Stable composition (versions), medication (versions) and methods of treatment and prevention of skin infections and infections of skin structures, caused by bacteria, sexually transmitted diseases and infections of reproductive tract, caused by bacteria, nasopharyngeal infections, caused by bacteria, in humans or animals

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical composition for local application, which possesses antibacterial properties.

EFFECT: invention represents pharmaceutical stable semi-hard compositions for local application, which contain from 0.2 to 5 wt % of desfluoroquinolone compound, suitable for ointment or cream production.

24 cl, 5 ex, 15 tbl

 

The technical field to which the invention relates.

The present invention describes compositions for topical application which contain dispergirovannogo connection.

The level of technology

Despite advances in antimicrobial therapy in the last 20 years, increasing the proportion of infections caused by gram-positive organisms with multiple drug resistance, which are the major pathogens in uncomplicated primary skin infections and skin structure infections (impetigo, folliculitis, furunculosis, acne, secondarily infected traumatic injury, secondarily infected dermatoses and secondarily infected burns). Recently described increased levels of community-acquired infections methicillinsensitive Staphylococcus aureus (MRSA) and the emergence of plasmid resistance to mupirocin also among MRSA. Osinochkin is a new non-fluorinated quinolone compound, which demonstrated a high level of activity against gram-positive organisms, including common-resistant chinolone bacteria. Osinochkin, due to its bidirectional mechanism of action, active against a number of resistant mutant strains. Thus osinochkin is a good potential antibacterial drug to overcome susestudio present mechanisms of antibiotic resistance due to its high activity against resistant gram-positive bacteria.

Osinochkin active against a large number of pathogens, such as Propionibacterium acnes, Staphylococcus aureus, methicillinsusceptible Staphylococcus aureus (MSSA), methicillinsensitive Staphylococcus aureus (MRSA), including strains resistant to ciprofloxacin, methicillinsusceptible Staphylococcus epidermidis (MSSE), methicillinsensitive Staphylococcus epidermidis (MRSE), Streptococcus pyogenes, Streptococcus group G, penitsillinoustoychivyh Streptococcus pneumoniae positive for β-lactamase Haemophilus influenzae, Netherway strains of Haemophilus influenzae, positive for β-lactamase Moraxella catarrhalis, Neisseria meningitides, Legionella pneumophila, Mycoplasma pneumoniae, Legionella pneumophila, Mycobacterium tuberculosis, Streptococcus agalactiae group b Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, Helicobacter pylori, Bacteroides fragilis, Clostridium perfringens, Escherichia coli, kinologostika Escherichia coli, Salmonella spp., Shigella spp., ciprofloxacinresistant Pseudomonas aeruginosa, Clostridium difficile, and Listeria monocytogenes.

Osinochkin (I) first described in the patent US6335447 and patents-analogues. Its chemical name 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid. Its chemical formula is:

Topical application of antimicrobial agents is an effective tool for the treatment of skin infections and skin structure infections, sexually transmitted diseases and reproductive tract infections, as well as the poison systemic infections, sensitive to local treatment. Local antimicrobial therapy has several potential advantages over systemic therapy. First, it can avoid unnecessary exposure of intestinal flora, which can lead to selection for resistance. Secondly, expect a high local concentration of the drug in the local application and little systemic absorption should suppress many forms of mutational resistance. Thirdly, it is less likely that local application compared with systemic treatment causes side effects. Accordingly, some local compositions containing osinochkin described in the technical field.

JP2002356426A reveals ointments and gels for skin. Ointment containing ostoksilla 1 wt.%, N-methyl-2-pyrrolidone 8 wt.%, propylene glycol and 14.9 wt.%, oleic acid in 0.9 wt.%, diisopropanolamine 2.3 wt.%, polyethylene glycol 400 at 20.2 wt.%, polyethylene glycol 4000 of 50.2 wt.% and water of 3.2 wt.%, described in example 2.

JP2003226643A discloses aqueous solutions containing osinochkin, the cyclodextrin component, which imparts viscosity.

ERA discloses a liquid dispersion of fine particles containing osinochkin, which is designed for use in the manufacture of pharmaceutical compositions.

WO2007015453A1 reveals lotions containing osinochkin.

JP2007119456A discloses aqueous suspensions containing nanoparticles and soluble granules ostoksilla intended for use in the manufacture of pharmaceutical compositions. Mainly mention eye solutions.

The combined use ostoksilla, magnesium ions and hydroxypropyl-β-cyclodextrin, in particular for ophthalmic applications, described in the article Yamakawa, T. et al., Journal of Controlled Release (2003), 86(1), 101-103.

Semi-solid compositions for topical application are an effective alternative to liquid compositions, because they are easier to manipulate and as a result, they are preferred for patients. However, despite the large variety of components present in the semi-solid compositions disclosed in the technical field, there has been no quantitative studies of their stability. Thus, there is a need for proven stable semi-solid compositions for topical application, containing osinochkin as an active ingredient for which certified microbiological and therapeutic activity, as shown stable long-pharmaceutical stability.

Disclosure of inventions

Accordingly, an object of the present invention relates to stable pharmaceutical semi-solid compositions for topical application containing from 0.2 to 5 wt.% composition ostoksilla and media suitable for production of ointment or cream. Preferably, when the number ostoksilla is from 0.5 wt.% up to 2 wt.%, and more preferably is 1 wt.%. In the present invention, all percentages are expressed in weight percents, until determined otherwise.

According to the present invention include ointments, in which a suitable carrier selected from white wax, colorless soft paraffin and mixtures thereof. Colorless soft paraffin is preferred.

According to the present invention, provide for a cream containing a suitable medium contains a mixture of emulsifiers, surfactants, waxes with low melting point, dispergiruyushchie in the water components and preservatives that do not emit formaldehyde.

Accordingly, the present invention provides for the cream contains

a) 0,2÷5 wt.% ostoksilla and

b) a suitable carrier containing:

b.1) 15÷25 wt.% one or more emulsifiers;

b.2) 10÷20 wt.% one or more surface-active

substances;

b.3) 5÷15 wt.% oil component;

b.4) 1÷10 wt.% one or more waxes with low melting point selected from fatty acids with 8 to 30 carbon atoms, fatty alcohols with 8 to 30 carbon atoms esters of fatty acids with 8 to 30 carbon atoms, amides of fatty acids with 8 to 30 carbon atoms, silicon what's waxes and mixtures thereof;

b.5) water;

b.6) 10÷20 wt.% one or more dispergiruyushchie in the water component selected from polyethylene glycol 400, hexyleneglycol, propylene glycol, ether methylglucose and polypropylenglycol 10, ethoxydiglycol, polyethylene glycol 6 glycerides Caprylic/capric acid, monobutyl ether of ethylene glycol, polyethylene glycol 8 glycerides of Caprylic/capric acid, 3-methoxy-3-methyl-1-butanol, dimethylselenide and their mixtures and

b.7) 0,01÷1 wt.% one or more preservatives, not forming formaldehyde;

moreover, the number of component b.5 represents the number supplementing the composition to 100 wt.%, and all percentages are wt.% and based on the total weight of the composition.

According to one of embodiments, the present invention provides for the cream, in which the medium contains:

18÷22 wt.% component b.1;

13÷15 wt.% component b.2;

7÷9 wt.% component b.3;

3÷5 wt.% component b.4;

component b.5;

13÷17 wt.% component b.6;

0,05÷0,15 wt.% component b.7;

moreover, the number of component b.5 represents the number supplementing the composition to 100 wt.%.

According to the following alternative implementation, the present invention provides for the cream, in which the medium contains:

20 wt.% component b.1;

14 wt.% component b.2;

8 wt.% component b.3;

4 wt.% b.4;

component b.5;

15 wt.% component b.6;

0.1 wt.% component b.7;

moreover, the number of component b.5 represents the number supplementing the composition to 100 wt.%.

According to the following variant of implementation, the amount of water in the medium is 30÷45 wt.%.

In the present invention, the emulsifiers selected from ethylenglykolether, arbitrational, the mixture PEG stearate, glocalsearch and PEG stearate, and hydrogenated lecithin and mixtures thereof, preferably, when the emulsifier is a mixture of PEG stearate, glocalsearch and PEG stearate.

