Crystalline azithromycin l-malate monohydrate and pharmaceutical composition including it

FIELD: chemistry.

SUBSTANCE: invention concerns crystalline azithromycin L-malate monohydrate of formula (I) with high stability, solubility and non-hygroscopicity. Also invention concerns pharmaceutical composition for microbe infection treatment, based on compound of the formula (I), and method of obtaining compound of the formula (I), involving: a) interaction of azithromycin with malic acid in aqueous organic solvent, or b) recrystallisation of water-free azithromycin L-malate from aqueous organic solvent.

EFFECT: obtaining crystalline azithromycin L-malate monohydrate of formula (I) with high stability, solubility and non-hygroscopicity.

15 cl, 7 tbl, 7 dwg, 18 ex

 

The technical field to which the invention relates

The present invention relates to the crystalline monohydrate L-malate azithromycin consisting of one molecule of azithromycin, two molecules of L-malic acid and one molecule of H2O, the method of its production and its containing pharmaceutical compositions.

Description of the prior art

Azithromycin, 9 desoxo-9a-Aza-9a-methyl-9a-homoerythromycin A (nomenclature of medicines taken in the United States (USAN)) of the formula (II)described previously in U.S. patent No. 4517359 and 4474768, is a semisynthetic macrolide antibiotic belonging to the subclass ofof azalides, is used to treat bronchial infections, infections transmitted through sexual contact, and dermatological infections (see H.A. Kirst and G.D. Sildes, Antimicrob. Agents Chemother. 1989, 33, 1419-1422).

Azithromycin described in the above patents, is in the form vysokochastotnoi and unstable crystallineanhydrous form or in the form of a monohydrate and is not suitable for use in pharmaceutical drug.

To solve this problem, European patent EP 0298605 described hygroscopic crystalline dihydrate azithromycin. In the European patent EP 0984020 and published PCT application no WO 2002/085898 described form of azithromycin, solvated Neto is, or toxic alcohol.

However, the dihydrate azithromycin has low solubility in water, which at 37°C is 1.1 mg/ml, which with the introduction of the pharmaceutical composition, for example, in the form of capsules or tablets containing a high dose, adversely affects the speed of release of drug and absorption in vivo. Thus, to increase the absorption rate of the drug in vivo, it is used together with a solubilizer, for example, when you want an introduction by injection.

Azithromycin contains two groups of the tertiary amine and, consequently, to improve the solubility can be converted into the form of an acid additive salt. For example, in U.S. patent No. 4474768 described acid additive salts of azithromycin with organic or inorganic acid, for example hydrochloric acid. It was also reported various salts of azithromycin with hydrochloric acid, itestosterone acid, acetic acid, L-aspartic acid and lactobionic acid (see S. Djokic et al., J. Chem. Research (S), 1988, 152-153 or J. Chem. Research (M), 1988, 1239-1261). Moreover, in publications patents CN No. 1123279, 1157824, 1205338 and 1334541 described salts of azithromycin with glutamic acid, aspartic acid, lactic acid, citric acid, acetic acid, glucuronic acid, N-acetylcysteine, metallernas to what slotow, ascorbic acid and sulphuric acid.

However, most of the above salts are amorphous substances, obtained by removing the solvent used during the formation of the salt, by freeze-drying, spray drying or vacuum distillation. In the European patent EP 0677530 proposed amorphous azithromycin dihydrochloride, obtained by sedimentation. Such amorphous salts, in addition to the problems arising due to the inclusion of varying amounts of residual water or organic solvent, are hygroscopic and unstable. Accordingly, they are unsuitable for pharmaceutical applications.

In PCT publication no WO 2004/106355 proposed crystalline salt of azithromycin with citric acid, i.e. hydrocitric of azithromycin. However, it proves difficult to maintain a constant water content in the specified salt in a humid environment.

The authors of the present invention attempted to obtain improved acid additive salt of azithromycin and found crystalline salt of azithromycin with much better stability, nephroscopes and solubility than known dihydrate azithromycin.

The invention

The main task of the present invention is to obtain an acid additive salt and is of ithromycin, with high solubility, stability, and nephroscopes, as well as the development of the method it was received.

According to one aspect of the present invention proposed a crystalline monohydrate L-malate azithromycin of formula (I):

The present invention further provides a pharmaceutical composition for treating microbial infections comprising as an active ingredient monohydrate L-malate azithromycin of formula (I).

Brief description of drawings

The above task and distinctive features of the present invention will be apparent from the following description of the invention considered together with the accompanying drawings, which respectively show:

FIGURE 1: x-ray powder diffraction pattern (XPRD) crystalline monohydrate L-malate of azithromycin according to the invention;

FIGURE 2: infrared (IR) absorption spectrum of the crystalline monohydrate L-malate of azithromycin according to the invention;

FIGURE 3: XPRD range of anhydrous L-malate azithromycin;

FIGURE 4: the IR absorption spectrum of anhydrous L-malate azithromycin;

FIGURE 5: time-dependent changes of water content (%) in the crystalline monohydrate L-malate of azithromycin according to the invention;

6: time-dependent changes in the number and the effective azithromycin (%) monohydrate L-malate of azithromycin according to the invention compared with the dihydrate azithromycin; and

FIG.7: the pharmacokinetic profile in vivo monohydrate L-malate of azithromycin according to the invention compared with the dihydrate azithromycin.

Detailed description of the invention

Monohydrate L-malate azithromycin of formula (I) according to the present invention can be obtained (a) by the interaction of azithromycin of formula (II) with malic acid of formula (III) in aqueous organic solvent, or b) recrystallization of anhydrous L-malate azithromycin of formula (IV) from aqueous organic solvent:

In particular, the compound of formula (I) according to the invention can be obtained by a process comprising the following stages: the suspension of the azithromycin of formula (II) in aqueous organic solvent; then add the malic acid of the formula (III); heating the mixture to a temperature in the range from room temperature to the boiling point of the used solvent; cooling the obtained transparent solution to a temperature in the range of 0°C to room temperature, filtering off and drying the precipitated crystals.

Azithromycin is of the formula (II)used in the present invention, may be in anhydrous form, in the form of a monohydrate, dihydrate or with whom Iwata.

Malic acid of formula (III)used in the present invention, may be L-malic acid, DL-malic acid racemate, or mixtures thereof, among which L-malic acid is preferred.

In accordance with the above method according to the present invention, only the L-malic acid stereochemical selectively interacts with a chiral molecule azithromycin obtaining monohydrate L-malate azithromycin of formula (I), even when the racemic mixture using DL-malic acid. Although each salt azithromycin with D - or D,L-malic acid can be obtained in another way, for example using the nonaqueous organic solvent, such salt get in anhydrous form.

Therefore monohydrate L-malate azithromycin of formula (I) L-malate means salt of L-(-)-malic acid, whose asymmetric carbon atom preferably has the S-configuration.

