 47.249,0%

Conclusion:

Pre-mixing the API using different conditions, have changed the functionality of the composition. The latter were then given an opportunity to increase or reduce functionality if required for the product. The use of two different mixers is also a determining factor.

1. A method of obtaining a dry powder pharmaceutical composition for inhalation, at which stage:
a) providing two active ingredients and two of pharmaceutically acceptable excipients;
b) education pre-mixes for each of the active ingredients and each of pharmaceutically acceptable excipients;
C) mixing the two pre-mixes with receiving a fraction of the medication;
where two of the active ingredient are salmeterol and fluticasone or their pharmaceutically acceptable salt, solvate or ester;
where these two pharmaceutically acceptable excipient have a d50 value about 125-145 μm and approximately 50-100 microns and are mono - or disaccharides; and the mass ratio of the excipients in these two pre-mixtures is from 1 to 5.

2. The method according to claim 1, where the excipients differ in chemical nature.

3. The method according to claim 1, where excipients selected from the group consisting of lactose, with as for inhalation, preferably alpha - lactose monohydrate in the form of crystalline lactose, powdered lactose or micronized lactose.

4. Pharmaceutical composition for inhalation, which is obtained by the method according to any one of claims 1 to 3.

5. The pharmaceutical composition is about 4, which is represented in the form of an inhaler, preferably in the form of the delivery devices containing fraction of a drug and one or more than one auxiliary agent, capable of delivering a specified fraction of the drug in the pulmonary system of the patient.

6. The pharmaceutical composition according to claim 4 or 5 for the treatment of asthma, COPD (chronic obstructive pulmonary disease), allergies and infectious diseases.



 

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4 cl, 4 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) in free form or in form of a pharmaceutically acceptable salt or solvate, which are useful in treating inflammatory or obstructive airways, pulmonary hypertension, pulmonary fibrosis, liver fibrosis, muscle diseases and systemic skeletal disorders and other diseases which are mediated by activity of the ALK-5 receptor or ALK-4 receptor. The invention also relates to a method of producing compounds of formula (I) and pharmaceutical compositions. In formula , T is a pyridin-2-yl which is optionally substituted in one position with R1; T1 is a pyridinyl which is optionally substituted in one or two positions with R1, R2, R5, C1-C4-alkoxy group, C1-C4-alkoxycarbonyl or cyano group; and Ra and Rb are independently hydrogen; C1-C8-alkyl, optionally substituted in one, two or three positions with R4; C3-C10-cycloalkyl, which is optionally substituted in one or two positions with a hydroxy group, amino group, C1-C8-alkyl, C1-C8-alkoxy group, halogen, cyano group, oxo group, carboxy group or nitro group; or C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, amino group, cyano group, oxo group, carboxy group, nitro group or R5; R1 is C1-C8-alkyl; R2 is C6-C15-aryl, optionally substituted in one, two or three positions with a halogen, hydroxy group, R1, R5, C1-C8-alkylthio group, amino group, C1-C8-alkylamino group, etc. The rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of using said compounds.

20 cl, 2 tbl

Organic compounds // 2482838

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to method of reducing tendency of glycopyrronium salt to aggregate and/or form agglomerates during storage. Claimed method includes crushing glycopyrronium salt with obtaining particles with the average size of 10 mcm and processing of crushed glycopyrroneum salt with dry medium at temperature from 40°C to 120°C for from 6 to 96 hours. Invention also relates to inhaled composition of dry powder, which contains glycopyrroneum salt, proceeds by said method.

EFFECT: invention makes it possible to reduce tendency of crushed glycopyrroneum salt to aggregate and/or form agglomerates without application of solvents for provision of medication stability.

8 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , wherein R2 means methyl, Y means carbon or nitrogen, and R1, R3 and R4 have the value specified in the patent claim. Also, the invention refers to a pharmaceutical composition for the use as a pharmaceutical drug having activity of a phosphatidylinositol-3-kinase inhibitor, to the use of the compounds of formula I for preparing the pharmaceutical drug for treating a disease mediated by phosphatidylinositol 3-kinase and to a method for preparing the compounds of formula I .