In the present invention a surfactant selected from arbitrational/propylene glycol, mono - and diglycerides of C8/C10fatty acids from coconut oil, soy lecithin, egg phosphatides, esters of monoglycerides and citric acid esters of monoglycerides and lactic acid, esters of monoglycerides and diatsetilvinny acid, esters of monoglycerides and succinic acid esters of sucrose and fatty acids, poliglecaprone of glycerides of oleic acid, poliglecaprone of glycerides of linolenic acid, a complex polyglyceryl esters of fatty acids, including fatty acids with long and medium chain and complex polyglyceryl mixed esters the fatty acids and mixtures thereof. Preferably, when surfactants are poliglecaprone glycerides of oleic acid.

In the present invention the oil components selected from alcohols Emblem with a basis of fatty alcohols containing 8 to 10 carbon atoms, esters With6-22unbranched fatty acid with unbranched or branched C6-22fatty alcohols, esters of branched C6-13carboxylic acids with unbranched or branched C6-22fatty alcohols, esters unbranched6-22fatty acid with 2-ethylhexanol, esters With3-38alkylhydroxylamines acid with unbranched or branched C6-22fatty alcohols, esters unbranched or branched fatty acids with policereported or alcohols Emblem, triglycerides based on the C6-10fatty acids, liquid mixtures of mono-, di - and triglycerides based on the C6-18fatty acids, esters With6-22fatty alcohols or alcohols Emblem with benzoic acid, esters With2-12dicarboxylic acids with unbranched or branched alcohols containing 1-22 carbon atoms or polyols containing 2 to 10 carbon atoms and 2-6 hydroxyl groups, vegetable oils, branched primary alcohols, substituted cyclohexanes, n is branched and the branched carbonate 6-22fatty alcohols, carbonates Emblem based on fatty alcohols containing 8 to 10 carbon atoms, esters of benzoic acid with unbranched or branched C6-22alcohols, unbranched or branched, symmetrical or asymmetrical dialkylamino ethers containing 6 to 22 carbon atoms in the alkyl group, the opening cycle products of esters epoxydecane fatty acids with polyols, silicone oils and aliphatic or naphthenic carbohydrates and mixtures thereof. Preferably, when the oil components are alcohols Emblem based on fatty alcohols containing 8 to 10 carbon atoms, such as 2-octyldodecanol (Eutanol®G PH).

Because they are the primary, branched and have a high molecular weight alcohols Arms have a low potential to cause irritation, represent the liquid to extremely low temperatures and have low volatility, effective as superfatted components and are good lubricating substances.

In the present invention, a wax with a low melting point selected from a fatty acid of 8 to 30 carbon atoms, fatty alcohols of 8 to 30 carbon atoms, esters of fatty acids of 8 to 30 carbon atoms, fatty acid amides of 8-30 carbon atoms, silicone waxes, and mixtures thereof.

Preferably, when the wax with a low melting point are fatty alcohols of 8 to 30 carbon atoms. More preferably, when fatty alcohols choose stearyl alcohol.

Due to the characteristics contributing to consistency, stearyl alcohol acts as a convenient viscosity regulator.

In the present invention dispergirujutsja in the water components are selected from polyethylene glycol 400, hexyleneglycol, propylene glycol, ether methylglucose and polypropylenglycol 10, ethoxydiglycol, polyethylene glycol 6 glycerides Caprylic/capric acid, monobutyl ether of ethylene glycol, polyethylene glycol 8 glycerides of Caprylic/capric acid, 3-methoxy-3-methyl-1-butanol, dimethylselenide and mixtures thereof. Preferably, when despergiruemaya in the water component is a propylene glycol.

In the present invention preservatives that do not form formaldehyde selected from a benzoate ammonium propionate ammonium, benzisothiazolinone, benzoic acid, benzotriazole, benzyl alcohol, benzylparaben, 5-bromo-5-nitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, butylbenzoate, butylparaben, calcium benzoate, parabens calcium, calcium propionate, calcium salicylate, sorbate calcium, chlorhexidindigluconat, chlorhexidindigluconat, chlorhexidindigluconat, chloracetamide, chlorine is butanol, p-chloro-m-cresol, chlorophene, p-chlorophenol, chlorphenesin, chlorinol, chloroxine, m-cresol, o-cresol, p-cresol, DHA, dibrompropamidine diisocyanate, dimethyloxazolidine, dictionarybased, domeena, ethylformate, ethylparaben, ferulic acid, glyoxal, geksamidina, hexamethylmelamine, hexamethylmelamine, 4-hydroxybenzoic acid, gidroximetilpropilzelluloza, iodoplatinate, isobutylparaben, indecipherable, isopropylpyrazole, isopropylparaben, isopropylcarbonate, lauryldimethylamine HCl, magnesium benzoate, magnesium propionate, methyl-chlorination, methylparaben, acilitation, benzoate panttilainaamo ether, ventilago alcohol, phenol, Phenoxyethanol, phenoxyethylamine, phenoxyisopropyl, phenylbenzoate, phenylpropene, o-phenylphenol, polimetallicheskogo of oxazolidine, potassium benzoate, butylparaben potassium, ethylparaben potassium, methylparaben potassium, paraben potassium, phenoxide potassium, potassium propionate, potassium propyl paraben,potassium sorbate, propionic acid, propylbenzoate, propyl paraben, quaternium-8 (methyl - and stearoylbenzoylmethane, and stereoselectivity (translated in Quaternary form) dimethylsulfate), quaternium-14 (ethanamine, N,N,N-trimethyl-2-[(2-methyl-1-oxo-2-propenyl)oxy]-, matilal the dude the homopolymer), quaternium-15 (ethanamine, N,N,N-trimethyl-2-[(2-methyl-1-oxo-2-propenyl)oxy]-chloride, polymer with 2-propenamide), sodium benzoate, butylparaben sodium, sodium p-chloro-m-cresol, dehydroacetate sodium, ethylparaben sodium formate sodium, hydroxyethanesulfonic sodium, hydroxymethylglycinate sodium, isobutylparaben sodium, isopropylparaben sodium, lauryldimethylamine sodium, methylparaben sodium, paraben sodium, vinylsulfonate sodium, peroxide sodium, sodium phenylphenate, propionate sodium, propyl paraben sodium sorbate, sodium, sorbic acid, tea-sorbate (triethanolaminato), ciotola (2,7-dimethyl-thianthrene), triclocarban, triclosan and undecylenoyl PEG parabens (complex ester undecylenate acid and PEG parabens and mixtures thereof. Preferably, when the preservative, which is formaldehyde, which is a benzoic acid.

Another object of the present invention is the use of compositions of the present invention, in the treatment or prevention (prophylaxis) of skin infections and skin structure infections in humans or animals. Accordingly, the present invention provides for the use of ointments and creams of the present invention, in the treatment or prevention of skin infections and infections of skin structures and non-limiting examples of these skin infections and infections of skin structures are impetigo, folliculitis, furunculosis, acne, secondarily infected traumatic injury, secondarily infected dermatoses and secondarily infected burns, as well as those skin infections and infections of the skin structures that cause methicillinsusceptible Staphylococcus aureus (MSSA), methicillinsensitive Staphylococcus aureus (MRSA), including strains resistant to ciprofloxacin, methicillinsusceptible Staphylococcus epidermidis (MSSE), methicillinsensitive Staphylococcus epidermidis (MRSE), Streptococcus pyogenes and Streptococcus group G.

Another object of the present invention is the use of new compositions in the treatment or prevention of sexually transmitted infections and reproductive tract infections in humans or animals. Accordingly, the present invention provides for the use of ointments and creams of the present invention, in the treatment or prevention of sexually transmitted infections and reproductive tract infections such as caused by Streptococcus agalactiae group B, Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum.

Another object of the present invention is the use of new compositions for combating infections of the nasopharynx of asymptomatic nasal carriers of a person or animal. Accordingly, the present invention provides for the use of ointments and creams of the present invention, l what I struggle with infections of the nasopharynx of asymptomatic nasal carriers, with infections caused methicillinsusceptible Staphylococcus aureus (MSSA), methicillinsensitive Staphylococcus aureus (MRSA), including strains resistant to ciprofloxacin, penitsillinoustoychivyh Streptococcus pneumoniae positive for β-lactamase Haemophilus influenzae, Netherweave strains of Haemophilus influenzae, positive for β-lactamase Moraxella catarrhalis, Neisseria meningitides, Legionella pneumophila, Mycoplasma pneumoniae, Legionella pneumophila and Mycobacterium tuberculosis.