In the present invention L-malic acid is preferably used in a quantity amounting 2-2,5 molar equivalent per 1 molar equivalent of azithromycin.

Water organic solvents that can be used in the present invention include aqueous acetone, methyl ethyl ketone, methyl isobutyl ketone, ethanol, 1-propanol, 2-propanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, methyl acetate and etelaat is, preferably acetone and 2-propanol; and preferably the water content is 2-10% by volume.

In the present invention the aqueous organic solvent is preferably used in a quantity amounting 3-20 ml, preferably 4 to 10 ml per 1 g of azithromycin.

Alternatively, monohydrate, L-malate azithromycin can be obtained by recrystallization anhydrousL-malate azithromycin from aqueous organic solvent described above.

Monohydrate L-malate azithromycin of formula (I) according to the invention, thus obtained, forms a crystalline structure, which consists of one molecule of azithromycin, two molecules of L-malate and one molecule of H2O, as can be shown in figure 1 and 2. In particular, x-ray diffraction spectrum (XRD) of the compounds according to the invention (FIG 1) shows major peaks having values of I/Ioconstituting at least 10% (I represents the intensity of each peak; I0represents the intensity of the highest peak), at values of 2θ±0,2 equal 9,6; 10,6; 11,2; 12,0; 12,4; 14,3; 14,6; 15,0; 16,6; 17,5; 18,1; 18,6; 19,3; 19,7; 20,2; 20,5; 21,4; 22,6; 23,6; 24,0; 24,6; 27,1; 27,7 and 34.4. Range infrared (IR) absorption of the compounds according to the invention shows significant absorption peaks at wave numbers (cm-1) 3411, 3059, 2971, 1742, 1716, 1619, 1594, 149, 1457, 1345, 1286, 1177, 1112, 1080, 1056, 1013, 1001, 900, 773 and 637 (FIGURE 2). In addition, the crystalline monohydrate L-malate of azithromycin according to the invention demonstrates a melting point in the range 173-176°C, indicating stability when heated.

Crystal structure proposed in the present invention monohydrate L-malate azithromycin differs from the crystal structure of the anhydrous salt, which can be obtained by drying and degidrirovaniya monohydrate forms under reduced pressure (1.0 mm RT. Art.) and a temperature of 100°C or higher for several hours; or by the interaction of azithromycin with L-malic acid in a nonaqueous organic solvent, as shown in the XRD spectrum (FIGURE 3) and in the IR absorption spectrum (FIGURE 4). Anhydrous form demonstrates a melting point in the range 180-184°C.

Unlike conventional amorphous salts, obtained by removing the solvent by vacuum distillation, freeze-drying or spray drying or by precipitation of the crystalline monohydrate L-malate of azithromycin according to the present invention is non-hygroscopic, as follows from the results in table 1, which were obtained after storage for 24 hours at 40°C and a relative humidity of 75%.

tr>
the table 1

Obtaining an acid additive salt of azithromycin
AcidThe amount of acid (mol)Solventa)CrystallizationInitial water content (%)Form salts
Hydrochloric acid22-PropanolDispersed precipitation ofb)5,0Amorphous, hygroscopic
2EthanolEvaporation of solventthe 4.7Amorphous, hygroscopic
2WaterDrying by freezing5,1Amorphous, hygroscopic
Hydrobromic acid2AcetoneEvaporation of solvent-Amorphous, hygroscopic
Sulfuric acid1AcetoneEvaporation of solvent-Amorphous, hygroscopic
p-Toluensulfonate1AcetoneEvaporation of solvent3,4Amorphous, hygroscopic
2-Naphthalenesulfonate1Acetone Precipitation3,5Crystalline, hygroscopic
Citric acid1EthanolEvaporation of solvent4,4Amorphous, hygroscopic
2/3EthanolEvaporation of solventthe 3.8Amorphous, hygroscopic
2/3WaterDrying by freezing-Amorphous, hygroscopic
Fumaric acid1AcetonePrecipitation6,1Crystalline, hygroscopic
12-PropanolPrecipitation5,8Crystalline, hygroscopic
Maleic acid1AcetoneEvaporation of solvent2,7Amorphous, hygroscopic
2AcetoneEvaporation of solvent-Amorphous, hygroscopic
Succinic acid1AcetoneEvaporation of solvent-Amorphous, hygroscopic
L-tartaric acid1AcetonePrecipitation4,8Crystalline, hygroscopic
L-lactic acid2The ethyl acetatePrecipitation2,9Crystalline, hygroscopic
2AcetonePrecipitation3,0Crystalline, hygroscopic
L-malic acid195% AcetonePrecipitation2,0Crystalline, non-hygroscopicc)
295% AcetonePrecipitation1,9Crystalline, non-hygroscopicc)
295% 2-PropanolPrecipitation1,9Crystalline, non-hygroscopicc)
2Anhydrous 2-propanolPrecipitation0,4Crystalline, hygroscopicd)
DL-malic acid295% 2-PropanolPrecipitation1,9Crystalline, non-hygroscopicc)
2Anhydrous 2-propanol Precipitation0,4Crystalline, hygroscopice)
D-malic acid295% 2-PropanolEvaporation of solvent-Crystalline, hygroscopicf)
2Anhydrous 2-propanolPrecipitation0,4Crystalline, hygroscopicf)
a) the Solvent may contain a small amount of water to stimulate the formation of hydrate

b) Dispersed deposition can be carried out by adding isopropyl ether into a solution of 2-propanol

c) Monohydrate, L-malate according to the present invention

d) AnhydrousL-malate

e) AnhydrousDL-malate

f) AnhydrousD-malate

In addition, proposed in the present invention, the crystalline monohydrate L-malate azithromycin of formula (I) has a significantly higher solubility in water than the well-known dihydrateazithromycin, which is the only pharmaceutical ingredient used hitherto in the art, and thus, he (monohydrate) has significantly improved pharmacokinetic profile of azithromycin suitable for making superior is oppozitsii for treating various microbial infections.

Accordingly, the present invention proposed a pharmaceutical composition for treating microbial infections comprising as an active ingredient monohydrate L-malate azithromycin of formula (I).

Examples of microbial infections include community-acquired pneumonia-related infections caused by Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Chlamydiapneumoniae; pharyngitis and tonsillitis related to infections caused by Streptococcus pyogenes; chronic obstructive pulmonary disease and acute otitis media-related infections caused by Haemophilus influenzae,MoraxellacatarrhalisorStreptococcus pneumoniae; uncomplicated skin infections related to infection by Staphylococcusaureus,Streptococcus pyogenes or Streptococcus agalactiae; infections of urinary ways, related to infections caused by Neisseria gonorroeae or Chlamydia trachomatis; and disseminated disease with mycobacterium avium complex(MAC),related to infections caused by Mycobacterium avium.