EFFECT: preparing the compounds of formula I possessing activity of the phosphatidylinositol-3-kinase inhibitor.

10 cl, 5 tbl, 51 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I

or its pharmaceutically acceptable salts wherein R1-3, R5-7, a, X, Y, Y', Y" and Z have the values specified in cl. 1 of the patent claim which are muscarinic receptor antagonists. The invention also refers to pharmaceutical compounds, methods for preparing and methods for using such compounds.

EFFECT: preparing the compounds applicable as muscarinic receptor antagonists.

25 cl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: dry powder composition for pulmonary inhalation Parkinson's disease contains apomorphine and magnesium stearate with a nominal dose of apomorphine being 3 to 10 mg and providing a dose of fine particle fraction (FPF) making 2 to 6 mg when administered. A method for preparing the composition involves the stages of combining the apomorphine particles with the magnesium stearate particles by mixing and milling, milling including compression.

EFFECT: composition under the invention contains apomorphine in a stable dry powder form suitable for the direct administration of low doses of the drug with minimal adverse side effects.

15 cl, 12 dwg, 13 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solution for producing an inhalation preparation containing fenoterol hydrobromide as an active agent, purified water and excipients with the excipients presented by sodium benzoate, an acidity regulator representing an organic acid in the following proportions, mg/ml: fenoterol hydrobromide 1.0-1.1; sodium benzoate 0.2-2.0; organic acid 1.4-1.7; purified water the rest provided pH makes 3.2-3.5.

EFFECT: solution has the high value of respirable fractions and high stability.

6 cl, 3 ex

FIELD: tobacco industry.

SUBSTANCE: imitative smoking device (1,51) contains an imitative cigarette having an essentially cylindrical cigarette-like shape and a charging unit (2, 50) having an essentially rectangular body shaped like a cigarette packet. The filling device (2, 50) contains charging gas (32, 59) for the imitative cigarette and a means for elective retention of the imitative cigarette. The imitative cigarette may be completely retained inside the body (3, 52). The cigarette may be retained at a place other than the charging place. A dose counter may be envisaged to give visual indication of doses in the charging device.

EFFECT: technical result achieved using the imitative cigarette device and the charging device for the imitative device according to the invention consists in smoking skill imitation, the imitative cigarette charging and its usage simplification.

7 cl, 15 dwg

FIELD: medicine.

SUBSTANCE: there are disclosed method and composition for intensifying mucus excretion and treating pulmonary disorders, such as cystic fibrosis. They use together with osmotically active substance a synthetic pulmonary surfactant containing one or more pharmaceutically acceptable phospholipids mixed with SP-B polypeptide or its fragment, or polypeptide containing at least 10 amino acid residues and no more than about 60 amino acid residues, said polypeptide containing a sequence having variable areas of hydrophobic and hydrophilic amino acid residues presented by formula (ZaUb)cZd, wherein surfactant activity of mixed phospholipids and polypeptide higher than that of one phospholipid, has osmolarity varying between 220-1200 mOsm/kg, the concentration of free anions varying between 20-200 mmole/l and the pH value varying between 6.8 and 8.0, and the surfactant provides the pulmonary delivery of a daily dose varying between approximately 20 and 200 mg of total phospholipid equivalent.

EFFECT: invention provides intensified mucus excretion and improved quality of life in the patients suffering cystic fibrosis, bronchitis, bronchiectasis, ciliary diskinesia, COPD, or sinusitis.

15 cl, 2 dwg, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely pharmacology. A pharmaceutical composition contains an active component selected from a group of pharmacologically active substances: having an effect on a central nervous system, peripheral neurotransmitter processes, cardiovascular system, coagulation system, neoplastic processes, metabolic processes, showing antibacterial activity, an excipient, cyclodextrin as a component ensuring high bioavailability, and a component modulating a duration of the pharmacologically active substance representing polymer. The pharmaceutical composition is presented in the form of a powder of particle size within 0.4 to 2 mcm. A method for administration of the pharmaceutical composition provides the pulmonary oral administration in the form of a dry or liquid aerosol with mass median aerodynamic diameter 0.8 to 2.0 mcm and degree of polydispersity 0.8 to 2.0.

