Microparticles with antibiotic for inhalation

FIELD: medicine.

SUBSTANCE: claimed invention relates to capsule for application with inhalator of dry powder, which contains composition in form of dry powder for pulmonary introduction, which contains mechanosynthesised microparticles, consisting of antibiotic and magnesium stearate.

EFFECT: invention relates to method of obtaining claimed capsule and its application in treatment of bacterial infection, associated with certain lungs diseases.

10 cl, 4 ex, 3 tbl, 1 dwg

 

Field of the INVENTION

The present invention relates to compositions for inhalation containing microparticles consisting of an antibiotic and magnesium stearate.

The invention also relates to a method of obtaining these microparticles and their use in the treatment of bacterial endobronchial infections associated with certain lung diseases.

PRIOR art

Cystic fibrosis, also known as MB or cystic fibrosis is a lethal genetic disorder.

Although it is formally considered as a rare disease, it is one of the most common inherited diseases, leading to reduced life expectancy, and affects more than 60,000 people worldwide.

He is associated with impaired transport of chloride ions across the membranes of epithelial cells of exocrine glands, which leads to the decrease of water content in their secrets. Morphological changes in the form of expansion and hypertrophy of bronchial glands are accompanied by the formation of mucous plugs. This viscous mucus in the Airways leads to the possibility of bacterial colonization and the subsequent development of infection in the respiratory tract, which contributes to continuous tissue damage.

Haemophilus influenzae and Staphylococcus aureus are the first choice�and pathogens, colonizing the respiratory tract in childhood. With the progression of lung disease occurs colonization by the pathogen Pseudomonas aeruginosa.

After the unstable period of the colonization of Pseudomonas aeruginosa in the majority of patients with MB develop chronic colonization, non-eradication.

Among other things, the currently used parenteral antibiotics belonging to the class of aminoglycosides, and, in particular, tobramycin.

These antibiotics prevent the progression of MB, reducing lung damage and improving their functions.

However, aminoglycosides penetrate poorly into the endobronchial secrets (sputum) than due to the need for intravenous administration of high doses to achieve effective concentrations at the site of infection. These high doses of lead risk in patients nephrotoxic and ototoxic effects.

These problems can be overcome by the introduction of drugs into the lungs by spraying, since with this method of introduction of these antibiotics are poorly absorbed through the epithelial surface of the lung, while maintaining chemical stability.

In particular, aqueous compositions for injection tobramycin [(2S,3R,4S,5S,6R)-4-amino-2-{[(1S,2S,3R,4S,6R)-4,6-diamino-3-{[(2R,3R,5S,6R)-3-amino-6-(aminomethyl)-5-hydroxyhexane-2-yl]oxy}-2-

hydroxy�illogical]oxy}-6-(gidroximetil)t-3,5-diol] with the use of different types of nebulisers are currently on sale under the trademark TOBI® (Novartis Pharm Corp) and BRAMITOB® (Chiesi Farmaceutici SpA).

However, the introduction of using nebulizers does not provide complete patients ' adherence to treatment, as patients require the delivery devices in a hospital or at home.

Moreover, many of the presentations shown bacterial contamination of nebulizers used by patients with MB, which leads to the need for regular cleaning and disinfection. Another disadvantage of nebulizers may be their low efficiency.

Compositions in powder form for the introduction of suitable devices known as dry powder inhalers (DPI), can be considered as a suitable alternative to tobramycin compositions for administration with the use of nebulizers, because these systems can provide a simpler and more rapid administration of the drug.

In particular, due to their high therapeutic dose, capsule dry powder inhaler should be considered as a suitable device.

Some of the problems that need to be addressed to ensure the effective composition of tobramycin in the form of a dry powder, which are problems commonly encountered in the manufacture of compositions of this type, i.e., the composition should exhibit a suitable flowability, suitable chemical and physical stability in ustroystva use and provide good respirable fraction while also delivering accurate therapeutically active dose of the active ingredient.

In particular, given a high dose and, consequently, a large amount of powder in each capsule (15 mg or more) it is necessary that the composition showed a suitable flow properties to ensure the efficient emptying of the capsule during use of the inhaler and, therefore, reproducible doses sprayed.

Moreover, it is well known that tobramycin is hygroscopic.

Because in addition to the influence on the chemical stability of humidity can also affect the flowability, special attention should be paid to reducing the quantity of residual water, as well as the accumulation of water in storage.

The solution of these problems by making the composition of tobramycin to use, apparently, is not easy, because so far the sale has not been one such product.

In WO 03/053411 and WO 2006/066367 disclosed tobramycin compositions containing phospholipids. However, their use raises concerns about their physical and chemical stability.

Recently Parlati et al (Pharm Res, 2009, 26(5), 1084-1092) presented data on tobramycin powder containing sodium stearate, obtained by spray drying.

However, there is still a need in the powder containing antibiotics belonging to the group of aminoglycosides, such as t�breezin, suitable for insertion using ICP-AES.

In particular, it will be also very useful to establish a composition which is easy to manufacture without the use of solvents, and in particular, without the use of aqueous solvents, as residual water can affect the chemical stability and/or flowability of the powder.

The composition of the present invention overcomes the problems and disadvantages of the prior art.

A BRIEF SUMMARY of the INVENTION

According to the invention the composition is in the form of a dry powder for pulmonary administration, containing mechanosensation microparticles, consisting of particles of an antibiotic belonging to the group of aminoglycosides, in the amount of 90% mass/mass or more and magnesium stearate in an amount of 10% mass/mass or less, where magnesium stearate covers at least 50% of the entire surface of the particles of the drug, and possibly physiologically acceptable pharmacologically inert carrier.

Preferably, the antibiotic is a tobramycin.

In another aspect, the invention relates to mechanosensation the microparticles.

According to the invention also provides a capsule for use with a dry powder inhaler filled with the composition in the form of a dry powder according to the invention.

In another aspect, the ACC�SSS to the invention a method of producing microparticles according to the invention mechanosynthesis.

In another aspect according to the invention proposed microparticles, consisting of particles of an antibiotic belonging to the group of aminoglycosides, in the amount of 90% mass/mass or more and magnesium stearate in an amount of 10% mass/mass or less, where magnesium stearate covers at least 50% of the entire surface of the particles of the drug received by mechanosynthesis.