Proposed in the present invention, a pharmaceutical composition comprising as an active ingredient crystalline monohydrate L-malate azithromycin may be entered in various ways, including oral application, the application in the form of injections and ophthalmic application.

When orally administered pharmaceutical composition for the present and the finding may be in the form of tablets, capsules, suspensions, powders and the like, administered in a single dose or in divided doses. Such a composition may contain pharmaceutically acceptable carriers, diluents or excipients such as binding agents, filling agents, buferiruemoi agents, lubricating agents, dezintegriruetsja agents, sweetening agents, flavoring agents, surfactants and covering substance.

Examples dezintegriruetsja agents include starches, gelatinising starch, sodium starch glycolate, carboxymethylcellulose sodium, croscarmellose sodium, microcrystalline cellulose, alginates, gums, surfactants, effervescent compositions, aqueous silicate of aluminum and transversely crosslinked polyvinylpyrrolidone. Examples of the coupling agent include gum; cellulose derivatives such as methylcellulose, carboxymethyl cellulose, hypromellose, hydroxypropylcellulose and hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylate, polyvinylpyrrolidone, sorbitol, starch, gelatinising starch, xanthan resin, alginates, magnesium aluminosilicate, polyethylene glycol and bentonite.

Examples of filling agents include lactose, anhydrous lactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose derivatives, such to the to microcrystalline cellulose, and calcium phosphate, calcium carbonate and calcium sulfate in anhydrous form or in the form of a dihydrate. Examples of the lubricating agent include magnesium stearate, talc, polyethylene glycol, a polymer of ethylene oxide, sodium lauryl sulfate or magnesium, sodium oleate, sodium fumarate, DL-leucine and colloidal silicon dioxide. Examples of flavoring agents include extracts and synthetic or natural fragrant oil derived from essential oils, flowers, different kinds of fruit, and mixtures thereof.

Examples covering agents include hypromellose, hydroxypropylcellulose and a copolymer of acrylic acid and methacrylic acid, which can allow for easy swallowing, control release, as well as improve the shape and taste of the drug. Examples of sweetening agents include aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose. Examples BufferedReader agent include citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide. Examples of surfactants include sodium lauryl sulfate, Polysorbate etc.

Pharmaceutical composition for oral administration may be prepared in the form of divided doses containing 50-700 mg of azithromycin, or in the form of a single dose containing 700-3500 mg azithr mizina, and it preferably contains a crystalline monohydrate L-malate azithromycin of formula (I) in an amount of 20-80 parts by weight per 100 parts by weight of the composition. For example, 500 mg (100%) pharmaceutical compositions containing 250 mg (50,0%) of azithromycin, can be composed of 345,53 mg (69,1%) monohydrate L-malate azithromycin of formula (I) and 154,47 mg (30.9 percent) of appropriate additives such as carriers, diluents or excipients.

The pharmaceutical composition of the present invention for sterile administration by injection can be obtained directly by filling vials crystalline monohydrate L-malate of azithromycin according to the invention and a pharmaceutically acceptable carrier is sterile, or filling bottles amorphous powder obtained by dissolving crystalline monohydrate L-malate of azithromycin and a pharmaceutically acceptable carrier in sterile water with subsequent freeze-drying. The song before the introduction dissolved in sterile water. Preferably, when the pharmaceutical composition for administration by injection contains crystalline monohydrate L-malate azithromycin of formula (I) in an amount of from 50 to 250 mg/ml

For ophthalmic injection of the pharmaceutical composition of the present invention can be obtained in the form of 0.05 to 1.0% aqueous solution of manage the rata of L-malate azithromycin in isotonic saline solution, phosphoric acid or borate buffer solution or with the same antioxidant as sodium sulfite or hydrosulfite sodium, or without antioxidant.

The present invention will be described in more detail with reference to examples. However, it should be understood that the present invention is not limited to the specific examples.

EXAMPLES

Example 1: Getting monohydrate L-malate azithromycin from L-malic acid

100,00 g dihydrate azithromycin (127 mmol) was dissolved in 1000 ml of 95% 2-propanol and added to 34.1 g of L-malic acid (254 mmol)having an optical purity of 99.7% ee(error tolerance), followed by stirring the resulting solution overnight at room temperature and then for 2 hours at a temperature of 0-5°C. the Resulting precipitate was filtered, washed with cold 2-propanol and dried at 45°C obtaining 118,3 g specified in the title compound (yield: 90%)as a white crystalline substance.

MP: 173˜175°C

Specific rotation, [α]D20: -32,8° (c=1, methanol)

The moisture content (instrument for titration Karl Fischer): 1,80% (calculated value monohydrate - 1,74%)

Optical purity of malic acid after the formation of the salt (HPLC): 99,9% ee L-malic acid

The relative content of azithromycin (by HPLC): 74,6% (from R the account in one molecule, 72,35%)

The relative content of L-malic acid (titration of 0.1 N. KOH): 25,8% (based on two molecules, 25,91%)

IR (KBr, cm-1): 3411, 3059, 2971, 1742, 1716, 1619, 1594, 1493, 1457, 1345, 1286, 1177, 1112, 1080, 1056, 1013, 1001, 900, 773, 637

The obtained x-ray powder diffractogramcrystalline monohydrate L-malate of azithromycin (FIGURE 1) shows that the monohydrate L-malate azithromycin is a crystal having distinct characteristic principal peaks (peaks with values of I/I0and d, constituting at least 10%).

Table 2
2θ(±2)dI/I0(%)2θ(±2)dI/I0(%)
9,69,19100,019,34,5920,2
10,68,3252,319,74,4720,2
11,2a 7.9250,220,24,4025,9
to 12.07,3411,720,54,3242,8
12,47,1618,621,44,1515,4
14,36,1715,8 22,63,9314,9
14,66,0511,723,63,7610,7
15,0of 5.8911,024,03,7112,4
16,65,3457,824,63,6226,6
of 17.5of 5.0547,527,13,2914,3
18,14,9150,227,73,2212,9
18,64,7718,734,42,60to 12.0
2θ: diffraction angle, d: the distance within each crystal face, I/I0(%): relative intensity of the peak

Examples 2-6: Getting monohydrate L-malate azithromycin from L-malic acid

Repeating the procedure of example 1, except that to obtain specified in the header connections use the azithromycin L-malic acid and the solvent listed in table 3.

Table 3
ExampleThe form and amount of azithromycinThe amount of L-malic acidR is storytell The output specified in the connection header
2Anhydrous form, 95,1 g34,1 g95% 2-propanol, 1.0 l115,0 g (87%)
3Monohydrate, 97,4 g34,1 g95% 2-propanol, 1.0 lof 116.7 g (89%)
4Dehydrate, 100.0 g17.1 g95% 2-propanol, 1.0 l69.7 g (53%)
5Dehydrate, 100.0 g34,1 g95% acetone, 1.0 l122,3 g (93%)
6Dehydrate, 100.0 g34,1 g95% ethanol, 0.5 l85,5 g (65%)

Melting point, XPRD and range of the IR absorption spectrum of the obtained compounds were similar to that shown in example 1.