Compositions corresponding to the present invention, can be used by direct application to the affected or sensitive skin or genital region. In addition, the composition can be used by introducing into the nasal cavity, preferably in the nasopharynx, in particular, the front part of the nasopharynx.

In addition, the composition corresponding to the present invention, can be used to treat skin infections and skin structure infections, sexually transmitted diseases and reproductive tract infections, and for fighting infections of the nasopharynx of asymptomatic nasal carriers when these infections are resistant to common antibiotics for topical use, for example, to mupirocin, guideway acid, retapamulin quinolone compounds, i.e. nadifloxacin.

Another object of the present invention is to develop new methods of treating or preventing cutaneous infektsii infections skin structures at a person or animal, need in the introduction of the compositions of the present invention.

Another object of the present invention is to develop new methods of treating or preventing diseases, sexually transmitted and reproductive tract infections in humans or animals in need in the introduction of the compositions of the present invention.

Another object of the present invention is to develop new ways of dealing with infections of the nasopharynx of asymptomatic nasal carriers of a person or animal in need in the introduction of the compositions of the present invention.

Compositions corresponding to the invention, can be effectively and safely used without clinically significant dermatological or systemic harmful events, because the absorption of skin ostoksilla slightly.

Throughout the description and claims the word "contain" and variations of this word, such as "contains", do not allow the exclusion of other technical characteristics, additives, components or steps. Additional objects, advantages and features of the invention will be obvious to a competent specialists in the field of technology based on the study of the description, or may be found in the practical implementation of the invention. The following examples are presented in the form of illustrate and are not intended to limit the present invention.

The implementation of the invention

Example 1. Ointment containing 1 wt.% ostoksilla

a) 100 g of the composition

Osinochkin1 g
Colorless soft paraffin99 g

b) the Manufacture

Colorless soft paraffin (99 part) melt until smooth at 70-75°C in the reactor corresponding volume for making party, equipped with a low-speed stirrer (anchor stirrer) and high-speed stirrer and heating and cooling. The paraffin is cooled to 50-55°C. Add osinochkin (1 part) and is dispersed in the paraffin mixing. The final dispersion is cooled to 25-30°C. Obtain a homogeneous pale yellow ointment with oily basis. End-ointment Packed in aluminum tubes with a volume of 20 ml using an automatic system.

c) Stability

The inert nature of the media in the form of liquid paraffin ensures that the ointment can be stably stored for at least 18 months.

Example 2. Cream containing 1% ostoksilla

a) 100 g of the composition

Osinochkin1 g (1 wt.%)
PEG stearate and picoliter the t and PEG stearate (Tefose ®63)20 g (20 wt.%)
Olaolmagan-6-glycerides (Labrafil®M CS)14 g (14 wt.%)
2-octyldodecanol (Eutanol®G PH)8 grams (8 wt.%)
Stearyl alcohol (Lanette®18)4 g (4 wt.%)
Propylene glycol15 g (15 wt.%)
Benzoic acid0.1 g (0.1 wt.%)
Distilled waterof 37.9 g (37.9 wt.%)

b) the Manufacture

1. Propylene glycol (15 parts) and water (37.9 parts) is added to the reactor for semi-solid compositions of the corresponding volume.

2. The mixture is heated at 70-75°C With slow stirring.

3. The mixture Tefose®63 (20 parts), Labrafil®M 1944 CS (14 parts), Lanette®18 (4 parts) and benzoic acid (0.1 part) is melted at 70-75°C in glass/aluminium glass of the relevant volume at a low-speed stirring.

4. The final mixture obtained in stage 3 (organic phase), add in a reactor with a semi-solid composition. The mixture is stirred at low speed with an anchor stirrer at high speed with high the high-speed mixer with a shift within 5 minutes.

5. The mixture Eutanol®G PH (8 parts) and ostoksilla (1 part) is added to the glass of the appropriate volume, equipped with the appropriate mixer. The mixture is heated at 50-55°C. under stirring.

6. The suspension obtained in stage 5, is added to the emulsion obtained in stage 4, and stirred at low speed with an anchor stirrer at high speed using a high-speed mixer with a shift within 20 minutes.

7. The temperature of the resulting cream is allowed to drop to 25-30°C, stopping the heating. Check the homogeneity of the mass.

8. The final cream is Packed in aluminum tubes with a volume of 20 ml with lid made of high density polyethylene with an automated system.

C) Stability

In tables 1-12 summarize the results of the stability studies conducted with some experimental batches.

Table 1
Loading capacity: 600 gThe source datat=6 months
Experimental conditions:
25±2°C/60%±5% RH (1)
Appearance
Analysis of the active ingredient (wt.%; average)100,91100,61
Analysis of impurities (wt.%)Unknown impuritiesN.O. (2)the concentration is
Total impuritiesthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)102,14105,65
Particle size (D 90 micron)of 4.443,90
Viscosity (CP)300406212344
pH3,973,99
(1) relative humidity; (2) determine the t - period

Table 2
Loading capacity: 600 gThe source datat=6 months
Experimental conditions:
30±2°C/65%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)100,91100,96
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration is
Total impuritiesthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)102,14108,76
Particle size (D 90 micron)of 4.445,46
Viscosity (CP)300406304312
pH3,973,89

Table 3
Loading capacity: 600 gThe source datat=1 montht=3 monthst=6 months
Experimental conditions:
40±2°C/75%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)100,91schedule rate is now 99.14100,8599,73
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration isthe concentration is the concentration is
Total impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration isthe concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)102,14100,12102,65108,75
Particle size (D 90 micron)of 4.44and 5.305,97for 9.64
Viscosity (CP)300406360031280969398719
pH3,973,914,103,89

pH
Table 4
Loading capacity: 600 g The source datat=6 months
Experimental conditions:
25±2°C/60%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)101,33100,81
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration is
Total impuritiesthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)103,85109.0
Particle size (D 90 micron)4,183,88
Viscosity (CP)498375395062
4,044,18

Table 5
Loading capacity: 600 gThe source datat=6 months
Experimental conditions:
30±2°C/65%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)101,33100,41
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration is
Total impuritiesthe concentration isthe concentration is

Loading capacity: 600 gThe source datat=6 months
Experimental conditions:
30±2°C/65%±5% RH
Analysis of the decomposition products (wt.%)the concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)103,85110,03
Particle size (D 90 micron)4,185,01
Viscosity (CP)498375198156
pH4,044,22

Table 6
Loading capacity: 600 gThe source datat=1 montht=3 monthst=6 months
Experimental conditions:
40±2°C/75%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)101,3399,82101,22100,56
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
Total impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration isthe concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)103,85103,22107,47111,47
Particle size (D90, μm)4,18is 4.936,07,86
Viscosity (CP)498375555500 324719506062
pH4,043,933,934,06

Table 7
Load capacity: 8 kgThe source datat=3 monthst=6 monthst=12 months
Experimental conditions:
25±2°C/60%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)102,16103,38101,79of 99.98
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration is the concentration isthe concentration is
Total impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration isthe concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)100,59100,20103,71102,54
Particle size (D 90 micron)5,856,02of 3.642,89
Viscosity (CP)400234209531320094384188
pH4,184,424,214,05

Table 8
About the eat to load: 8 kg The source datat=1 montht=3 monthst=6 monthst=12 months
Experimental conditions:
30±2°C/65%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)102,16101,67103,12102,9298,98
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration isthe concentration isthe concentration isthe concentration is
Total impuritiesthe concentration isthe concentration isthe concentration isthe concentration is the concentration is

Load capacity: 8 kgThe source datat=1 montht=3 monthst=6 monthst=12 months
Experimental conditions:
30±2°C/65%±5% RH
Analysis of the decomposition products (wt.%)the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)100,5999,70101,38105,21103,26
Particle size (D 90 micron)5,855,55,033,683,79
Viscosity (CP)400234350875224031334219338812
pH4,183,954,053,954,04

Total impurities
Table 9
Load capacity: 8 kgThe source datat=1 montht=3 monthst=6 months
Experimental conditions:
40±2°C/75%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)102,16100,17102,89to 102.43
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
the concentration isthe concentration isthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration isthe concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)100,59103,35102,28103,21
Particle size (D 90 micron)5,58,275,96of 3.56
Viscosity (CP)4002344392503084373285,62
pH4,183,973,993,83

