Organic compounds

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutics and concerns a solid pharmaceutical composition applicable for oral introduction and containing: (a) S1P receptor agonist; and (b) sugar alcohol.

EFFECT: invention provides homogeneous distribution of an active component in the solid composition with its high stability.

18 cl, 2 tbl, 39 ex

 

The present invention relates to pharmaceutical compositions containing the agonist of sphingosine-1-phosphate receptor. Sphingosine-1-phosphate (below in the present description are marked as "S1P") is a naturally occurring serum lipid. Currently, there are 8 of S1P receptors, namely S1P1 - S1P8. Agonists of the receptor S1P have the ability to accelerate homing lymphocytes.

Agonists of the receptor S1P are immunomodulators that cause lymphopenia caused by redistribution, preferably reversible, lymphocytes from blood flow in the secondary lymphatic tissue, which leads to generalized immunosuppression. Estimulando cells are destroyed, there is stimulation of the migration of CD4 - and CD8-T-cells and b-cells from the bloodstream to the lymph nodes (LU) and Peyer's patches (BP), resulting in inhibited infiltration of cells in transplanted organs.

Various known agonists of the receptor S1P have structural similarity, which causes the associated problems when creating the desired product. First of all, there is a need to create containing the agonist S1P receptor drug, well adapted for oral administration in solid form, for example in the form of tablets or capsules.

In accordance with this, in the present and the proposed finding solid pharmaceutical composition for oral administration, containing receptor agonist S1P and sugar alcohol.

With the invention it has been unexpectedly found that a solid composition containing a sugar alcohol, allow to create drugs, the most well adapted for oral administration of agonists of the receptor S1P. Songs are a convenient tool for system administration of agonists of the receptor S1P, do not have the disadvantages inherent in liquid preparations for injection or for oral administration, and have good physicochemical properties and ability to storage. First of all, the composition proposed in the present invention, can be characterized by a high degree of uniformity of distribution of the receptor agonist S1P in the composition, as well as high stability. The composition proposed in the invention can be prepared by high speed automatic equipment, and thus is not required to perform capsulati manually.

Agonists of the receptor S1P typically represent analogs of sphingosine, such as 2-substituted 2-aminopropan-1,3-diol or 2-aminopropanol derivatives. Examples of suitable agonist of S1P receptor are, for example, compounds described in EP 627406 A1, for example a compound of the formula I

in which R1denotes a straight or branched (C12-C22 )-carbon chain

and the chain can carry the bond or heteroatom selected from a double bond, a triple bond, O, S, NR6where R6denotes H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or

- may have as a substituent alkoxygroup, alkenylacyl, alkyloxy, aralkylated, acyl, alkylamino, allylthiourea, allmenalp, alkoxycarbonyl, alkoxycarbonylmethyl, alloctype, allylcarbamate, a nitrogroup, halogen, amino, hydroxyimino, the hydroxy-group or carboxypropyl; or

R1means

- phenylalkyl, in which alkyl denotes a straight or branched (C6-C20)carbon chain; or

- phenylalkyl, in which alkyl denotes a straight or branched (C1-C30)-carbon chain, where phenylalkyl replaced

- straight or branched (C6-20)carbon chain optionally substituted with halogen,

- C6-C20alkoxygroup straight or branched chain, optionally substituted with halogen,

- C6-C20alkenylacyl straight or branched chain,

- vinylalcohol, halogenocarboxylic, generalkonsulat, phenoxyethoxy or tenoxicam,

- cycloalkyl, substituted C6-C20the alkyl,

- g is teraelectron, replaced With6-C20the alkyl,

- heterocyclic6-C20the alkyl, or

- heterocyclic-alkyl, substituted C6-C20the alkyl,

and where

the alkyl group may bear

- in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond. O, S, sulfinil, sulfonyl or NR6where R6has the above values, and

as Deputy alkoxygroup, alkenylacyl, alkyloxy, aralkylated, acyl, alkylamino, allylthiourea, allmenalp, alkoxycarbonyl, alkoxycarbonylmethyl, alloctype, allylcarbamate, the nitro-group, a halogen, an amino group, a hydroxy-group or carboxypropyl; and

R2, R3, R4and R5each independently of the other represents H, C1-C4alkyl or acyl,

or its pharmaceutically acceptable salt;

the compounds described in EP 1002792 A1, for example the compound of formula II

in which m denotes 1-9 and R'2, R'3, R'4and R'5each independently of one another denotes H, alkyl or acyl,

or its pharmaceutically acceptable salt;

the compounds described in EP 0778263 A1, for example the compound of formula III

in which W represents N; C1-C6alkyl, C2-the 6alkenyl or2-C6quinil; unsubstituted or substituted HE is a phenyl group; R4O(CH2)n; or (C1-C6alkyl, substituted by 1-3 substituents selected from the series comprising halogen, C3-C8cycloalkyl, phenyl and phenyl substituted IT;