Example 7: Getting monohydrate L-malate azithromycin from anhydrousL-malate azithromycin

50.0 g of anhydrous L-malate azithromycin (moisture content of 0.4%) was dissolved by heating in 400 ml of 95% 2-propanol and the resulting solution was stirred overnight at room temperature and then for 2 hours at a temperature of 0-5°C. the Resulting precipitate was filtered, washed with cold 2-propanol and dried at 45°C with getting to 43.1 g specified in the title compound (yield: 85%) as a white crystal.

TPL: 173DC; 175°C

The moisture content (instrument for titration Karl Fischer): 1,83% (calculated value monohydrate - 1,74%)

The results XPRD and IR absorption spectrum for the obtained compounds were similar to the results of example 1.

Example 8: Getting monohydrate L-malate azithromycin from DL-malic acid

100.0 g of the dihydrate azithromycin (127 mmol) was dissolved in 1000 ml of 95% 2-propanol and added to 34.1 g of DL-malic acid (254 mmol, optical purity of 1.7% ee in favor of L-malic acid), followed by stirring the resulting solution overnight at room temperature and then for 2 hours at a temperature of 0-5°C. the Resulting precipitate was filtered, washed with cold 2-propanol and dried at 45°C with getting to 61.8 g of white crystalline powder (yield: 47%).

TPL: 170˜174°C

Specific rotation, [α]D20: -33,7° (c=1, methanol)

The moisture content (instrument for titrationKarl Fischer): 1,85%

Optical purity of malic acid after the formation of the salt (HPLC): 80,0% ee in favor of L-malic acid

56,0 g of crystalline powders obtained above was recrystallized from 95% 2-propanol with the receipt of 45.2 g specified in the title compound (yield: 80%).

TPL: 172˜175°C

Specific rotation, [α]D20: -33,0° (c=1, methanol)

The content owner is Ki (instrument for titration Karl Fischer): 1,81%

Optical purity of malic acid (HPLC): 98,9% ee L-malic acid

XPRD and IR absorption spectra of the compounds thus obtained were similar to those obtained in example 1.

Reference example 1: Obtaining anhydrousL-malate azithromycin

The way A

10.0 g of monohydrate L-malate azithromycin obtained in one of examples 1-8, dried under reduced pressure (1 mm Hg) at 100°C for 10 hours, getting mentioned in the title compound as a white powder.

Method In

of 37.5 g of anhydrousazithromycin (50 mmol, the moisture content of 0.2%) was dissolved in 400 ml of anhydrous 2-propanol was added to 13.4 g L-malic acid (100 mmol), followed by stirring the resulting solution overnight at room temperature and then for 2 hours at a temperature of 0-5°C. the Resulting precipitate was filtered, washed with cold 2-propanol and dried at 45°C with the receipt of 47.3 g specified in the title compound (yield: 93%) as a white crystalline substance.

TPL: 182˜184°C

Specific rotation, [α]D20: -32,8° (c=1, methanol)

The moisture content (instrument for titrationKarl Fischer): 0,4% or less (after drying)

IR (KBr, cm-1): 3415, 3057, 2980, 2932, 2884, 1736, 1607, 1462, 1386, 1326, 1177, 1084, 1060, 1000, 939, 895, 726, 637.

Connection L-malate azithromycin, polucen the e above, were subjected to x-ray diffraction analysis, and the result showed that the compound has a crystalline structure having main peaks I/Iaboutvalues constituting at least 10%, at values of 2θ±0,2,equal 6,0; 10,0; 11,0; 11,4; 12,5; 13,9; 15,5; 16,2; 17,3; 18,0; 19,2; 20,0; 20,5; 20,8; 21,2; 22,6; 24,5; 25,7. Its anhydrous form was confirmed by the results of measuring the moisture content.

Anhydrous L-malate azithromycin, thus obtained, was kept for 10 hours at 40°C and a relative humidity of 75%, and found that the moisture content increased approximately up to 2.0%. That is, anhydrous L-malate azithromycin transformed into a hydrated form.

Reference example 2: Obtaining anhydrous D-malate azithromycin

10.0 g of the dihydrate azithromycin (12.7 mmol) was dissolved in 100 ml of anhydrous 2-propanol was added to 3.41 g of D-malic acid (25,4 mm)with optical purity of 98.2% ee, followed by stirring overnight at room temperature and then for 2 hours at a temperature of 0-5°C. the Resulting precipitate was filtered, washed with cold 2-propanol and dried at 45°C, receiving 10.4 g specified in the title compound (yield 79%) as a white crystalline substance.

TPL: 160˜163°C

Specific rotation, [α]D20: -39,5° (c=1, methanol)

The optical purity of D-malic KIS is the notes after the formation of the salt (HPLC): 98,9% ee

The moisture content (instrument for titration Karl Fischer): 0,4% or less (after drying)

IR (KBr, cm-1): 3427, 2974, 2937, 2882, 1735, 1598, 1466, 1385, 1179, 1171, 1080, 1060, 1013, 1002, 899, 726.

The compound D-malate azithromycin, obtained above, was subjected to x-ray diffraction analysis, and the result showed that the compound has a crystal structure showing the main peaks (values (I/Iaboutconstituting at least 10%) at values of 2θ±0,2,equal 5,7; 9,9; 10,9; 11,3; 12,3; 15,9; 17,1; 17,8; 18,2; 19,9; 20,6; 22,2. Its anhydrous form was confirmed by the results of measuring the moisture content. However, soaking for 10 hours at 40°C and a relative humidity of 75%, was found to increase the moisture content of 8% or higher.

Anhydrous D-malate azithromycin, obtained above, is not converted in the form of hydrate in water, a solvent used in examples 1-8.

Reference example 3: Obtaining anhydrous DL-malate azithromycin

10.0 g of the dihydrate azithromycin (12.7 mmol) was dissolved in 100 ml of anhydrous 2-propanol was added to 3.41 g of DL-malic acid (25,4 mmol, optical purity of 1.7% ee in favor of L-malic acid), followed by stirring overnight at room temperature and then for 2 hours at a temperature of 0-5°C. the Resulting precipitate was filtered, washed with cold 2-propanol and dried in pécs is at 40° C, receiving 10.3 g specified in the title compound (yield 78%) as a white crystalline powder.