Table 10
Load capacity: 8 kgSource of data the t=3 monthst=6 monthst=12 months
Experimental conditions:
25±2°C/60%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)99,70102,59100,4599,30
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
Total impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration isthe concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)102,72101,14103,71103,06
Particle size (D 90 micron)to 4.685,962,972,41
Viscosity (CP)309312264656247500317875
pH4,30of 4.383,894,29

Table 11
Load capacity: 8 kgThe source datat=1 montht=3 monthst=6 monthst=12 months
Experimental conditions:
30±2°C/65%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)99,70100,65102,37100,9099,54
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration isthe concentration isthe concentration isthe concentration is
Total impuritiesthe concentration isthe concentration isthe concentration isthe concentration isthe concentration is

Load capacity: 8 kgThe source datat=1 montht=3 monthst=6 monthst=12 months
Experimental conditions:
30±2°C/65%±% S
Analysis of the decomposition products (wt.%)the concentration isthe concentration isthe concentration isthe concentration isthe concentration is
The analysis of benzoic acid (wt.%, average)102,72102,0EUR 102.11104,11103,78
Particle size (D 90 micron)to 4.686,46and 5.30br4.61as 4.02
Viscosity (CP)309312321250257843304437340750
pH4,303,984,103,89as 4.02

Table 12
Load capacity: 8 kgThe source datat=1 month t=3 monthst=6 months
Experimental conditions:
40±2°C/75%±5% RH
Appearance
Analysis of the active ingredient (wt.%; average)99,70100,68102,94101,58
Analysis of impurities (wt.%)Unknown impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
Total impuritiesthe concentration isthe concentration isthe concentration isthe concentration is
Analysis of the decomposition products (wt.%)the concentration isthe concentration isthe concentration isthe concentration is
The analysis of benzoic acid (wt.%, average) 102,72102,98103,09104,75
Particle size (D 90 micron)of 5.68to 6.674,823,86
Viscosity (CP)309312400937303625310844
pH4,303,97as 4.023,86

Example 3. Antibacterial activity of ointment containing 1 wt.% ostoksilla

a) experiment

Antibacterial activity evaluated in models of infection, consisting of a skin wound, infected with Staphylococcus aureus (ATSS 6538), in mice after topical application of the ointment, corresponding to Example 1.

Male mice CD-1 (45 animals) weighing 22-27 g at the beginning of treatment is placed in a standard laboratory conditions (temperature 22±1°C and relative humidity 65±10%; 12-hour light (7:00-19:00/12 - hour dark cycle).

In order to infect suture thread, they are immersed for 30 minutes in a daily broth of S. aureus at a concentration of 108 CFU (colonialism the existing units)/ml, previously announced in accordance with the data spectrophotometry.

Thread take out and leave to dry on filter paper. Each suture thread cut two segments of length 1 cm, and each segment is shaken in a test tube with 1 ml of 0.2 wt.% yeast extract. Make breeding data broth and transferred in duplicate and in parallel on agar with deficiency of cystine-lactose-electrolyte (cled operating temperature) to determine the concentration on the suture thread. The remainder of the suture thread stored in the refrigerator prior to use.

The day before the experiment the animals are shaved and hold hair removal using commercial cream depilatory.

Mice are randomly allocated to three groups of 15 animals. Group code, to provide treatment for the blind, according to Table 13.

Table 13
CodeMedicationConcentrationForm
#Group
1AndPlaceboOintment
2InMupirocin2 wt.%Ointment
3Osinochkin1 wt.%Ointment

Day 1 at the beginning of the experiment the animals spend anesthesia with isoflurane. The infection is called with a needle with silk suture thread, pre-infected with AMF inoculum of S. aureus in a certain concentration. Make puncture, only to puncture the skin at the height of the shoulder girdle and below approximately 1 cm

At each end of the thread tying knots, to ensure that it does not move from the subcutaneous position. Then make an external incision with a scalpel between two nodes, not reaching the muscle layer.

Various medications are used after one and eight hours after infection. Drugs applied topically to the affected area. All treatment is performed by rubbing the infected area for at least 30 seconds. The use of preparations continue for another four days, and they are applied with a 12-hour intervals.

The applied volume is 0.1 ml/animal. Placebo receive the carrier used in the composition of testirovanie, in the form of ointment. Treatment code before applying them.

Animals daily weigh and note any clinical signs related to the test.

Day 6 after approximately 16 hours after application, the animals killed offset neck. The area of skin, approximately 1×2 cm, which includes wound, removed and weighed. This sample is homogenized in 5 ml of physiological solution. This solution (0.1 ml) and three serial dilutions 1:10 original 5-ml solution is placed in parallel to plates with agar cled operating temperature+50 mm MgCl2. In the group receiving mupirocin, 50 mm MgCl2replace 2 wt.% activated carbon. For the group receiving placebo, using agar Cup two types.

MgCl2added to the agar cled operating temperature in order to act as a chelator of quinolones, to suppress the activity of the antibiotic on the Cup, while activated charcoal (2 wt.%) use to avoid transferring mupirocina in skin samples of animals treated with 2 wt.% mupirocin ointment. Homogenized samples stored in the refrigerator until the final calculations when the calculations must be repeated.

b) Results

The values obtained on agar cled operating temperature+2 wt.% activated charcoal

In the group receiving placebo, when calculating the gain values 6,53±0,218 (mean ±SEM (standard error)for log (CFU/g skin is). Growth is observed in all the cups.

In the group treated with 2 wt.% mupirocin ointment, the values of Log(CFU/g skin) make up to 4.92±0,236. Growth is observed in all the cups. See a statistically significant difference (check on student test, p<0,01) between mupirocin and placebo.

The indicator of treatment effectiveness for 2 wt.% mupirocin ointment is 24% compared with the group receiving placebo.

The values obtained on agar cled operating temperature+50 mm MgCl2

In the group receiving placebo, when calculating the gain values 6,32±0,264 (mean ±SEM) for log(CFU/g skin). Growth is observed in all the cups.

In the group treated with 1 wt.% adenocarcinomas ointment, the values of Log(CFU/g skin) form of 3.56±0,248. Growth is observed in 13 of 15 cups. See a statistically significant difference (check on student test, p<0,01) between adenocarcinoma and placebo.

The indicator of treatment effectiveness for 1 wt.% adenocarcinomas ointment is 44%, compared with the group receiving placebo.

C) Conclusion

A 5-day application of ointments containing osinochkin 1 wt.%, causes statistically significant and stronger reduction of bacterial growth in an experimental model of Staphylococcus aureus infection in mice than that obtained by the use of ointments containing mupirocin 2 wt.%. Don't see any harmful local effects after use of the drug.

Note the p 4. Antibacterial activity of a cream containing 1 wt.% ostoksilla

a) experiment

Antibacterial activity of cream, corresponding to Example 2, and evaluated similarly to the method described in Example 3A. The only difference relates to pharmaceutical forms, which are shown in Table 14.

Table 14
CodeMedicationConcentrationForm
#Group
1AndPlaceboCream
2InMupirocin2 wt.%Ointment
3Osinochkin1 wt.%Cream

b) Results

The values obtained on agar cled operating temperature+2 wt.% activated charcoal

In the group receiving placebo, when calculating the gain values to 6.80±0,145 (average is e±SEM) for log(CFU/g skin). Growth is observed in all the cups.

In the group treated with 2 wt.% mupirocin ointment, the values of log(CFU/g skin) are 5,01±0,218. Growth is observed in all the cups. See a statistically significant difference (check on student test, p<0,01) between mupirocin and placebo.

The indicator of treatment effectiveness for 2 wt.% mupirocin ointment is 26% compared with the group receiving placebo.

The values obtained on agar cled operating temperature+50 mm MgCl2

In the group receiving placebo, when calculating the gain values to 6.67+0,171 (mean±SEM) for log(CFU/g skin). Growth is observed in all the cups.

In the group treated with 1 wt.% adenocarcinoma cream, values of Log(CFU/g skin) make up 3,10±0,154. Growth is observed in 13 of 15 cups. See a statistically significant difference (check on student test, p<0,01) between adenocarcinoma and placebo.

The indicator of treatment effectiveness for 1 wt.% adenocarcinoma cream is 54%, compared with the group receiving placebo.