The invention also relates to mechanosensation the microparticles according to the invention for use in the treatment of endobronchial bacterial infection associated with lung disease.

The invention also relates to the application mechanosensation of microparticles according to the invention in the manufacture of medicinal products for the treatment of endobronchial bacterial infection associated with lung disease.

In another aspect the invention relates to mechanosensation the microparticles according to the invention for the treatment of endobronchial bacterial infection associated with lung disease.

In another aspect according to the invention a method for treatment of endobronchial bacterial infection associated with pulmonary disease in a patient, comprising administering a therapeutically effective amount mechanosensation of microparticles according to the invention.

DEFINITION

The terms "active drug", "active� ingredient", "active agent" and "active substance", "active compound" and "therapeutic agent" are used here as synonyms.

The dry powder inhaler can be divided into two main types:

1) single-dose inhalers for the introduction of a separate single doses of active compounds; each single dose is usually presented in a capsule;

2) multi-dose dry powder inhalers, pre-filled quantities of active substances, sufficient for longer treatment cycles.

The term "coating" means that the lubricant magnesium stearate forms a film around the active particles.

The coating is only a partial, if the amount of magnesium stearate sufficient to form a film over the entire surface of all the particles of the active ingredient.

The term "substantially pure" means an active ingredient with a chemical purity of more than 90% mass/mass, preferably 93% mass/mass or more.

Usually the particle size is determined by measuring a characteristic equivalent sphere diameter (characteristic equivalent sphere diameter, known as volume diameter volume diameter), laser diffraction.

The particle size can also be determined by measuring the mass diameter mass diameter) using suitable tools well known to those skilled in the art.

Volume diameter (VD) is associated � mass diameter (MD) through the density of the particles (assuming, what is the density of the particles depends on their size).

The term "mechanosensory" refers to microparticles consisting of two different substances, where the first substance is mechanically applied to the second substance is dry method.

The particle size is expressed in units of volume diameter and distribution of particle size expressed in units (1) volume median diameter (VMD), corresponding to the diameter of 50 percent of the particles by weight or volume, respectively, and (2) volume diameter (VD) in micron of 10% and 90% of the particles, respectively.

The term "agglomerated" is used here in two different meanings.

The term "agglomerated microparticles" refers to particles composed of more than one microparticle, linked with each other. For example, the agglomerated micro-particle size of 1.5 μm ([d(v,0,5)]) can consist of many interlocking of microparticles, each of which has a smaller diameter.

In contrast, the term "loosely agglomerated microparticles" refers to particles in the form of soft agglomerates capable of quick disintegration with the formation of the individual microparticles.

The term "suitable flow properties" refers to a composition that is easy to handle in the manufacturing process and is able to provide precise and reproducible delivery of a therapeutically effective dose. Expressed�e "accurate therapeutically active dose of the active ingredient" refers to a composition, when the average administered dose is 60% of the nominal dose or more, more preferably 65%, even more preferably more than 70%.

The expression "chemically stable" refers to a composition that, when deposited complies with the guidance CPMP/QWP/122/02 European Agency for the evaluation of medicinal products (EMEA) with the title "Evaluation of stability of existing active substances and related end-products" ("Stability Testing of Existing Active Substances and Related Finished Products").

The expression "physically stable" refers to a composition, physical state of which is changed in the device prior to use and during storage.

The expression "respirable fraction" refers to the percentage of active particles reaching the lower lung of the patient.

Respirable fraction, also called the fraction of fine particles (FPF), evaluated in vitro using a suitable device, typically a multistage impactor (Multistage Cascade Impactor) or multistage liquid of impingere (Multi Stage Liquid Impinger, MLSI) according to the methods described in conventional pharmacopoeias. However, can be successfully used other devices, such as two-stage device (Twin Stage Apparatus) or the SprayTec device, as described in the Examples.

These calculations are carried out against the inhaled dose corresponding cha�the tics, having a diameter less than approximately 5 microns, and delivered (sprayed) doses.

Respirable fraction (FPF) is significantly greater than 30%, is a good indicator of aerosol properties.

The term "therapeutically effective amount" means the amount of antibiotic that belongs to the group of aminoglycosides, which, upon delivery to the lungs using the compositions in the form of a dry powder as described herein, provides the desired biological effect.

DESCRIPTION of GRAPHIC MATERIALS

Fig.1 shows images obtained by scanning electron microscopy (SEM) mechanosensation of microparticles according to the invention, consisting of: (a) 99% of tobramycin and 1% magnesium stearate; and (b) 95% tobramycin and 5% magnesium stearate.

The invention is partly based on the discovery that the dry coating of the active particles of an antibiotic belonging to the group of aminoglycosides, such as tobramycin, with magnesium stearate using mechanosynthesis improves aerosol properties of these particles.

Thus, in one aspect, the invention relates to compositions in the form of a dry powder for pulmonary administration, containing mechanosensation microparticles, consisting of particles of an antibiotic belonging to the group of aminoglycosides, in the amount of 90% mass/mass or more and magnesium stearate in an amount of 10% mA�with/mass, or less.

Preferably, the antibiotic that belongs to the group of aminoglycosides, may be selected from the group consisting of tobramycin, kanamycin A, dibekacin, amikacin and arbekacin.

These aminoglycosides in the microparticles of the invention can be used in the form of the base or in the form of its pharmaceutically acceptable salts, such as sulfate, nitrate, chlorite, and bromide.

The preferred antibiotic is tobramycin, which is preferably used in the form of the base. When it is used in the form of salt is the preferred salt is the sulfate tobramycin in a stoichiometric ratio 2:5.

Alternatively, it may be used other salts of tobramycin, such as nitrate.

Magnesium stearate in the microparticles of the invention are shown in the amount of 10% mass/mass or less. Preferably, magnesium stearate is presented in an amount of from 0.1 to 10%, more preferably 0.5% to 5% mass/mass.

In one embodiment, this amount may be from 0.5 to 2% wt/wt. Instead, in another embodiment the amount may be from 5 to 10% mass/mass, or from 2 to 5% mass/mass.

In a particularly preferred embodiment the amount is from 0.5 to 1.0% mass/mass.