TPL: 169˜172°C

Specific rotation, [α]D20: -35,5° (c=1, methanol)

Optical purity of malic acid (HPLC) of 3.4% ee L-malic acid

The moisture content (instrument for titrationKarl Fischer): 0.5% or less (after drying)

IR (KBr, cm-1): 3410, 2973, 2937, 2882, 1736, 1603, 1458, 1385, 1170, 1076, 1060, 1016, 1008, 895, 641

Connection DL-malate azithromycin, obtained above, was subjected to x-ray analysis, which showed a crystalline structure having main peaks (values (I/I0constituting at least 10%) at values of 2θ±0,2 equal to5,9; 9,9; 10,9; 11,3; 12,4; 16,0; 17,2; 17,9; 19,9; 20,6; 22,5; 24,4. In addition, measurement of moisture content showed anhydrous form. However, soaking for 10 hours at 40°C and a relative humidity of 75%, the moisture content in the sample increases up to 6% or higher.

Meanwhile,,in conditions of water solvent instead of anhydrous DL-malate azithromycin, obtained above, crystallized, non-hygroscopic monohydrate L-malate of azithromycin, as shown in example 8.

Experimental example 1: Test solubility

Monohydrate L-malate of azithromycin according to the present invention and dihydrate azithromycin was dissolved to saturation corresponding what about in deionized water and in buffer solution of phosphoric acid (pH 7). The solubility of each of the saturated solutions were analyzed by HPLC according to the method described in US Pharmacopoeia, to determine the amount of dissolved azithromycin. The results are shown in table 4.

Table 4
SolSolubility (mg/ml, 25°C)a)
Deionized waterBuffer solution (pH 7)
Monohydrate L-malate azithromycin393392
The dihydrate azithromycin0,15,1
a) the solubility was measured in relation to the number of dissolved azithromycin

As shown in table 4, the solubility of the monohydrate L-malate of azithromycin according to the invention is considerably increased in comparison with known solubility dihydrate azithromycin, which means that the salt of azithromycin according to the invention preferred for use in vivo.

Experimental example 2: Test nephroscopes

Monohydrate L-malate of azithromycin according to the invention continuously kept at 25 or 40°C and relative humidity 40-90% for more than 15 days. The moisture content in the salt according to the image is the shadow, measured by using a device for Karl Fischer titration with storage time 0, 3, 7 and 15 days are shown in table 5 and figure 5.

Table 5
The moisture content (wt.%)
40% (25°C)60% (25°C)75% (40°C)90% (40°C)
Source1,751,751,751,75
3 days1,781,821,801,87
7 days1,751,801,821,85
15 days1,731,801,851,85
The calculated moisture content: 1,74%

As shown in table 5, monohydrate, L-malate of azithromycin according to the invention was substantially non-hygroscopic, preserving the original moisture content, mainly in conditions of low humidity.

Experimental example 3: Test resistance

Measured time-dependent stability monohydrate L-malate of azithromycin according to the invention at high temperatures and compared them with known resistance dihydrate azithromycin.

the particular monohydrate L-malate of azithromycin according to the present invention and dihydrate azithromycin kept in a sealed state under conditions of voltage at 60°C and relative humidity 75%, respectively, and the remaining number of active azithromycin after 7, 14, 21 and 28 days were measured by HPLC according to the method described in the US Pharmacopoeia. The results are shown in table 6 and figure 6.

Table 6
The number m of azithromycin (µg/mg)
Monohydrate L-malate azithromycinThe dihydrate azithromycin
Source986,4976,5
7 days984,6974,6
14 days985,1975,3
21 days987,0973,2
28 days985,4971,6

As shown in table 6, the dihydrate azithromycin within 28 days has undergone significant degradation, whereas the monohydrate L-malate of azithromycin according to the invention is distinguished by a high stability.

Experimental example 4: Measurement of time-dependent changes in the concentration of azithromycin in the blood (pharmacokinetics the s test)

Pharmacokinetic exposure in vivo monohydrate L-malate of azithromycin according to the invention, having high solubility in water, was tested using greyhounds, and compared with exposure in vivo dihydrate azithromycin.

In particular, Marshall twelve greyhounds (Beijing, average weight: 9,5±0.5 kg) were divided into two groups, each of six dogs. Each of the split dogs were subjected to fasting for 16 hours and then orally injected is contained in a gelatin capsule, single dose, which is at 20 mg/kg, monohydrate L-malate of azithromycin according to the invention (test group) or dihydrate azithromycin (control group). After the introduction periodically carried out fences blood, followed by the separation of plasma. Samples of azithromycin extracted from plasma were subjected to LC/MS/MS analysis to measure it in the number of azithromycin and calculation of pharmacokinetic parameters. The results are shown in table 7 and figure 7

Table 7
Monohydrate L-malate azithromycin (test group)The dihydrate azithromycin (control group)The test group/control group
Cmax(ng/ml)3783,7&x000B1; 1377,11952,4±709,61,94
Tmax(h)0,6±0,20,8±0,30,75
AUC0-24(ngml)27624,0±6862,620552,8±6636,5of 1.34
AUC0-48(ngml)37331,9±8834,327876,7±9709,7of 1.34
* Cmaxis the maximum observed concentration

** Tmaxisthe time that is Cmax< / br>
*** AUC0-timeis the area under the curve "concentration-time" from time 0 to time of last measurable concentration

As shown in table 7, monohydrate, L-malate of azithromycin according to the invention detects superior pharmacokinetic parameters compared to the dihydrate azithromycin. For example, the value of Cmaxmonohydrate L-malate according to the invention was approximately two times higher than Cmaxdihydrate. Therefore, monohydrate, L-malate of azithromycin according to the present invention has a high initial concentration in the blood, which is effective for the treatment of infections caused by resistant pathogens.

Monohydrate L-malate of azithromycin according to the present invention can be obtained separately or in whom is inali with pharmaceutically acceptable additives in accordance with any of the conventional ways, used for making soft or hard capsules, tablets, suspensions, powders and solutions.

The following examples of the preparation are intended to further illustratethisthe invention, without restricting its scope.