C) Conclusion

A 5-day application of the cream containing osinochkin 1%, causes a statistically significant and stronger reduction of bacterial growth in an experimental model of Staphylococcus aureus infection in mice than that obtained by the use of ointments containing mupirocin 2 wt.%. Don't see any harmful local effects after use of the drug.

Note the p 5. The cream containing 2 wt.% ostoksilla

100 g of the composition

Osinochkin2 g (2 wt.%)
PEG stearate and glycolethers and PEG stearate (Tefose®63)20 g (20 wt.%)
Oleoyl macrogol-6 glycerides (Labrafil®M CS)14 g (14 wt.%)
2-octyldodecanol (Eutanol®G PH)8 grams (8 wt.%)
Stearyl alcohol (Lanette®18)4 g (4 wt.%)
Propylene glycol15 g (15 wt.%)
Benzoic acid0.1 g (0.1 wt.%)
Distilled water36.9 g (36.9 wt.%)

A method of manufacturing the same as described in Example 2. The results of stability similar to those obtained for Example 2.

Example 6. Phase I clinical trials of the drug 2 wt.% adenocarcinoma cream.

Purpose

The main objective is to evaluate the systemic absorption after repeated local application of 2 wt.% adenocarcinoma cream by analyzing the pharmacokinetic parameters, p is obtained on the basis of concentrations ostoksilla in plasma.

A further purpose is to evaluate the safety and tolerability after repeated local application of 2 wt.% adenocarcinoma cream.

The method

Conduct multi-dose, double-blind, randomized clinical trial controlled placebo with two-factor transition. Include 20 healthy male Caucasian race - volunteer test participants aged 18-60 years. The dose is 0.5 g 2 wt.% adenocarcinoma cream/90 cm2. Each participant is tested daily to 3 times a day put 0.5 g of 2 wt.% adenocarcinoma cream for 6 days and 1 time put 0.5 g of 2 wt.% adenocarcinoma cream in day 7 or 3 times a day, apply the cream placebo for 6 days and 1 time apply the cream to placebo at day 7, and in each of the periods in accordance with the code of randomization.

Blood samples for measurement of concentration ostoksilla in plasma taken before 1 and 2 application on day 1, before 2 application in day 2, before 1 and 3 application in day 3 and day 4, before each application in day 5 and day 6, before application in day 7 and through 0,5, 1, 2, 4, 8, 12, 24, 48 and 72 hours after application (day 7).

Results

After repeated topical application of 10 mg ostoksilla (2% cream) three times daily for seven days at all concentrations ostoksilla plasma also remain below the threshold for quantitative determination. Thus not see any systemic absorption.

After repeated topical application of 2% adenocarcinoma cream preliminary results show good tolerability profile. The most frequently reported adverse events are itching in the area of application and erythema. Not described any difficult or dangerous events. All adverse events classified according to the intensity as mild or moderate.

We can conclude that 2 wt.% adenocarcinomas cream is well tolerated and dermal absorption is negligible.

Embodiments of the invention:

1. Pharmaceutical stable semi-solid composition for topical application, containing from 0.2 to 5 wt.% composition ostoksilla the medium suitable for production of ointment or cream.

2. The composition corresponding to the option exercise 1 or 2, in which the number ostoksilla is from 0.5 wt.% up to 2 wt.%.

3. The composition corresponding to the option exercise 2, in which the number ostoksilla is 1 wt.%.

4. Ointment containing composition corresponding to any one of embodiments 1-3, containing 0.2+5 wt.% ostoksilla, in which a suitable carrier selected from white wax, colorless soft paraffin and mixtures thereof.

5. Ointment, the relevant option exercise 4, in which a suitable carrier is a colorless soft paraffin.

6. To the eat, containing a composition corresponding to any one of embodiments 1-3, in which a suitable carrier contains a mixture of emulsifiers surfactants, oil components, waxes with low melting point, water, dispergiruyushchie in the water components and not forming formaldehyde preservatives.

7. Cream, corresponding to the implementation of the 6, in which the carrier includes in the following proportions cream:

emulsifiers, 15÷25 wt.%;

surfactants, 10÷20 wt.%;

oil components, 5÷15 wt.%;

wax with a low melting point, 1÷10 wt.%;

water, 30÷45 wt.%;

dispergirujutsja components in water, 10÷20 wt.% and

do not form formaldehyde preservatives, 0,01÷1 wt.%.

8. The cream according to claim 7, in which the carrier includes in the following proportions cream:

emulsifiers, 18÷22 wt.%;

surfactants, 13÷15 wt.%;

oil components, 7÷9 wt.%;

wax with a low melting point, 3÷5 wt.%;

water, 35÷40 wt.%;

dispergirujutsja components in water, 13÷17 wt.% and

do not form formaldehyde preservatives, 0,05÷0,15 wt.%.

9. Cream, corresponding to the implementation of the 8 in which the carrier includes in the following proportions cream:

emulsifiers, 20 wt.%;

surfactants, 14 wt.%;

oil components, 8 wt.%;

wax with a low is the temperature of melting,

4 wt.%;

water, of 37.9 wt.%;

dispergirujutsja components in water, 15 wt.% and

do not form formaldehyde preservatives, 0.1 wt.%.

10. Cream that matches any one of embodiments 6 to 9, in which the emulsifier is selected from ethylenglykolether, arbitrational, the mixture PEG stearate, glocalsearch and PEG stearate, and hydrogenated lecithin and mixtures thereof.

11. Cream, corresponding to 10, in which the emulsifier is a mixture of PEG stearate, glocalsearch and PEG stearate.

12. Cream that matches any one of embodiments 6 to 11, in which the surfactant is selected from arbitrational/propylene glycol, mono - and diglycerides With8/S10fatty acids from coconut oil, soy lecithin, egg phosphatides, esters of monoglycerides and citric acid esters of monoglycerides and lactic acid, esters of monoglycerides and diatsetilvinny acid, esters of monoglycerides and succinic acid esters of sucrose and fatty acids, poliglecaprone of glycerides of oleic acid, poliglecaprone of glycerides of linolenic acid, a complex polilizinov esters of fatty acids, including fatty acids with long and medium chain and complex polyglyceryl esters mixed the IRNA acids and mixtures thereof.

13. Cream, corresponding to implement 12 in which surfactants are poliglecaprone glycerides of oleic acid.

14. Cream that matches any one of embodiments 6 to 13, in which the oil components selected from alcohols Emblem with a basis of fatty alcohols containing 8 to 10 carbon atoms, esters With6-22unbranched fatty acid with unbranched or branched C6-22fatty alcohols, esters of branched C6-13carboxylic acids with unbranched or branched C6-22fatty alcohols, esters unbranched6-22fatty acid with 2-ethylhexanol, esters With3-38alkylhydroxylamines acid with unbranched or branched C6-22fatty alcohols, esters unbranched or branched fatty acids with policereported or alcohols Emblem, triglycerides based on the C6-10fatty acids, liquid mixtures of mono-, di - and triglycerides based on the C6-18fatty acids, esters With6-22fatty alcohols or alcohols Emblem with benzoic acid, esters With2-12dicarboxylic acids with unbranched or branched alcohols containing 1-22 carbon atoms or polyols containing 2 to 10 carbon atoms and 2-6 hydroxyl is Rupp, vegetable oils, branched primary alcohols, substituted cyclohexanes, unbranched and branched carbonates With6-22fatty alcohols, carbonates Emblem based on fatty alcohols containing 8 to 10 carbon atoms, esters of benzoic acid with unbranched or branched C6-22alcohols, unbranched or branched, symmetrical or asymmetrical dialkylamino ethers containing 6 to 22 carbon atoms in the alkyl group, the opening cycle products of esters epoxydecane fatty acids with polyols, silicone oils and aliphatic or naphthenic carbohydrates and mixtures thereof.

15. Cream, corresponding to implement 14 in which the oil component is an alcohol Emblem 2-octyldodecanol.

16. Cream that matches any one of embodiments 6 to 15, in which the wax with a low melting point selected from a fatty acid of 8 to 30 carbon atoms, fatty alcohols of 8 to 30 carbon atoms, esters of fatty acids of 8 to 30 carbon atoms, fatty acid amides of 8-30 carbon atoms, silicone waxes, and mixtures thereof.