The remainder of the antibiotic can be calculated accordingly.

For Microcat�IC according to the invention is necessary to magnesium stearate covered at least 50% of the entire surface of the particles of the medicinal product, preferably at least 60%, preferably at least 75%, more preferably at least 80% of the entire surface of the particles of the drug.

The presence of the coating can be qualitatively identified by visualization techniques such as scanning electron microscopy (SEM).

In contrast, the degree of coverage may be determined by other known methods. For example, the degree of coating of the microparticles according to the invention can be determined by x-ray photoelectron spectroscopy (XPS), a well-known method of determining the degree and the uniformity of the distribution of certain elements on the surface of other substances. In a device for XPS photons with a specific energy used for the excitation of electronic States of atoms beneath the surface of the sample. The electrons emanating from the surface, filtered by energy using a hemispherical analyzer (HSA) before recording their intensity relative to certain energy detector. Since the core electrons in the atoms of the solid phase are quantized, the resulting energy spectra are resonance peaks characterizing the electronic structure of the atoms of the sample surface.

Usually XPS measurement�tion is carried out on the instrument Axis-Ultra, available from Kratos Analytical (Manchester, UK), using monochromatizing radiation A1 Kα (1486,6 eV) when the emission current of 15 mA and the anode voltage of 10 kV (150 watts). To compensate the charge of the insulator used e-reader floodlight low energy. Review images on the basis of which get quantitative data about the detected items, get energy when passing the analyzer 160 eV and a step size of 1 eV. Get images of areas With 1s, O 1s, Mg 2s, N 1s and Cl 2p high resolution at the energy of the passing of 40 eV and a step size of 0.1 eV. The size of the study area is approximately 700 μm ×300 μm for review of images, and for images of high resolution, the diameter of the study area is 110 microns.

Typically report on the accuracy of the regular XPS-experiments

Alternatively, the degree of surface coating of an antibiotic with magnesium stearate may be determined first by measuring the contact angle of the microparticles with water and then applying the equation known in the literature as the equation Cassie and Baxter (Cassie and Baxter), see page 338 in Colombo I et al, II Farmaco 1984, 39(10), 328-341.

Measurement of contact angle with water can be carried out as described on page 332 in Colombo et al, i.e., using the method of sitting or stationary drops, involves placing a drop of liquid on the pore surface�scale in the form of a disc, obtained by molding method of a disc of compressed powder). Can be used device for evaluation of wettability, available from Lorentzen Wettre (Sweden).

Other methods that may be advantageously used in the measurement of the degree of surface coating of an antibiotic with magnesium stearate, are infrared spectroscopy and Raman scattering spectroscopy in combination with SEM or time-of-flight mass spectroscopy secondary ion Time-of-Flight Secondary Ion Mass Spectrometry, TOF-SIMS). These methods are known to those skilled in the art, and instructions for their use are included in his General knowledge.

Unlike microparticles, obtained from solutions such as microparticles obtained by spray drying, having a spherical shape, Fig.1 can be also seen that the shape mechanosensation of microparticles according to the invention is incorrect and not spherical.

For the qualitative assessment of the properties of microparticles according to the invention, such as particle shape and the structure of their surface, can be used scanning electron microscopy (SEM) or optical microscopy.

Gives a smoothed and coated with a lubricant surface, apparently, reduce the strength of interaction between particles (intermolecular surface forces and friction forces) powder, providing,�the case, the best dispersion properties when spraying.

Mechanosensation microparticles according to the invention can be crystalline or amorphous. However, % formlessness, expressed as mass % relative to the entire mass of the microparticles can vary considerably and may amount to 50% or more, preferably at least 70%, even more preferably at least 90%.

A specified percentage of amorphous can be determined with the use of x-ray diffraction on powder or other known techniques known to the person skilled in the art, such as differential scanning calorimetry (DSC) or microcalorimetry.

The size of the microparticles according to the invention is less than 15 μm. Preferably, at least 90% of particles have volume diameter less than approximately 10 microns. More preferably, no more than 10% of the microparticles have a volume diameter [d(v,0,1)] less than 0.1 μm. Preferably, not more than 50% of the particles have a volume diameter [d(v,0,5)] less than 0.6 and preferably [d(v,0,5)] is from 0.7 to 2.0 μm, more preferably from 0.8 to 1.5 microns.

The particle size can be measured by laser diffraction according to known methods.

Mechanosensation microparticles according to the invention can be in the form of non-agglomerated, i.e., separate, or stable agglomerated �of tricastin, the size of which is included in one of the above-described ranges.

Microparticles of the invention contain a very small amount of residual water, e.g., less than 5.0% mass/mass, preferably from 4.8% to 4.5% mass/mass, as determined according to known methods such as a method of Karl-Fischer.

Indeed, it was found that the amount of residual water in the microparticles of the invention are not significantly increased compared with the antibiotic as such.

It was also found that magnesium stearate, coating at least partially, the surface of the particles of active ingredient that can protect the micro-particles from the ambient humidity.

As stated above, because in addition to the influence on the chemical stability of humidity can also adversely affect the flowability, and this can be seen as additional advantage. With regard to flowability, the microparticles according to the invention also have the following properties:

- bulk density of from 0.16 to 0.35 g/ml;

is the density after abrasion from 0.25 to 0.60 g/ml;

- coefficient of pressuremost less than 50%, preferably 46% or less, more preferably less than 40%.

These technological features make appropriate compositions suitable for pulmonary administration capsule dry powder inhaler (capsule-based Dry Powder Inhaler).

Composite� can only consist of microparticles according to the invention or may contain physiologically acceptable pharmacologically inert carrier. Such media can serve as just a filler, when it is desirable to reduce the concentration of active agent delivered to a patient powder, or can improve the dispersion properties of the powder in the apparatus for spraying powder to provide more efficient and reproducible delivery of the active agent, improving the properties of the active agent (e.g., flowability and consistency) and to facilitate the manufacture and packing of the powder.

The carrier can be made of any amorphous or crystalline physiologically acceptable inert substances of animal or vegetable origin, or combinations thereof. Preferred substances are crystalline sugar, for example, monosaccharides, such as glucose or arabinose, or disaccharides, such as maltose, saccharose, dextrose or lactose. Can also be used polyhydric alcohols, such as mannitol, sorbitol, maltitol, lactitol. The preferred substance is a monohydrate of α-lactose.