Example obtain 1:Capsule azithromycin

A gelatin capsule was obtained using the following ingredients:

IngredientNumber
Monohydrate L-malate azithromycin*345,53 mg (69,11%)
Microcrystalline cellulose90,37 mg (18,07%)
Corn starch30,00 mg (6,00%)
The lactose monohydrate15,10 mg (3,02%)
Magnesium stearate9,00 mg (1,80%)
Aspartame10,00 mg (2,00%)
The total number of500,00 mg (100,00%)
* Contains 250 mg of azithromycin

Example of getting a 2: Tablet azithromycin

The tablet was obtained using the following ingredients:

IngredientNumber
Monohydrate L-malate azithromycin*345,53 mg (57,59%)
Microcrystalline cellulose115,07 mg (MT 19 : 18%)
Corn starch49,40 mg (8,23%)
The lactose monohydrate20,00 mg (3,33%)
Aqueous ethyl cellulose powder30,00 mg (5.00%)
The polymer aminoalkylsilane20,00 mg (3,33%)
Magnesium stearate9,00 mg (1,50%)
Sodium lauryl sulfate1.00 mg (0,17%)
Aspartame10,00 mg (1,67%)
The total number of600,00 mg (100,00%)
* Contains 250 mg of azithromycin

An example of obtaining 3: azithromycin Powder for oral administration in the form of suspension

Powder for oral administration were obtained using the following ingredients:

IngredientNumber
Monohydrate L-malate azithromycin*691,05 mg (6,91%)
Sucrose4875,20 mg (48,75%)
Sorbitol4126,25 mg (41,26%)
Xanthan gum50,00 mg (0,50%)
Hydroxypropylcellulose50,00 mg (0,50%)
Aerosol dry cherry flavor 32.50 to mg (0,33%)
Synthetic vanilla cream100,00 mg (1,00%)
Aerosol dry banana flavoring75,00 mg (0,75%)
The total number of10000,mg (100,00%)
* Contains 500 mg of azithromycin

As discussed above, monohydrate, L-malate azithromycin in accordance with the present invention has a significantly higher solubility in water than the well-known dihydrate azithromycin, as well as good heat resistance and nephroscopes. Additionally, salt according to the invention is superior to known salt indicators pharmaceutical effects in animal experiments. Accordingly, monohydrate, L-malate of azithromycin according to the present invention can be advantageously used for the treatment of various microbial infections.

Although the invention is described relative to specific embodiments, it should be understood that the specialists in this field of technology can make to the invention various modifications and changes are also included in the scope of the invention defined by the attached claims.

1. Crystalline monohydrate L-malate azithromycin of formula (I)

2. Crystal monog the dratha L-malate of azithromycin according to claim 1, x-ray powder diffraction pattern which detects the main peaks with values of I/I0constituting at least 10%, at values of 2θ±0,2 equal 9,6; 10,6; 11,2; 12,0; 12,4; 14,3; 14,6; 15,0; 16,6; 17,5; 18,1; 18,6; 19,3; 19,7; 20,2; 20,5; 21,4; 22,6; 23,6; 24,0; 24,6; 27,1; 27,7 and 34.4.

3. A method of obtaining a crystalline monohydrate L-malate of azithromycin according to claim 1, comprising a) interactions of azithromycin of formula (II) with malic acid of formula (III) in an aqueous organic solvent or (b) recrystallization of anhydrous L-malate azithromycin of formula (IV) from aqueous organic solvent:

4. The method according to claim 3, in which the malic acid of the formula (III) is L-malic acid, racemate DL-malic acid or mixtures thereof.

5. The method according to claim 3, in which water, an organic solvent selected from the group consisting of acetone, methyl ethyl ketone, isobutyl ketone, ethanol, 1-propanol, 2-propanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, methyl acetate, ethyl acetate and mixtures thereof.

6. The method according to claim 3, in which the water content of the aqueous organic solvent is 2-10% by volume.

7. The method according to claim 3, in which in step a) the aqueous organic solvent is used the amount which is 3-20 ml per 1 g of azithromycin.

8. The method according to claim 3, in which in step a) the content of L-malic acid malic acid of formula (III) corresponds to 2-2,5 molar equivalents per 1 molar equivalent of azithromycin.

9. Pharmaceutical composition for treating microbial infections comprising as an active ingredient crystalline monohydrate L-malate of azithromycin according to claim 1.

10. The composition according to claim 9, which is injected in the form of oral sterile injectable or ophthalmic drug.

11. The composition according to claim 10, in which oral drug is in the form of tablets, capsules, suspensions or powder.

12. The composition according to claim 10, in which the oral preparation contains carriers, diluents and excipients selected from the group consisting of binding agents, fillers, superyoshi agents, lubricating agents, dezintegriruetsja agents, sweeteners, flavoring agents, surfactants, coating substances and their mixtures.

13. The composition according to item 12, in which the number monohydrate L-malate azithromycin is 20-80 parts by weight per 100 parts by weight of the composition.

14. The composition according to claim 11, in which the tablet or capsule product contains azithromycin in number 50-3500 mg.

15. The composition according to claim 9, which is used to treat microbial infections selected from pneumonia, headlamp is Rita, tonsillitis, chronic obstructive pulmonary disease, acute otitis media, uncomplicated skin infections, infections of the genitourinary system and disseminated mycobacterium avium complex.



 

Same patents:

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention relates to new non-steroidal anti-inflammatory compounds represented with the formula I: , where M is a macrolide subunit of the formula , D is a non-steroidal subunit, obtained from a non-steroidal anti-inflammatory drug, L is a connecting group with the formula X1-(CH2)m-Q-(CH2)n-X2, or their pharmaceutically permissible salts or separate diastereoisomer. Apart from that, this invention relates to the method of obtaining compounds of the formula I (versions), to the pharmaceutical composition on the basis of the compounds of formula I or their pharmaceutically permissible salts and also to the administration of formula I or their pharmaceutically permissible salts to obtain medicine (versions). The values of the substitutes R1-R6, A, B, E, U, Y, Z, W, S1, M, D, X1, X2, Q, m, are shown in the formula of the device.

EFFECT: obtaining new non-steroidal anti-inflammatory compounds.

11 cl, 1 tbl, 7 dwg, 23 ex

FIELD: chemistry.

SUBSTANCE: invention concerns (a) new compounds of the formula I: , where M is a macrolipid subunit (macrolipid group) obtained from a macrolipid inclined to accumulation in inflamed cells, S is a steroid subunit (steroid group) obtained from a steroid medicine with anti-inflammatory effect, and L is a linker molecule connecting M and S; (b) their pharmacologically acceptable salts, prodrugs and solvates; (c) methods and mediators for their obtaining; and (d) methods of their application in treatment of human and animal inflammation diseases and conditions. The claimed compounds are inhibiting many cytokines and immune mediators participating in immune reactions that cause inflammation, allergy or alloimmunity, including IL (interleukin)-1, 2, 4, 5, 6, 10, 12, GMCSF (Granulocyte Macrophage Colony Stimulating Factor), ICAM (Intercellular Adhesion Molecule) and TNF (tumour necrosis factor) - α without limitation. At that, antiinflammation steroids have immediate anti-inflammatory effect due to the link to glycocorticosteroid receptor.

EFFECT: application in treatment of human and animal inflammation diseases and conditions.