17. Cream, corresponding to implement 16, in which the wax with a low melting point are fatty alcohols of 8 to 30 carbon atoms.

18. Cream, corresponding to implement 17, in which walls the silt alcohol selected from fatty alcohols.

19. Cream that matches any one of embodiments 6 to 18, in which dispergirujutsja in the water components are selected from polyethylene glycol 400, hexyleneglycol, propylene glycol, ether methylglucose and polypropylenglycol 10, ethoxydiglycol, polyethylene glycol 6 glycerides Caprylic/capric acid, monobutyl ether of ethylene glycol, polyethylene glycol 8 glycerides of Caprylic/capric acid, 3-methoxy-3-methyl-1-butanol, dimethylselenide and mixtures thereof.

20. Cream, corresponding to the implementation of the 19, which despergiruemaya in the water component is a propylene glycol.

21. Cream that matches any one of embodiments 6 to 20, in which preservatives that do not form formaldehyde selected from a benzoate ammonium propionate ammonium, benzisothiazolinone, benzoic acid, benzotriazole, benzyl alcohol, benzylparaben, 5-bromo-5-nitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, butylbenzoate, butylparaben, calcium benzoate, parabens calcium, calcium propionate, calcium salicylate, sorbate calcium, chlorhexidindigluconat, chlorhexidindigluconat, chlorhexidindigluconat, chloracetamide, chlorbutanol, p-chloro-m-cresol, chlorophene, p-chlorophenol, chlorphenesin, chlorinol, chloroxine, m-cresol, o-cresol, p-cresol, DHA, dibrompropamidine deseti the Nata, dimethyloxazolidine, dictionarybased, domeena, ethylformate, ethylparaben, ferulic acid, glyoxal, geksamidina, hexamethylmelamine, hexamethylmelamine, 4-hydroxybenzoic acid, gidroximetilpropilzelluloza, iodoplatinate, isobutylparaben, indecipherable, isopropylpyrazole, isopropylparaben, isopropylcarbonate, lauryldimethylamine HCl, magnesium benzoate, magnesium propionate, methyl-chlorination, methylparaben, acilitation, benzoate panttilainaamo ether, ventilago alcohol, phenol, Phenoxyethanol, phenoxyethylamine, phenoxyisopropyl, phenylbenzoate, phenylpropene, o-phenylphenol, polimetallicheskogo of oxazolidine, potassium benzoate, butylparaben potassium, ethylparaben potassium, methylparaben potassium, paraben potassium, potassium phenoxide, potassium propionate, potassium propyl paraben, potassium sorbate, propionic acid, propylbenzoate, propyl paraben, quaternium-8 (methyl - and stearoylbenzoylmethane, and stereoselectivity (translated in Quaternary form) dimethylsulfate), quaternium-14 (ethanamine, N,N,N-trimethyl-2-[(2-methyl-1-oxo-2-propenyl)oxy]-, methyl sulfate, a homopolymer), quaternium-15 (ethanamine, N,N,N-trimethyl-2-[(2-methyl-1-oxo-2-propenyl)oxy]-chloride, polymer with 2-propenamide), sodium benzoate, butylparaben sodium, sodium phlor-m-cresol, dehydroacetate sodium, ethylparaben sodium formate sodium, hydroxyethanesulfonic sodium, hydroxymethylglycinate sodium, isobutylparaben sodium, isopropylparaben sodium, lauryldimethylamine sodium, methylparaben sodium, paraben sodium, vinylsulfonate sodium, peroxide sodium, phenylphenate sodium propionate sodium, propyl paraben sodium sorbate, sodium, sorbic acid, tea-sorbate (triethanolaminato), ciotola (2,7-dimethyl-thianthrene), triclocarban, triclosan and undecylenoyl PEG parabens (complex ester undecylenate acid and PEG parabens and mixtures thereof.

22. Cream, corresponding to the implementation of 21, in which the preservative, which is formaldehyde, which is a benzoic acid.

23. The use of a composition corresponding to any one of embodiments 1-3, in the treatment or prevention of skin infections and skin structure infections in humans or animals.

24. Application of ointments corresponding to any one of embodiments 4 and 5, in the treatment or prevention of skin infections and skin structure infections in humans or animals.

25. The application of the cream, corresponding to any one of embodiments 6 to 22, for the treatment or prevention of skin infections and skin structure infections in humans or animals.

26. The use of any of the vari is now implementation 23-25, where skin infections and infections of skin structures are impetigo, folliculitis, furunculosis, acne, secondarily infected traumatic injury, secondarily infected dermatoses and secondarily infected burns, as well as those skin infections and infections of the skin structures that cause methicillinsusceptible Staphylococcus aureus (MSSA), methicillinsensitive Staphylococcus aureus (MRSA), including strains resistant to ciprofloxacin, methicillinsusceptible Staphylococcus epidermidis (MSSE), methicillinsensitive Staphylococcus epidermidis (MRSE), Streptococcus pyogenes and Streptococcus group G.

27. The use of a composition corresponding to any one of embodiments 1-3, in the treatment or prevention of sexually transmitted infections and reproductive tract infections in humans or animals.

28. Application of ointments corresponding to any one of embodiments 4 and 5, in the treatment or prevention of sexually transmitted infections and reproductive tract infections in humans or animals.

29. The application of the cream, corresponding to any one of embodiments 6 to 22, for the treatment or prevention of sexually transmitted infections and reproductive tract infections in humans or animals.

30. The use of any one of embodiments 27 to 29, in which sexually transmitted diseases and reproductive tract infections Streptococcus agalactiae group B, Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma hominis and Ureaplasma urealyticum.

31. The use of a composition corresponding to any one of embodiments 1-3, to combat infections of the nasopharynx of asymptomatic nasal carriers of a person or animal.

32. Application of ointments corresponding to any one of embodiments 4 and 5, to combat infections of the nasopharynx of asymptomatic nasal carriers of a person or animal.

33. The application of the cream, corresponding to any one of embodiments 6-22, to combat infections of the nasopharynx of asymptomatic nasal carriers of a person or animal.

34. The use of any one of embodiments 31 to 33, in which infection of the nasopharynx cause methicillinsusceptible Staphylococcus aureus (MSSA), methicillinsensitive Staphylococcus aureus (MRSA), including strains resistant to ciprofloxacin, penitsillinoustoychivyh Streptococcus pneumoniae positive for β-lactamase Haemophilus influenzae, Netherway strains of Haemophilus influenzae, positive for β-lactamase Moraxella catarrhalis, Neisseria meningitides, Legionella pneumophila, Mycoplasma pneumoniae, Legionella pneumophila and Mycobacterium tuberculosis.

1. A stable composition in the form of a cream for topical application, comprising 0,2÷5 wt.% ostoksilla and a suitable carrier containing:
15÷25 wt.% at least one emulsifier selected from the group comprising of ethylene glycol monostearate, sorbitan of tristearate, with whom thou PEG stearate, glocalsearch and PEG stearate, hydrogenated lecithin, and mixtures thereof;
10÷20 wt.% at least one surfactant selected from the group comprising sorbifolia of monoline/propylene glycol, mono - and diglycerides of C8/C10fatty acids from coconut oil, soy lecithin, egg phosphatides, esters of citric acid and monoglycerides, esters of lactic acid and monoglycerides, complex esters, diacetyl tartaric acids and monoglycerides, esters of succinic acid and monoglycerides, esters of sucrose and fatty acids, poliglecaprone glycerides of oleic acid, poliglecaprone glycerides of linolenic acid, a complex polyglyceryl esters of fatty acids and complex polyglyceryl esters of mixed fatty acids and their mixtures;
5÷15 wt.% the oil component, which is an alcohol Emblem (2-octyldodecanol);
1÷10 wt.% at least one wax with a low melting point selected from the group comprising fatty alcohols with 8 to 30 carbon atoms and mixtures thereof;
10÷20 wt.% at least one dispergiruyushchei in the water component selected from the group comprising PEG, hexyleneglycol, propylene glycol, ether methylglucose and polypropylenglycol 10, etokxidiglicol, PEG glycerides of Caprylic/capric acids, monobutyl the ethyl ether is a glycol, PEG glycerides of Caprylic/capric acid, 3-methoxy-3-methyl-1-butanol, dimetridazole and mixtures thereof;
0,01÷1 wt.% at least one preservative, which is formaldehyde, and
water, and the amount of water represents the amount that supplements the composition to 100 wt.%.