The composition may also contain one or more than one active ingredient, preferably another antibiotic for inhalation treatment of bacterial infection or other suitable excipient, such as corrigenda and agents, taste masking.

A composition according to the invention, comprising microparticles according to the invention, provided�Ivan doesn, when spraying, excellent respirable fraction, preferably more than 30%, more preferably more than 35%, more preferably 40%, more preferably more than 50%.

Spray the dose may preferably be more than 60%, preferably more than 70%.

In certain embodiments, when the amount of magnesium stearate is 0.5 to 1.0%, to further increase as the sprayed dose and respirable fraction, microparticles of the invention may be subjected to a loose agglomeration of obtaining the loosely agglomerated microparticles, preferably by sieving the powder through two vibrating screens with openings 180 and 710 microns.

In another aspect according to the invention a method of producing microparticles according to the invention mechanosynthesis.

Synthesis is a simple dry mechanical method developed for depositing thin layers of lubricants on the surface of the particles.

Micronized particles of the active ingredient particles and magnesium stearate are placed in a working capacity for mechanosynthesis where they're influenced by centrifugal force and are pressed on the inner wall of the vessel. The powder is pressed between a fixed surface of the wall of the drum and curved inner element at high relative speed of the drum and the element relative�separate each other. The inner wall and the curved element together form a gap or clamp in which there is a co-extrusion of the particles. As a result, particles are very large shear forces and very strong compressive stresses, since the particles are clamped between the inner surface of the drum and the inner element (curvature greater curvature of the inner surface of the drum).

The particles collide with each other with great force, and the energy of these collisions is sufficient to locally heat and soften, break, deformation, smoothing and distribution of the particles of hydrophobic material around the Central particle to form a coating. In most cases, this energy is sufficient for disintegration of agglomerates, while the particle size of the active ingredient is essentially not changed.

For relative movement of the outer receptacle and inner element relative to each other can be rotated to either the outer container or inner element. The gap between these surfaces is relatively small and is usually less than 10 mm and preferably less than 5 mm, more preferably less than 3 mm. This gap is constant, and the result is better control of the energy of compression than when using mills or other shapes such as ball mills. In addition, the working surfaces of the mill �predpochtitelno not in contact with each other, to minimize wear and, as a result, contamination.

There may be a scraper for grinding any caked material accumulating on the surface of the container. This is especially useful when using fine cohesive source of nutrients. Local temperature can be controlled using a heating/cooling jacket that is built into the wall of the drum capacity. May re-powder passing through the tank.

Preferably, use such devices as devices for mechanosynthesis Nobilta® and Nanocular® from Hosokawa Micron Corporation, Japan. Both systems include a cylindrical vessel with a rotating rod. In the device, Nobilta® depart from the terminal to the longitudinal blade swings to within approximately 1 mm to the vessel wall. Thus, upon rotation of the rod the edges of the blades are constantly moving within the vessel wall, providing a permanent and intensive movement of the powder. Thanks to the high speed of rotation of the blades powder is shifted closer to the wall, and as a result the edge of the blade to the mixture is exposed to very large shear forces and, between the wall and the blade, very strong compressive stresses.

The device Nanocular® functions similarly, but with less impact on the particles due to the absence of blades and with large compressive stresses m�waiting for the wall and the pillow press.

Processing time will depend on the specific device and can be appropriately corrected by a specialist in the art depending on the party size. In some embodiments the processing can be performed for at least 2 minutes, preferably for at least 5 minutes, more preferably for at least ten minutes. In some embodiments of the invention, the processing time can be from 10 to 20 minutes. In addition, the speed of rotation will depend on the specific device to mechanosynthesis and the size of the treated batch.

Usually can be used rotation speed up to 10000 rpm, preferably not more than 6000 rpm, preferably from 1000 to 5000 rpm, more preferably from 2000 to 3000 rpm.

Alternatively, the rotation speed can be determined not in rpm, and the average blade tip speed in m/s.

The speed of the end of the blade will depend on the diameter of the rotor. When the rotor diameter of approximately 9.2 cm is preferably used the average blade tip speed is over 5 m/s, preferably greater than 10 m/s, more preferably greater than 25 m/s.

Preferably, can be used other similar apparatus, such as Cyclomix® (Hosokawa) and Hybridiser (Nara).

Upon receipt of the microparticles as described above, the antibiotic in the microparticle� remains essentially chemically pure.

Dose of antibiotic in the microparticles of the invention can vary within wide limits depending on the nature of the bacterial infection, the type of disease being treated and the type of the patient.

Specialist in the art can determine therapeutically effective amount for each patient and, through this, to determine the appropriate dose. In the case of tobramycin usual single standard dose for inhalation treatment of endobronchial infections caused by Pseudomonas aeruginosa associated with cystic fibrosis, may be in the range of 20 mg to 160 mg (calculated in the form of the free base), preferably from 30 to 90 mg, for administration to a patient one to three times a day.

Depending on the ISP single standard dose can be administered from a single container, or, preferably, it can be divided into several containers, such as capsules for sequential injection, or it can be entered from multiple containers, located in the ISP. Therefore, each capsule individually filled in less than a single standard dose.

For example, a single standard dose may be divided into from two to six capsules, preferably from three to five capsules.

Usually when you use tobramycin each capsule is filled 12-40 mg top�mizina (calculated in the form of the free base), preferably from 15 to 30 mg.

In one of preferred embodiments to increase respirable fraction each capsule contains 15 mg of powder.

Can be used any capsule for pharmaceutical use, for example, the capsules of hydroxypropylmethylcellulose (HPMC) or gelatin capsules 3 sizes.

The composition of the present invention can be used in the treatment of any endobronchial bacterial infection associated with pulmonary disease such as cystic fibrosis (MB), bronchiectasis not related to MB, pneumonia, chronic obstructive pulmonary disease and tuberculosis. Preferably, it can be used in the treatment of infections caused by gram-negative bacteria such as Pseudomonas aeruginosa.

In particular, the composition according to the invention can be used to treat patients with cystic fibrosis, which was confirmed by the colonization of Pseudomonas aeruginosa.