EFFECT: ensured effective delivery of the pharmacologically active substances in the systemic circulation and alveolar inhalations of min 75% of solid or liquid aerosol particles.

5 cl, 5 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared invention refers to chemical-pharmaceutical industry, and concerns new, taste-masking powders specified in a group consisting of biologically active substances for treating, relieving and preventing diseases in humans and animals, with average particle diameter d50 1 to 40 mcm and coating thickness 1 to less than 20 mcm of a hydrophobic coating material containing 50 to 90 wt % (relative to total powdered solid substance and coating material) with the hydrophobic coating material being wax of fusion temperature within 30 to 180°C, resin, polymethacrylate or its copolymer for inhalation or oral administration.

EFFECT: what is offered is a simple method for preparing and applying them for introducing the biologically active substances.

10 cl, 3 ex

FIELD: medicine.

SUBSTANCE: as an active substance, an aerosol contains aprotinin taken in the amount 23 to 30 mg in 100 ml of the preparation; a propellant is 1,1,1,2-tetrafluoroethane 70-84 vol. %; the solvents are ethanol 8-15 vol. %, glycerine 5-10 vol. %, water and a stabiliser is peppermint oil. The aerosol is pressurised in an aerosol container with a measuring valve.

EFFECT: preparation under the invention preserves native use and long storage antiprotease and antiviral properties of aprotinin.

6 cl, 2 tbl

FIELD: medicine; pharmaceutics.

SUBSTANCE: application of an antidepressant for manufacture of a medical product in the form of a dry powder for treatment of premature ejaculation, the corresponding way of treatment, an inhaler of dry poropps, containing a medical product of an antidepressant and a blister with an antidepressant (for example, tricyclic clomipramine depressant) for application in an inhaler of a dry powder are offered. The invention provides achievement of therapeutic effect during not more than 20 minutes at reduction of a dose and by-effects (in comparison with peroral intake of antidepressants). Thus bond deposition in a drink was less than 10%.

EFFECT: acceleration of achievement of therapeutic effect.

30 cl, 3 dwg, 3 tbl

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns pharmaceutical composition of metered aerosols containing antiasthmatic agents in the form of suspensions, solutions and emulsions. The metered aerosols are characterised with improved pharmaceutical properties and high storage stability. The pharmaceutical composition of metered aerosols containing antiasthmatic agents in the form of suspensions, solutions and emulsions, contains therapeutically effective amounts of Salbutamol or its salts, or formoterol fumarate or budesonide or beclomehasone dipropionate, propellent R 134A and target additives including ethyl alcohol, glycerine, isopropyl myristate, Tween 80, water.

EFFECT: suitable for treatment of various obstructive pulmonary diseases such as bronchial asthma, bronchitis, pneumonia etc.

4 cl, 12 ex

FIELD: medicine.

SUBSTANCE: ejection liquid is capable to stable ejection by means of the device using thermal energy. This liquid contains at least one substance chosen from the group, consisting of the proteins and peptides. Possibility of application of a liquid in the ink-jet device using thermal energy, improves addition at least one substance chosen from group, consisting of amino acids both their salts, and surface-active substance to the water solution containing at least one substance, chosen of the group consisting of proteins and peptides.

EFFECT: stability of adjustable ejection of an albuminous solution or peptide with obtaining of desirable volume of a microdrop.

14 cl, 9 dwg

Drug form // 2493830

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to drug form, preferably, to pill for per oral application, for pain treatment with controlled release of pharmacologically active composition (A), which it contains. Drug form contains pharmacologically active composition (A), which is potential for abuse, representing opioid or opioid derivative, and hydrophilic polymer (C). Part of surface of drug form by invention is convex, and the other part of its surface is concave. Drug form has tensile strength B1, at least, 500 H in direction of tension E1 and has tensile strength B2 lower than 500 H in direction of tension E2.

EFFECT: drug form by invention is stable to rupture and stable against abuse.

16 cl, 21 dwg, 6 ex

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