30 cl, 40 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns avermectin B1 and avermectin B1 monosaccharide derivatives of the general formula I , where n is 0 or 1; A- B is -CH=CH- or -CH2-CH2-; R1 is C1-C8-alkyl, C3-C8-cycloalkyl or C2-C8-alkenyl; R2 is C1-C8-alkyl or C2-C8-alkenyl, optionally substituted by a subsitutde selected out of the group of -OH, - N3, -NO2, C1-C8-alkoxy-, C1-C6-alkoxy-C1-C6-alkoxy, C1-C8-alkylthio, C1-C8-alkylsulfinyl, C1-C8-alkylsulfonyl, -NR4R6, -X- C(=Y)-R4, -X-C(=Y)-Z-R4, or phenyl substituted optionally by halogen; R3 is H or C1-C8-alkyl substituted by halogen; or R2 and R3 together are a 3-7-membered alkylene bridge substituted optionally by C1-C4-alkyl, or form together a -CH2-CH2-O-CH2- or -CH2-CH2-C(=O)-CH2- group; X is -O- or NR5; Y is -O-; Z is -O-; R4 is hydrogen or C1-C8-alkyl substituted optionally by C1-C6-alkoxy; R5 is hydrogen or C1-C8-alkyl; R6 is hydrogen or C1-8-alkyl if the compound is not a avermectin B1a or B1b derivative where n is 1, R3 is H and R2 is -CH2-CH2-OCH3 or -CH2-CH2-O-phenyl; and is not a B1a or B1b derivative where n is 1, and R2 and R3 form together an unsubstituted -CH2-CH2-CH2- group; while their E/Z isomers, mixes of E/Z isomers and/or tautomers, in a free or salt form in each case.

EFFECT: production of insecticide composition and method of cultivated plant pest eradication.

7 cl, 5 tbl, 27 ex

FIELD: chemistry.

SUBSTANCE: invention concerns macrolide compounds of the formula I , where R is hydrogen or methyl; R1 is hydrogen, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide, N-(C1-C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino-(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of the formula: , where A is hydrogen, phenyl or thiazolyl; X is O or NR6 where R6 is hydrogen; Y is thiazolyl, pyrinidyl or NR6 where R6 is hydrogen; r is a whole number of 1 to 3; m is a whole number of 1 to 6; n is a whole number of 0 to 2; R2 is hydrogen; or R1 and R2 together form a link; R3 is a hydroxygroup or forms a =N-O-R5 group together with R4, where R5 is hydrogen, alkyl or a chain of the formula -(CH2)r-X-(CH2)m-Y-(CH2)n-A where r, m, n are the whole number as defined above; A is hydrogen, thiazolyl, furanyl or thiophenyl; X is NR6 where R6 is hydrogen; Y is a phenylene group or NR6 where R6 is hydrogen; R4 is hydrogen or forms =N-O-R5 group together with R3, with the same R5 as defined above; and its pharmaceutically acceptable salts, on the condition that R1 is not a dimethylamino group when R3 is a hydroxy group, and both R2 and R4 are hydrogen; R1 is not a dimethylamino group when in the =N-O-R5 substitute in 9 position R5 is hydrogen, linear or branched (C1-C5)alkyl; R1 is not a methylamino group when in the =N-O-R5 substitute in 9 position R5 is hydrogen, linear or branched (C1-C5)alkyl. The invention also concerns a method of obtaining the claimed compounds by elimination of L-cladinose residuum in the 3 position in compounds of the general formula II , where R, R1, R2, R3 and R4 are the same as defined above. Besides, the invention also concerns compounds of the general formula II, where R is hydrogen or methyl; R1 is hydrogen, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide, N-(C1- C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of the formula: where A is hydrogen, phenyl or thiazolyl; X is O or NR6 where R6 is hydrogen or C1-C3alkoxycarbonyl; Y is thiazolyl, pyrinidyl or NR6 where R6 is hydrogen or C1- C3alkoxycarbonyl; r is a whole number of 1 to 3; m is a whole number of 1 to 6; n is a whole number of 0 to 2; R2 is hydrogen; or R1 forms a link together with R2; R3 is a hydroxy group; R4 is hydrogen; and their pharmaceutically acceptable salts; on the condition that (i) R1 is not N,N-dimethylamino or (ii) R1 is not N,N-dimethylamino-N-oxide when R is hydrogen. The invention also concerns pharmaceutical composition based on the compound of the formula I, exhibiting anti-inflammatory effect.

EFFECT: obtaining of compounds with anti-inflammatory effect.

29 cl, 78 ex

FIELD: antibiotics.

SUBSTANCE: invention relates to azithromycin as a stable monohydrate comprising from 4.0% to 6.5% of water and to a method for its preparing. Invention provides preparing the stable form of azithromycin monohydrate.

EFFECT: improved preparing method.

3 cl, 2 tbl, 2 ex

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention describes crystalline forms A, C and D of erythromycin derivative of the formula (VII): . Crystalline forms are prepared by recrystallization of crude fumarate crystal from an alcoholic solvent (form A) and, additionally, from ethyl acetate (form C) or, additionally, from an aqueous ethyl acetate (form D). Also, invention relates to methods for preparing intermediate compounds. Prepared crystalline forms possess the better quality, in particular, high stability that is important in preparing pharmaceutical preparations.

EFFECT: improved preparing methods.

16 cl, 8 dwg, 13 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to a novel crystalline form E of erythromycin derivative fumarate salt represented by the formula (I)

and to a method for its preparing. Indicated crystalline form E shows strong roentgen diffraction peaks at diffraction angles (2θ) 5.6° and 10.4° that was established by roentgen diffractometry with Cu-Kα-radiation. Also, invention proposes crystalline form D of erythromycin derivative fumarate salt represented by the formula (I) showing average particles size 90 mcm or above and/or the content of residual solvent 1500 ppm or less. Method for preparing indicated crystalline form D involve suspending indicated crystalline form E in mixture ethyl acetate and water in the ratio = (99:1)-(97:3) at temperature from -20°C to 20°C. Invention provides reducing the content of residual solvent and elimination of difficulties in making tablets.

EFFECT: improved preparing methods.

14 cl, 1 tbl, 5 dwg, 6 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: invention relates to a method for preparing erythromycin oxime in homogenous conditions by oximylation of erythromycin A with hydroxylamine hydrochloride in dry methanol using triethylamine as a base. Method provides enhancing yield and quality of product.

EFFECT: improved method for preparing.

3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: production of macrolide road-spectrum antibiotic tylosine.

SUBSTANCE: claimed method includes tylosine deposition from organic tylosine base concentrate with organic solvent (hexane). Deposition is carried out by addition of organic tylosine base concentrate to hexane at velocity of 3-5 ml/min per 50 ml of concentrate.

EFFECT: method for production of tylosine base in granulated form with homogeneous composition.

2 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: medicine; veterinary science.