In conclusion, the advantages of microparticles of the present invention include the fact that the composition is physically and chemically stable, less prone to accumulation of water, provides a greater respirable fraction, provides accurate and reproducible delivery of a therapeutically effective dose and simpler and more economical to manufacture than known compositions.

The invention is illustrated more� detail in the following examples.

Example 1 - Obtaining microparticles of the invention

Micronized tobramycin and different amounts of magnesium stearate and 0.5%, 1%, 5% and 10% mass/mass, placed in a working capacity Nobilta® or Nanocular®.

The treatment was carried out under lot size of approximately 40 ml for 10 and 20 minutes at a rotation speed during the processing of 5000 rpm.

Collected received mechanosensation microparticles and determined their technological and aerosol properties.

Similarly can be obtained microparticles with other antibiotics belonging to the group of aminoglycosides.

Example 2 - Determination of technological properties of microparticles from

Example 1

Microparticles obtained in Example 1 was analyzed as follows.

Scanning electron microscopy (SEM). Morphological properties were investigated using scanning electron microscope (PhenomTM, FEI Company, Hillsboro, OR). Each sample was carefully mounted on the sample holder to provide representative images, and sprayed them gold. SEM-photomicrographs were obtained using the built-in software for image acquisition.

Representative images are shown in Fig.1 (a) and (b).

The size and shape of the microparticles of the invention are not significantly changed compared to Tabriz�nom as such, but powder is present in a smaller number of loose agglomerates.

Properties the density and flowability. Both density was calculated as described in the European Pharmacopoeia.

Bulk density (dv) was measured, slowly pouring the samples into a graduated measuring cylinder with a volume of 10 ml through a funnel located at a constant height above the cylinder. Density after abrasion (ds) was determined after 1250 shakes using an automatic analyzer (AUTOTAPTM, Quantachrome Instruments, Boynton Beach, FL, USA). The analyzer was provided by vertical shaking 3.18 mm amplitude with a frequency of 260 shakes per minute. The coefficient of pressuremost (KP) was calculated on the basis of bulk density and density after abrasion using the following equation:

KP(%a)=dsdvds×100.

Determination of particle size by laser diffraction. The size distribution of particles was measured by laser diffraction (Mastersizer® S, Malvern Instruments, Worcestershire, UK) using lenses 300 RF with a small capacity for making samples (volume 150 ml). The powders were dispersible in 0,065% dioctylsulfosuccinate sodium in n-hexane. Before measurement the sample Mgr�in addition, they delegated to ultrasound in the dispersing agent within 5 minutes.

The results in units of density, coefficient of pressuremost and particle size (mean+relative standard deviation) are shown in Table 1.

TMS - tobramycin; MgSt - stearate; RSD - relative standard deviation.

Table 1
Density, coefficient of pressuremost particle size
PartyBulk density (g/ml)Density after abrasion (g/ml)The coefficient of pressuremostD10 (µm)D50 (μm)D90 (µm)
TMS, 10% MgSt, synthesis, Nobilta, 10 minutesAverage0,300,530,430,130,899,47
RSD0,020,020,030,040,080,02
TMS, 10% MgSt, synthesis, Nobilta, 20 minutesAverage0,310,580,460,140,909,32
RSD0,010,020,020,040,110,03
TMS, 5% MgSt, synthesis, Nobilta, 10 minutesAverage0,280,510,460,140,969,03
RSD0,010,010,010,040,090,03

TMS, 5% MgSt, synthesis, Nobilta, 20 minutesAverage0,280,520,460,140,80/td> 8,65
RSD0,010,010,020,070,060,03
TMS, 1% MgSt, synthesis, Nobilta, 10 minutesAverage0,170,310,450,151,537,81
RSD0,010,030,030,080,110,02
TMS, 1% MgSt, synthesis, Nobilta, 20 minutesAverage0,180,330,450,191,238,30
RSD0,010,030,030,070,070,04
TMS, 10% MgSt, synthesis, Nanocular, 10 minutesAverage0,180,290,390,14Of 1.767,69
RSD0,020,030,030,040,100,63
TMS, 5% MgSt, synthesis, Nanocular, 10 minutesAverage0,190,340,450,171,40To 10.06
RSD0,020,040,050,080,150,05
TMS, 1% MgSt, synthesis, Nanocular, 10 minutesAverage0,160,270,430,13A 1.54 The 7.85
RSD0,010,010,020,060,080,02

Table 1 demonstrates that as the bulk density and the density after abrasion was increased by increasing the content of MgSt, indicating a more complete coating of the particles of tobramycin MgSt during its higher content. In General, these density changes after coating indicate a significant decrease in the cohesion between the particles of the powder.

Example 3 - Description of aerosol properties of microparticles from Example 1

Aerosol properties of microparticles according to the invention was evaluated by a laser diffractometer (Spraytec, Malvern Instruments, Worcestershire, UK) with an inhalation cell. Approximately 30 mg (or 15 mg further tests) of each powder was added to the HPMC capsules of 3 sizes (Capsugel, Peapack, NJ, USA). Before spraying each end of the capsule was punctured with a needle in stainless steel to allow release of the powder from the capsule with the formation of two holes with a diameter of approximately 1 mm. the Contents of each capsule were sprayed using the Monodose inhaler (Miat S. p.A. Milan, Italy) at a flow rate of 60 and 90 l/min. All measurements were repeated four times at room�Oh temperature (20°C, relative humidity 50%). Each measurement was performed for 4 seconds.

The retention of powder in the inhaler was calculated as the percentage of powder remaining in the capsule and inhaler from his total. The fraction of fine particles (FPF) was defined as the number of particles of the drug of size less than 5.4 μm as a percentage of the amount of powder sprayed from the inhaler.

It should be noted that all powders tested after removal of large agglomerates careful sifting of powders through a sieve with a mesh width of 250 μm. The results in the form of medium+RSD are shown in Table 2 (the air flow rate 90 l/min).