2. The composition according to claim 1 in which the emulsifier is a mixture of PEG stearate, glocalsearch and PEG stearate.

3. The composition according to claim 1 or 2, in which the surfactants are poliglecaprone glycerides of oleic acid.

4. The composition according to claim 1 or 2, in which the wax with a low melting point is a stearyl alcohol.

5. The composition according to claim 1 or 2, in which despergiruemaya in the water component is a propylene glycol.

6. The composition according to claim 1 or 2, which does not form formaldehyde preservatives are benzoic acid.

7. The composition according to claim 1 or 2, in which the medium contains, wt%:

emulsifier18÷22
surfactant13÷5
the oil component7÷9
wax with a low temperature 3÷5
despergiruemaya in the water component13÷17
preservative0,05÷0,15
waterrest

8. The composition according to claim 7, in which the medium contains, wt%:

emulsifier20
surfactant14
the oil component8
wax with a low temperature4
despergiruemaya in the water component15
preservative0,1
waterrest

9. The use of a composition according to any one of claims 1 to 8, as a drug for treating or preventing skin infections and skin structure infections caused by bacteria, human or animal.

10. The use of a composition according to any one of claims 1 to 8, as a drug for treatment or prevention of sexually transmitted infections, and infections of the floor of the new ways, caused by bacteria in humans or animal.

11. The use of a composition according to any one of claims 1 to 8, as a drug to treat or prevent infections of the nasopharynx caused by bacteria in humans or animals who are asymptomatic naselenie media.

12. Method for the treatment or prevention of skin infections and skin structure infections caused by bacteria, including the application of the needy in this patient the composition according to any one of claims 1 to 8.

13. Method for the treatment or prevention of sexually transmitted infections and reproductive tract infections caused by bacteria, including the application of the needy in this patient the composition according to any one of claims 1 to 8.

14. A method of treating or preventing infections of the nasopharynx of asymptomatic nasal carriers caused by bacteria, including the application of the needy in this patient the composition according to any one of claims 1 to 8.

15. A stable composition in the form of ointments for topical application, comprising 0,2÷5 wt.% ostoksilla and a suitable carrier selected from a group comprising white wax, colorless soft paraffin and mixtures thereof.

16. The composition according to item 15, in which the carrier is a colorless soft paraffin.

17. The composition according to item 15 or 16, which contains 0.5÷2 wt.% ostoksilla.

18. The composition according to 17, which contains 1 wt.% osinochkin is.

19. The use of a composition according to any one of p-18 as a drug for treatment or prevention of skin infections and skin structure infections caused by bacteria.

20. The use of a composition according to any one of p-18 as a drug for treatment or prevention of sexually transmitted infections and reproductive tract infections caused by bacteria.

21. The use of a composition according to any one of p-18 as a drug to treat or prevent infections of the nasopharynx caused by bacteria in asymptomatic nasal carriers.

22. Method for the treatment or prevention of skin infections and skin structure infections caused by bacteria, including introduction to the needy in this patient the composition according to any one of p-18.

23. Method for the treatment or prevention of sexually transmitted infections and reproductive tract infections caused by bacteria, including introduction to the needy in this patient the composition according to any one of p-18.

24. A method of treating or preventing infections of the nasopharynx of asymptomatic nasal carriers caused by bacteria, including introduction to the needy in this patient the composition according to any one of p-18.



 

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1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form for local application in the form of cream or ointment contains as effective amount of voriconazole or its pharmaceutically acceptable salt, or a pharmaceutical carrier. Said dosage form of voriconazole contains max. 3 wt % of water. What is also described is a method for preparing the dosage form of voriconazole for treating local and non-systemic mycotic infections in an individual.

EFFECT: dosage form for local application under the invention maintains storage stability at temperature approximately 40°C and relative humidity approximately 75% for at least three months and has total storage impurity content is no more than 9 wt % as related to total weight of the dosage form.

12 cl, 1 dwg, 30 ex

FIELD: medicine.

SUBSTANCE: offered invention refers to medicine, namely dentistry, and may be used for treating children suffering maxillofacial abscesses and phlegmons. That is ensured by opening of a suppurative focus, wound bathing and drainage. With underlying conventional antibacterial therapy, an ointment containing furacilin, lidocaine and dibunol as active agents and a styrene maleic anhydride copolymer, Lutrol F-127 and purified water in certain proportions as an ointment base is introduced in the suppurative cavity. Furacilin - 0.2, Lidocaine - 5.0, Dibunol - 5.0, Styrene maleic anhydride copolymer - 2.0, Lutrol F-127 2.0 and Purified water to 100.0.

EFFECT: use of the given invention reducing length of wound cleaning and epithelisation in children due to the use of the ointment in presented proportions.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein m is equal to 0, 1, 2; n is equal to 0, 1, 2, 3; each p, s, t is equal to 0 or 1; X represents CHR8 wherein R8 represents hydrogen; represents -CR9=C<, and then a dash line represents a bond, R9 independently represents hydrogen or C1-6-alkyl, or wherein R9 together with one of R2 or R20 forms a direct bond; R1 represents hydrogen; R2 and R20 are specified in: halogen, cyano, polyhalogen-C1-6-alkyl, C1-6-alkyl, morpholinyl, C1-6-alkyloxy with any of said groups is optionally and independently substituted by hydroxy, NR21R22 wherein R21 and R22 are independently specified in hydrogen, C1-6-alkylcarbonyl; or R2 and R20 together with a phenyl cycle whereto attached form a naphthaline group; or one of R2 or R20 have the values specified above, and the other of R2 or R20 together with R9 form a direct bond; R3 represents hydrogen; R4 and R5 independently represent hydrogen, C1-6-alkyl, hydroxy-C1-6-alkyl, C2-6-alkenyl or C1-6-alkyloxy; or R6 represents hydrogen; when p is equal to 1, then R7 represents hydrogen; Z represents one of the radicals presented in the patent claim. Also, the invention refers to a based pharmaceutical composition, using the compounds of formula (I) for producing the drug preparation for treating the disorders medicated by p53-MDM2 interaction for treating cancer, and to methods for producing the compounds of formula (I).

EFFECT: preparing the compounds of formula (I) as p53-MDM2 interaction inhibitors.

13 cl, 5 tbl, 31 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly gastroenterology, and may be applied in treating secondary lactase deficiency. For this purpose, with underlying diet and drug-induced therapy, bifiform 1 tablet 2-3 times a day and No-spa 1-2 tablets 3 times a day are additionally administered. The therapeutic course makes 14 days.

EFFECT: method enables higher clinical effectiveness in secondary lactase deficiency.

3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neurology, restorative medicine, and can be applied in treatment of consequences of infantile cerebral paralysis. For this purpose reflex low temperature impact on nerve plexuses of peripheral artery is performed. Said impact is performed first in lower third of forearm, and after three months in first interdigital space of foot. Cryoapplicator with diameter 2 mm is installed on exposed peripheral artery and double cryogenic impact with duration 10 seconds is performed at temperature minus 186°C. In the period between low temperature impacts complex drug therapy is carried out: in the first two weeks administered are detralex in dose 1 capsule 2 times per day, nicospan in dose 1 tablet 3 times; in the second two weeks grandaxin in dose 0.05 in the morning; spasgan in dose 1 tablet in the afternoon; atarax in dose 1/2 tablet before going to bed.

EFFECT: method ensures definite consistency, which makes it possible to compensate vegetative dystonia syndrome, normalise neuromuscular transmission, reduce muscle spasticity, optimise motor functions of upper and lower extremities and, therefore, improve coordination of movements and supportability of lower extremities.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely addictology, psychiatry and combustiology and may be used for anaesthesia in desomorphin addicted patients suffering thermal burns. After admission to hospital, the burns are localised with describing the aethiology, the comorbidity, the psychological and social characterisation of the patient. If observing the flame-caused injuries, and if the thermal injury localisation and severity are different from the circumstances described by the patient; if chemical burning smell and fly ash are seen, while the burns are found to be localised on face, neck, front and/or back trunk, hands, forearms; and in case of airway burn, signs of lymphangitis, phlebitis and thrombophlebitis, no criticism with persistent mental disturbances; if the patient is unemployed or does not study, desomorphine addiction is diagnosed. During a period of septic toxaemia, dressing procedures required a local anaesthetic to be used, while narcotic analgesics are introduced after the dressing procedures to be gradually replaced by non-narcotic analgesics.