SUBSTANCE: strains Streptococcus pyogenes No 289 and Pseudomonas aeruginosa No 5292, 4762, 5271, 5211, and 5002 are grown up separately, inactivated and added with adjuvant. Thereafter produced monovaccines are mixed in equal ratio. Herewith used are daily culture of strain Streptococcus pyogenes No 289 containing 106x0.5 million micr.kl., strain Pseudomonas aeruginosa No 5292 with titre in "РТГА" 1:512, strains Pseudomonas aeruginosa No 4762 and No 5271 - with titre in "РП" 1:16, strains Pseudomonas aeruginosa No 5211 and No 5002 with titre in "РП" 1:16.

EFFECT: prevention of losses in reproduction of fur-bearing animals within farms with unfavourable streptococcal and pseudomonas infection conditions.

3 ex

FIELD: medicine.

SUBSTANCE: during acute period of purulent meningitis (BPM) additionally, Wobenzyme is prescribed in daily dose 1 tablet per 6 kg of body weight 3 times a day within 10 days simultaneously with antibacterial therapy. Treatment of meningococcal and pneumococcal meningitis is ensured with prescribed benzylpenicillin in daily dosage 300 thousand units/kg. Haemophilic meningitis is treated by prescribed Ceftriaxone in daily dose 100 mg/kg.

EFFECT: higher efficiency of BPM specific therapy due to Wobenzyme ability to improve antibiotic penetration through blood-brain barrier and transport to inflammatory tissue and autointoxication reduction.

3 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns peptide compounds representing an amino acid sequence X1KEFX2RIVX3RIKX4FLRX5LVX6, where X1 is N-end segment which is IG; X2 is K or E; X3 is Q or E; X4 is D or R; X5 is N or E; X6 is C-end segment, which is a sequence selected out of PRTE or RPLR; where N-end segment is acetylated and/or C-end segment is amidated; with affinity to toxins, particularly to bacterial toxins, such as lipopolysaccharide or lipoteichoic acid. These compounds can inhibit or neutralise toxins. Invention also concerns pharmaceutical compositions and application of the claimed compounds in prevention or treatment of diseases or states caused by fungi or bacterial infection.

EFFECT: obtaining compounds for prevention or treatment of diseases or states caused by fungi or bacterial infection.

12 cl, 4 tbl, 4 ex

FIELD: medicine; biotechnologies.

SUBSTANCE: vaccine drug includes deactivated Escherichia coli bacteria of strain No 389 (078) and auxiliary substances. Additionally the drug includes aminoethylethyleneimine and liposome-forming mix as auxiliary substance at the following component rate in fluid form, wt %: aminoethylethyleneimine - 0.5-3; liposome-forming mix - 7.3-15; suspension of deactivated Escherichia coli bacteria of serotype 078 - 82.0-91.5.

EFFECT: harmless for fowl, enhanced antigenic and immunogenic activity.

3 cl, 4 tbl, 6 ex

FIELD: medicine; veterinary.

SUBSTANCE: medicine includes metal iodine and potassium iodide, prolongator and water. 1,2-propylene glycol is used as prolongator, and additionally vitamin A (retinol acetate), vitamin E (alpha-tocopherol acetate), vitamin B1 (thiamine hydrochloride), vitamin B2 (riboflavin), vitamin B6 (pyridoxine hydrochloride), vitamin B12 (cyanocobalamin), iron carbonate, magnium phosphate, manganese sulfate, copper sulfate, zinc sulfate, cobalt chloride, sodium chloride, amber acid, glucose, rectified ethyl alcohol (96%) are applied. Medicine components are taken at the following rate, g/100 ml of distilled water: metal iodine, chemically pure 0.112-0.187; potassium iodide, R 0.337-0.562; vitamin E (alpha-tocopherol acetate) 0.060-0.100; vitamin A (retinol acetate) 3.750-6.250 thousand mass units; vitamin B1 (thiamine hydrochloride) 0.052-0.087; vitamin B2 (riboflavin) 0.037-0.062; vitamin B6 (pyridoxine hydrochloride) 0.034-0.056; vitamin B12 (cyanocobalamin) 0.026-0.044; iron carbonate, R 0.337-0.562; magnium phosphate, R 0.337-0.562; manganese sulfate, R 0.172-0.287; copper sulfate, R 0.090-0.150; zinc sulfate, R 0.315-0.525; cobalt chloride, R 0.071-0.119; sodium chloride, R 0.589-0.981; amber acid, primary standard 0.225-0.375; glucose, AR 0.172-0.287; rectified ethyl alcohol (96%) 0.300-0.500 ml; 1,2- propylene glycol 0.900-1.500 ml. Method involves medicine administration with fodder in dosage of 1.00-1.50 mg per 1 kg of fish weight once per day for 5-7 days.

EFFECT: correction of needs for bioactive substances, prevention of avitaminosis, achievement of high antioxidant organism protection level, prevention of accumulation of non-saturated fatty acid peroxides harmful to fish.

2 cl, 3 tbl, 3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is used for treatment of bacteriemic infections, it is prepared as composition in the form of dry powder, adapted for delution by water with reception of the suspension important pH in a range from approximately 5.0 to approximately 5.5 at initial delution and which in addition contains the stabilizer pH which represents sodium-carboxymethyl cellulose. Besides, the invention concerns application sodium-carboxymethyl cellulose for reduction of degree of degradation clavunalate and for stabilisation pH the received suspension.

EFFECT: stability improvement in preparation.

7 cl, 1 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: method is implemented as follows: bacterial-enzymatic probiotic "Balance-narine-f" is introduced locally and orally in combination with inhalation of negative air ions.

EFFECT: allows for decrease of complications and higher efficiency of treatment.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: sterile aqueous inhalation solution containing active substance Tobramycine. Preparation of invention is offered with high content of active substance (approximately 80 to 120 mg/ml Tobramycine). Preparation also contains acid adjuvant and has low content of sodium chloride (maximum approximately 2 mg/ml). Preparation can be injected or introduced as aerosol with e.g. common sprays.

EFFECT: suitable for application in combination with recent sprays with vibrating membrane and gives the chance for application of an individual therapeutic dose.

24 cl, 1 tbl, 7 ex

FIELD: medicine; dentistry.

SUBSTANCE: treatment of inferior dental nerve neuritis caused by filling material delivery into mandibular canal is ensured with introduction of antibacterial agent before operation. Thereafter filling material is surgically removed from mandibular canal. Operation procedure is followed with introduction of antibacterial and immune correcting agents, antisensitisers, Reaferone, vitamins B1 and B12, adenosine triphosphate. Besides mandibular region is exposure to laser magnetotherapy with using dental apparatus Optodan, accompanied with intraoral HBO-therapy, hydromassage, hydrocortisone phonophoresis, 2% nicotinic acid solution amplipulse phoresis, Tambukan mud therapy, pine needle and pearl baths, acupuncture with using local and regional points.

EFFECT: higher treatment efficiency, restored blood circulation, accelerated rehabilitation, complete relief of evident pain syndrome and post-amputation pains, simplicity, efficiency.

3 ex

Up!