Table 2
Aerosol properties at the air flow rate 90 l/min
PartySprayed dose(%)<5,4 µm(%)
Untreated TMSAverage70,7732,58
RSD0,020,13
TMS, 10% MgSt, mahamasina�, Nobilta, 10 minutesAverage81,8653,26
RSD0,070,09
TMS, 10% MgSt, synthesis, Nobilta, 20 minutesAverageOf 64.7249,57
RSD0,010,05
TMS, 5% MgSt, synthesis, Nobilta, 10 minutesAverage67,1363,19
RSD0,040,05
TMS, 5% MgSt, synthesis, Nobilta, 20 minutesAverage64,7050,13

td align="left">
RSD0,060,03
TMS, 1% MgSt, synthesis, Nobilta, 10 minutesAverage81,5265,90
RSD0,040,02
TMS, 10% MgSt, synthesis, Nanocular, 20 minutesAverage79,7241,22
RSD0,050,13
TMS, 5% MgSt, synthesis, Nanocular, 10 minutesAverage72,33Footprint of 39.96
RSD0,070,06
TMS, 1% MgSt, synthesis, Nanocular, 10 minutesAverage62,9942,11
RSD0,050,01

The results showed that the raw powder of the drug is relatively poor aerosol properties, with FPF (%<5,4 µm) is approximately 30%.

After mechanosynthesis all batches of microparticles according to the invention show improved compared to untreated powder medicinal properties. Carried�only unexpected was the discovery that, what party mechanosensation particles with a lower content of MgSt 1% showed significantly improved dispersion properties, in some cases better than parties with a high content of MgSt.

Example 4 - the Effect of a loose agglomeration of aerosol properties

For additional improvements as atomized dose and FPF mechanosensation of microparticles with a small content of MgSt, for example, from 0.5% to 1%, the formation of loose agglomerates stimulated by sieving of powders using two vibrating screens with openings 180 and 710 microns. Before sieving, the powders were mixed to facilitate the formation of loose agglomerates. The results (mean +RSD) for loosely agglomerated powders are shown in Table 3.

Table 3
Aerosol properties loosely agglomerated powders of the drug when the air flow rate 90 l/min
Party90 l/minSprayed dose (%)<5,4 µm(%)
Untreated TMSAverage70,7732,58
RSD0,020,13
TMS, 1% MgSt, 10 minutes (without sifting)Average75,0969,19
RSD0,020,03
TMS, 1% MgSt, 10 minutes (screening, 180-720 μm)Average65,6568,15
RSD0,060,10
TMS, with 0.5% MgSt, 10 minutes (without sifting)Average59,3554,43
RSD0,060,02
TMS, with 0.5% MgSt, 10 minutes (screening, 180-710 μm)Average81,1766,90
RSD0,040,03

The results showed that after this education �oplotnik agglomerates sprayed dose mechanosensation microparticles with low content MgSt could be slightly improved and FPF has achieved a much higher level.

1. Capsule for use with a dry powder inhaler containing a composition in the form of a dry powder for pulmonary administration, containing mechanosensation microparticles consisting of tobramycin in an amount of from 99% to 99.5% wt./wt. and magnesium stearate in an amount of from 0.5 to 1.0% wt./wt., where magnesium stearate covers at least 50% of the entire surface of the particles of tobramycin, where the amount of residual water in said microparticles is less than 5% wt./wt. and where the specified capsule contains from 12 to 40 mg specified tobramycin in terms of the free base.

2. Capsule according to claim 1, wherein the composition further comprises a physiologically acceptable pharmacologically inert carrier.

3. Capsule according to claim 1, containing from 15 to 30 mg of the specified tobramycin in terms of the free base.

4. Capsule according to claim 1, containing 15 mg of the specified tobramycin in terms of the free base.

5. Capsule according to claim 1, which is a capsule from hydroxypropylmethylcellulose (HPMC), or a gelatin capsule.

6. Capsule according to claim 1 for use in the treatment of endobronchial bacterial infection associated with lung disease.

7. Capsule according to claim 6, where the disease is selected from the group consisting of cystic fibrosis (MB), bronchiectasis not related to MB, pneumonia, chronic obstructive pulmonary disease and tubercul�for.

8. Capsule according to claim 7, where the disease is a cystic fibrosis.

9. A method for producing a capsule according to claim 1, which includes stages
1) making the particles of tobramycin and magnesium stearate in the working capacity of the device to mechanosynthesis;
2) the handling of particles within a time period of at least 2 minutes and
3) collecting the resulting microparticles.

10. A method according to claim 9, where the particles are treated for a time period of at least 5 minutes.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and may be used for improving rheological properties of sputum and inhibiting the bacterial biofilm formation in bronchi in treating cystic fibrosis. That is ensured by using recombinant human deoxyribonuclease-1 covalently bond to homopolymeric polysaccharide containing 80 links of alpha-2,8 sialic acid as an inhalation agent. There are also presented a method and administration of a drug preparation for improving the rheological properties of sputum.

EFFECT: group of inventions enables maintaining a higher level of DNA-hydrolytic activity of the administered drug preparation in bronchial mucus.

3 cl, 3 dwg, 4 ex, 2 tbl

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: claimed is novel combination of active substances for creation of pharmaceutical composition, liquid water ambroxol-based medications for treatment of diseases of respiratory ways with formation of viscous sputum, which possess expectorant, mucolytic, anti-inflammatory effect. Preparation contains ambroxol, pharmaceutically suitable water-soluble salt of glycyrrizic acid and extract of thyme.

EFFECT: preparation in accordance with invention makes it possible to obtain efficient clinical results (reduction of coughing period duration and quicker recovery of patients with diseases of respiratory ways) and provides multi-directional action on cough pathogenesis in whole.

16 cl, 3 tbl, 10 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to occupational pathology, and can be used for pneumoconiosis prevention. That is ensured by the introduction of Aqua Maris nasal spray in each nasal passage by 4-6 injections for at least 6-8 times in a working shift. In addition, Bronchipret is administered by 20 drops in 1/2 glass of water once before a working shift. The therapeutic course is 2.5-3 months twice a year.

EFFECT: higher effectiveness of pneumoconiosis prevention ensured by more evident preventional effect on the upper and lower air passages.

6 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to an agent for mucociliary clearance improvement. The medicinal agent for mucociliary clearance improvement containing gamma-L-glutamyl histamine, fudosteine, leptin, growth transformation factor - β3, ectericide, glycerine, rotocan, yellow sweet clover blossom extract CK-CO2, dropwort blossom extract CK-CO2, origanum extract CK-CO2, taken in a certain ratio.