EFFECT: improved anaesthesia.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel tetrahydroisoquinoline derivatives of general formula (I) or pharmacologically acceptable salts thereof, where R1 is a phenyl aminocarbonyl group which can be substituted with 1-3 groups independently selected from a substituting group A, a heteroaryl aminocarbonyl group, where the heteroaryl is pyridine, pyrazine, thiazole, pyrazole or isoxazole, which can be substituted with 1 group selected from a substituting group A, benzoxazol-2-yl group, which can be substituted with 1 group selected from a substituting group A, benzothiazol-2-yl group, (C1-C6 alkyl which can be monosubstituted with a C3-C6 cycloalkyl group), aminocarbonyl group, (C3-C6 cycloalkyl)aminocarbonyl group or adamantyl aminocarbonyl group; R2 independently represents a C1-C6 alkyl group; R3 is a heterocyclic group, where the heterocycle is oxazole, oxadiazole, pyrazole, isoxazole or tetrazole, which can be substituted with 1 group selected from a substituting group A, a group of formula -C(=O)-O-R4, or a group of formula -C(=O)-N(R5)R6; R4 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1-2 groups independently selected from a substituting group B; R5 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1 group selected from a substituting group B, a C3-C6 cycloalkyl group which is monosubstituted with a carboxyl group, or a heterocyclic group, where the heterocycle is tetrazole, which can be substituted with 1 group selected from a substituting group A; R6 is a hydrogen atom or a C1-C6 alkyl group; in those cases when both R5 and R6 represent a C1-C6 alkyl group, which can be substituted with 1 group selected from a substituting group B, their carbon atoms can be bonded to each other to form a 5-member saturated ring; X is an oxygen atom, a methylene group, a group of formula -NH-, a methylene group which is monosubstituted with a C1-C6 alkyl group, or a group of formula -N(R7)-; R7 is a C1-C6 alkyl group; L is a single bond, a methylene group, a 1,1-dimethylmethylene group, an ethylene group, a group of formula - CH=, or a methylene group which is monosubstituted with a C1-C6 alkyl group; … denotes a single bond or a double bond (however, … denotes a single bond when L is a group of formula -CH=); m equals 1 or 2; n equals 0 or 1; substituting group A is a group of substitutes selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, a C1-C6 alkylthio group, a carboxyl group, a di-(C1-C6 alkyl)amino group, a cyano group, a hydroxy group, a C1-C6 alkylthionyl group and an oxo group; and substituting group B is a group of substitutes selected from a carboxyl group and a hydroxy group. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treating and/or preventing a disease.

EFFECT: obtaining novel tetrahydroisoquinoline derivatives, having excellent inhibiting action on acyl-coenzyme A: diacylglycerol-acyltransferase and excellent food intake suppression.

31 cl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel tetrahydroisoquinoline derivatives of general formula (I) or pharmacologically acceptable salts thereof, where R1 is a phenyl aminocarbonyl group which can be substituted with 1-3 groups independently selected from a substituting group A, a heteroaryl aminocarbonyl group, where the heteroaryl is pyridine, pyrazine, thiazole, pyrazole or isoxazole, which can be substituted with 1 group selected from a substituting group A, benzoxazol-2-yl group, which can be substituted with 1 group selected from a substituting group A, benzothiazol-2-yl group, (C1-C6 alkyl which can be monosubstituted with a C3-C6 cycloalkyl group), aminocarbonyl group, (C3-C6 cycloalkyl)aminocarbonyl group or adamantyl aminocarbonyl group; R2 independently represents a C1-C6 alkyl group; R3 is a heterocyclic group, where the heterocycle is oxazole, oxadiazole, pyrazole, isoxazole or tetrazole, which can be substituted with 1 group selected from a substituting group A, a group of formula -C(=O)-O-R4, or a group of formula -C(=O)-N(R5)R6; R4 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1-2 groups independently selected from a substituting group B; R5 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with 1 group selected from a substituting group B, a C3-C6 cycloalkyl group which is monosubstituted with a carboxyl group, or a heterocyclic group, where the heterocycle is tetrazole, which can be substituted with 1 group selected from a substituting group A; R6 is a hydrogen atom or a C1-C6 alkyl group; in those cases when both R5 and R6 represent a C1-C6 alkyl group, which can be substituted with 1 group selected from a substituting group B, their carbon atoms can be bonded to each other to form a 5-member saturated ring; X is an oxygen atom, a methylene group, a group of formula -NH-, a methylene group which is monosubstituted with a C1-C6 alkyl group, or a group of formula -N(R7)-; R7 is a C1-C6 alkyl group; L is a single bond, a methylene group, a 1,1-dimethylmethylene group, an ethylene group, a group of formula - CH=, or a methylene group which is monosubstituted with a C1-C6 alkyl group; … denotes a single bond or a double bond (however, … denotes a single bond when L is a group of formula -CH=); m equals 1 or 2; n equals 0 or 1; substituting group A is a group of substitutes selected from a halogen atom, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy group, a C1-C6 halogenated alkoxy group, a C1-C6 alkylthio group, a carboxyl group, a di-(C1-C6 alkyl)amino group, a cyano group, a hydroxy group, a C1-C6 alkylthionyl group and an oxo group; and substituting group B is a group of substitutes selected from a carboxyl group and a hydroxy group. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treating and/or preventing a disease.

EFFECT: obtaining novel tetrahydroisoquinoline derivatives, having excellent inhibiting action on acyl-coenzyme A: diacylglycerol-acyltransferase and excellent food intake suppression.

31 cl, 113 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for local application containing a therapeutic compound of an immune response modifier, sterilisation-resistant and applicable for local application immediately on tissue regions with skin damages wherein said composition is sterilised by electron-beam irradiation, and the therapeutic compound represents 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-4-amine (imiquimod). Also, the invention refers to a packed composition for local application containing a packing material and said pharmaceutical composition.

EFFECT: invention provides the sterilisation-resistant pharmaceutical composition.

26 cl, 5 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula where A is pyridinyl; and B is a condensed ring system consisting of: a. a phenyl ring bonded to a molecular residue, b. a second heterocyclic 5- or 6-member ring which is condensed with the phenyl ring, and has one nitrogen or oxygen atom, and to tautomeric forms thereof.

EFFECT: obtaining novel imidazole derivatives which are antagonists of adrenergic receptors.

6 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I) , where Ar denotes each of R2, R3, R4, R5, R4' and R5' denote hydrogen; A denotes C(O); D denotes oxygen or NR8; E denotes CR63R64CR65R66; R63 and R64 denote hydrogen; R65 and R66 independently denote hydrogen or C1-4alkyl; k equals 0; m equals 1; R6 denotes a group -(X)p-Y-(Z)q-R10, or R6 denotes α- or β-branched C3-6alkyl (optionally substituted with C6cycloalkyl); X and Z independently denotes a C1-4alkylene group; p and q are independently equal to 0 or 1; Y denotes a bond; R8 denotes hydrogen; R10 denotes hydrogen or a saturated 5-7-member ring system; R7 denotes a 6-member aromatic ring, optionally substituted with a halogen, carboxyl, C1-6alkyl, C1-2alkoxy or a 5-member heteroaromatic ring (which is optionally substituted with C1-6alkyl); or a pharmaceutically acceptable salt thereof. Compounds of formula (I) or a pharmaceutically acceptable salt thereof are used to produce a medicinal agent for treating respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma or rhinitis.

EFFECT: high efficiency of using said compounds.

7 cl, 1 tbl, 102 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and cosmetology and represents a method for preparing an aqueous adapalene gel which involves the following stages: i) preparing a gel-forming composition A by mixing water and propylene glycol and adding a gel-forming agent after propylene glycol wherein the composition A additionally contains a preserving agent to be dissolved in propylene glycol at room temperature; ii) preparing an adapalene composition B by dispersing adapalene in water with a surfactant added; wherein the stages i) and ii) are concurrent, or any of the stages i) or ii) follow the other; iii) adding the adapalene composition B to the gel-forming composition A; iv) reducing pH by adding a neutralising agent to prepare gel with each stage conducted at room temperature.

EFFECT: invention provides improving the method for preparing the aqueous adapalene gel commercially.

15 cl, 2 ex, 1 dwg

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