EFFECT: agent effectively improves mucociliary clearance, allows to improve considerably clinical effectiveness and to reduce treatment length in acute and chronic diseases, to prevent recurrence development and distribution of the pathological process.

2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pulmonology, and can be used for treating bronchial obstruction syndrome in a patient with bacterial inflammation of airway. That is ensured by inhalations of 250 mg of "Fluimucil-antibiotic IT". In 30 minutes after inhalation, the patient's chest is exposed to vibrations generated by HIVAMAT 200 apparatus for 15 minutes. In 6-7 hours later, inhalation of 250 mg of "Fluimucil-antibiotic IT" is performed again. Treatment is daily for 5-7 days.

EFFECT: method is effective, provides recovery in a relatively short time, being herewith noninvasive, painless and without by-effects that allows to be recommended for wide use in paediatrics.

1 ex

FIELD: medicine.

SUBSTANCE: present invention refers to application of antiinflammatory and local anaesthetic pharmaceutical compositions containing ambroxol or one of its pharmacologically acceptable salts for local application for skin diseases chosen from the group including anaesthesia, burning, itching, inflammation, mosquito stings and skin redness of allergic, immunologic or idiopathic origin, applied directly on the skin.

EFFECT: invention provides antiinflammatory and local anaesthetic action in skin application, increases duration of application and do not show collateral actions.

6 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to pulmonology and phthisiology, and can be applied in case of necessity of carrying out diagnostic bronchoalveolar lavage in patients. For this purpose first, instillation of 5-7 ml of 10% fluimucil solution is performed during 4-6 minutes. 10 minutes after that fibrobronchscopy with diagnostic bronchoalveolar lavage by means of physiological solution is carried out.

EFFECT: method allows to increase efficiency of diagnostic procedure due to preliminary dilution of bronchial secretion, which ensures its free removal.

2 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to pharmaceutical compositions meant for treating diseases for which there is excess mucus in the respiratory channel, such as cytofibrosis and chronic obstructive pulmonary disease. Proposed is a composition which promotes excretion of mucus, containing one or several glycosaminoglycans and amino acid, which is a dry mixture lung inhalation. Proposed is use of a pharmaceutical composition, which promotes excretion of mucus, in therapy. A method of treating lung disease is proposed. A method of producing a composition, involving spray drying of one or more glycosaminoglycans, is proposed. A method of producing a composition, involving jet grinding of one or more glycosaminoglycans, is proposed.

EFFECT: possibility of effective dosing mucoactive agents in form of dry powders.

32 cl, 3 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: medicine.

SUBSTANCE: combined application of the following medications by children additionally to basic step-wise therapy is administered: Enterosgel per orally 1.5-2 hours before or 2 hours after meal or after application of medications to children from 5 to 10 years old - 15 g 2 times per day, from 11 to 15 years - 15 g 3 times per day with 7-day course; Polyoxydonium by injection intramuscularly in dose by 0.1 mg/kg of child weight injections with interval 1-2 days with course duration 5-8-10 days; Reamberin 1.5% solution by injection drop-wise at age from 5 to 10 years - 200 ml 1 time per day or every second day, from 11 to 15 years - 400 ml 1 time per day or after day, in quantity 5-7 injections; Phenibutum per orally after meal in age dosing under 8 years - by 0.05-0.1 g per intake, over 8 years - 0.25 g per intake 2 times per day, with 30 day course, with course of combined application of said medications is realised 3-4 times per year.

EFFECT: effective prevention of uncontrolled forms of bronchial asthma development in children above 5, associated with influence of chemical toxicants - manganese and vanadium, which comes from atmospheric air, increase of organism resistance to claimed toxicants.

4 tbl

FIELD: medicine.

SUBSTANCE: what is presented is using Histochrom (same as echinochrome A or pentahydroxyethyl naphthoquinone) as an agent able to prevent pulmonary fibrosis developed under cytostatic agents. The invention can be used for the pharmacological prevention and correction of the pulmonary tissue disorders caused by administering the cytostatic agents.

EFFECT: preventing hypertrophy of interalveolar connective tissue in the lungs associated with administering bleomycin.

4 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula , which is a methylhydrofumarate (MHF) prodrug. In formula (I), radicals and symbols have the values specified in the patent claim. The invention also refers to a pharmaceutical composition containing the declared methylhydrofumarate drugs, to using the declared methylhydrofumarate drugs and the pharmaceutical composition containing them, for treating diseases, such as psoriasis, asthma, multiple sclerosis, inflammatory intestinal disease and arthritis, and to a method of treating the above diseases.

EFFECT: higher oral bioavailability and plasma MHF, dimethylfumarate and/or other metabolites.

47 cl, 1 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula I, possessing ability of binding with delta-opioid receptors. In formula R1 is selected from the group, consisting of i) phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxyl, di(C1-4alkyl), aminocarbonyl, chlorine and fluorine, in such a way that only one di(C1-4alkyl)aminocarbonyl is present; ii) naphthyl; iii) pyridinyl, optionally substituted with one substituent, selected from the group, consisting of C1-4alkyl, C1-4alcoxy, C1-4alkylthio, hydroxy, fluorine, chlorine and cyano; iv) pyrimidin-5-yl; v) furanyl; vi) thienyl; vii) 5-oxo-4,5-dihydro-[1,2,4]oxodiazol-3-yl; and viii) di(C1-2alkyl)aminocarbonyl; Y represents ethyl, vinyl or bond; or Y represents O, when R1 represents optionally substituted phenyl, where substituent represents C1-4alcoxy; R2 represents phenyl, optionally substituted with one-two substituents, independently selected from the group, consisting of C1-4alkyl, C1-4alcoxy, fluorine, chlorine and cyano, trifluoromethoxy and hydroxy; or R2 represents phenyl, substituted with one aminocarbonyl, di(C1-4alkyl)aminocarbonyl, C1-4alcoxycarbonyl or carboxysubstituent; R3 is selected from the group, consisting of i) 3-aminocyclohexyl; ii) 4-aminocyclohexyl; iii) piperidin-3-yl; iv) piperidin-4-yl; v) pyrrolodin-2-yl-methyl, in which pyrrolodin-2-yl is optionally substituted by 3-rd or 4-th position with one or two fluorine-substituents; vi) azetidin-3-yl; vii) 2-(N-methylamino)ethyl; viii) 3-hydroxy-2-aminopropyl; ix) piperidin-3-yl-methyl; x) 1-azabicyclo[2.2.2]octan-3-yl; and xi) 8-azabicyclo[3.2.1]octan-3-yl; or R3 together with Ra and nitrogen atom, which they both are bound to, form piperazinyl, optionally substituted with 4-C1-4alkyl; Ra represents hydrogen, 2-(N-methylamino)ethyl or C1-2alkyl, optionally substituted with azetidin-3-yl.

EFFECT: compounds can be used in treatment of pain in the range from medium to strong, caused by diseases or conditions, such as osteoarthritis, migraine, burn, fibromyalgia, cystitis, rhenite, neuropathic pain, idiopathic neuralgia, toothache, etc.

21 cl, 4 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutics. A medication represents derivatives of glutarimides of the general formula (I) or their pharmaceutically acceptable salts. The invention also relates to pharmaceutical compositions and a method of treatment.

EFFECT: ensured by the application of non-toxic derivatives of the said glutarimides for the treatment of eosinophilic diseases, mainly of an allergic origin.

16 cl, 12 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of treatment or relieving the severity of cystic fibrosis in a patient, where the patient has the cystic fibrosis transmembrane receptor (CFTR) with R117H mutation, including a stage of introduction to the said patient of an effective quantity of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

EFFECT: elaborated is the method of treating cystic fibrosis, based on the application of N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide.

3 cl, 4 tbl, 30 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely represents a method for the therapy of respiratory symptom. The method involves administering a liquid composition containing a gel former and/or a mucoactive polymer, a non-menthol cooling substance; and contacting the oral mucosa with the liquid composition. The invention also describes liquid compositions applicable in the method for the therapy of a respiratory disease.

EFFECT: implementing the method provides improving the cooling properties of the cooling agent N-(4-cyanomethylphenyl)-n-menthane carboxamide in the liquid composition by combining the non-menthol cooling substance with the gel former.

14 cl, 2 tbl, 5 dwg

FIELD: chemistry.

SUBSTANCE: disclosed are copolymers based on N-vinylpyrrolidone, having as terminal fragments a cyanovaleric acid residue and a hydrogen atom, having general formula (I) where the monomer link is a 4-vinylpyridine (4-VP) fragment, if X is or a 2-methyl-5-vinylpyridine (2-M-5-VP) fragment, if X is , wherein the content of monomer links which are 4-VP or 2-M-5-VP fragments is 20-90 mol%; the viscosity-average molecular weight Mµ of the copolymers is equal to 10-350 kDa, and the acid number is equal to (0.1-5.6)·10-3 mg KOH/g. Also disclosed is use of said copolymers as an anti-pneumoconiosis agent.

EFFECT: high efficiency of using the compound.

2 cl, 2 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel crystalline form of N-[-2[[(2,3-difluorophenyl)methyl]thio]-6-{[(1R,2S)-2,3-dihydroxy-1-methylpropyl]oxy}-4-pyrimidinyl]-1-azatidine-sulphonamide, which has an X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1.5418 E and containing, at least, one crystalline peak with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1; or containing, at least, 2 crystalline peaks with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1; or containing, at least, 3 crystalline peaks with a value 2-theta (in degrees) 21.0, 28.8 and/or 29.1. The said crystalline form can contain additional crystalline peaks with a value 2-theta (in degrees), selected from 12.9 and 18.0, obtained under the said conditions.

EFFECT: crystalline form has the X-ray powder diffractogram, measured with the application of a wavelength of X-rays of 1,5418 E, with the crystalline peaks with a value 2-theta (in degrees) 12,9, 13,1, 18,0, 21,0, 22,5, 25,1, 25,3, 28,8, 29,1 and 30,4, and has melting point (beginning) 152,7°C.

6 cl, 3 dwg, 2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel derivatives of pyrazole pyridine of formula , as well as to its tautomers, geometrical isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, where G1 represents H; G2 represents -CHR1R2; R1 and R2 independently on each other are selected from H; C1C6-alkoxy-C1C6-alkyl; C1-C6-alkyl; optionally substituted phenyl; optionally substituted phenyl-C1-C6-alkyl; optionally substituted morpholine-C1-C6-alkyl; or -CHR1R2 together form a ring, selected from an optionally substituted C3-C8-cycloalkyl and substituted piperidine; G3 is selected from an optionally substituted C1C6-alkoxy -C1-C6-alkyl; C1-C6-alkyl; substituted phenyl; substituted phenyl-C1C6-alkyl; G4 is selected from a substituted acyl-C1C6-alkyl, where acyl represents a group -CO-R and R stands for H or morpholine; optionally substituted C1-C6-alkyl; optionally substituted phenyl or indene; substituted phenyl-C1-C6-alkyl; optionally substituted pyridine- or furanyl-C1C6-alkyl; morpholine- or piperidine-C1-C6-alkyl; G5 represents H; where the term "substituted" stands for the groups, substituted with 1 to 5 substituents, selected from the group, which includes a "C1-C6-alkyl," "morpholine", "C1-C6-alkylphenyl", "di-C1-C6-alkylamino", "acylamino", which stands for the group NRCOR", where R represents H and R" represents a C1-C6-alkyl, "phenyl", "fluorine-substituted phenyl", "C1-C6-alkoxy", "C1-C6-alkoxycarbonyl", "halogen". The invention also relates to a pharmaceutical composition based on the formula (I) compound and particular compounds.

EFFECT: obtained are the novel derivatives of pyrasole pyridine, useful for the treatment and/or prevention of disorders or states, associated with NADPH-oxidase.

12 cl, 3 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a pharmaceutical composition, namely to a method of manufacturing a solid, coated pharmaceutical composition by the method of applying a coating by melt.

EFFECT: method is adapted to the provision of the solid, coated pharmaceutical composition, possessing fast release, by means of covering by melt.

6 ex, 8 tbl, 13 cl

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