X denotes H or unsubstituted or substituted alkyl straight chain, bearing R carbon atoms, or unsubstituted or substituted alkoxygroup straight chain carrier (p-1) carbon atoms, such as substituted by 1-3 substituents chosen from the series, including C1-C6alkyl, HE, C1-C6alkoxygroup, alloctype, an amino group, a C1-C6alkylamino, allmenalp, oxoprop, Gialos1-C6alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1-3 substituents chosen from the series, including C1-C6alkyl, HE, C1-C6alkoxygroup, acyl, alloctype, an amino group, a C1-C6alkylamino, allmenalp, Gialos1-C6alkyl and halogen; Y represents H, C1-C6alkyl, HE1-C6alkoxygroup, acyl, alloctype, an amino group, a C1-C6alkylamino, allmenalp, Gialos1-C6alkyl or halogen; Z2will denote a simple link or alkylene straight chain supporting q carbon atoms,

where p and q each is ezavisimo from each other represents an integer from 1 to 20, provided that 6≤p+q≤23, m' represents 1, 2 or 3, n denotes 2 or 3, R1, R2, R3and R4each independently of the other represents H, C1-C4alkyl or acyl,

or its pharmaceutically acceptable salt;

the compounds described in WO 02/18395, for example a compound of formula IVa or IVb

or

in which Xanddenotes O, S, NRis or a group -(CH2)na-where the group is unsubstituted or is substituted by 1-4 halogen atoms; nanddenotes 1 or 2, R1sdenotes N or C1-C4alkyl, where alkyl is unsubstituted or substituted with halogen; R1adenotes H, HE, C1-C4alkyl or O(C1-C4)alkyl, where the alkyl is unsubstituted or substituted by 1 to 3 halogen atoms; R1bdenotes H, HE or (C1-C4)alkyl, where the alkyl is unsubstituted or substituted with halogen;

R2aeach independently from each other selected from N or C1-C4of alkyl, where alkyl is unsubstituted or substituted with halogen; R3adenotes H, HE, halogen or O(C1-C4)alkyl, where the alkyl is unsubstituted or substituted with halogen; and R3bdenotes H, HE, halogen, C1-C4alkyl, where alkyl is unsubstituted or substituted by a hydroxy-group, or O(C1-C4)alkyl, where Ala is l is unsubstituted or substituted with halogen; Yadenotes-CH2-, -C(O)-, -CH(OH)-, -C(=NOH)-, O or S, and R4astands With4-C14alkyl or C4-C14alkenyl;

or its pharmaceutically acceptable salt or hydrate;

the compounds described in WO 02/076995, for example the compound of formula V

in which

mcdenotes 1, 2 or 3;

Xanddenotes O or a direct link;

R1cdenotes H, C1-C6alkyl, optionally substituted HE, acyl, halogen, C3-C10cycloalkyl, phenyl or hydroxyphenylazo; C3-C6alkenyl; C2-C6quinil; or phenyl, optionally substituted HIM;

R2cmeans

in which R5cdenotes H, C1-C4alkyl, optionally substituted by 1, 2 or 3 halogen atoms, and R6cdenotes N or C1-C4alkyl, optionally substituted with halogen;

R3cand R4ceach independently of the other represents H, C1-C4alkyl, optionally substituted by halogen, or acyl, and

Rcstands With13-C20alkyl, which optionally may bear in the chain an oxygen atom and which optionally may be substituted by a nitro-group,

halogen, amino, hydroxy-group or carboxypropyl; or a group of formula (a)

in which R7cdenotes H, C1-C4alkyl or C1-C4alkoxygroup, and R8cdenotes a substituted C1-C20alkanoyl, panels1-C14alkyl, where C1-C14alkyl optionally substituted with halogen or HE, cycloalkyl1-C14alkoxygroup or panels1-C14alkoxygroup where cycloalkyl or phenyl ring optionally substituted with halogen, C1-C4the alkyl and/or C1-C4alkoxygroup, panels1-C14alkoxyl1-C14alkyl,

venoxis1-C14alkoxygroup or venoxis1-C14alkyl,

Rcalso means a group of formula (a), in which R8crepresents C1-C14alkoxygroup, when R1cstands With1-C4alkyl, C2-C6alkenyl or C2-C6quinil,

or the compound of formula VI

in which

nxdenotes 2, 3 or 4

R1xdenotes H, C1-C6alkyl, optionally substituted HE, acyl, halogen, cycloalkyl, phenyl or hydroxyphenylazo; C2-C6alkenyl; C2-C6quinil; or phenyl, optionally substituted HIM;

R2xdenotes H; C1-C4alkyl or acyl

R3xand R4xeach independently will dragonsnakes N, With1-C4alkyl, optionally substituted by halogen or acyl,

R5xdenotes H, C1-C4alkyl or C1-C4alkoxygroup, and

R6xstands With1-C20alkanoyl, replaced by cycloalkyl; cycloalkyl1-C14alkoxygroup where cycloalkyl ring optionally substituted with halogen, C1-C4the alkyl and/or C1-C4alkoxygroup; phenyls1-C14alkoxygroup, where the phenyl ring is optionally substituted with halogen, C1-C4the alkyl and/or C1-C4alkoxygroup,

R6xmay denote also With4-C14alkoxygroup, when R1xstands With2-C4alkyl, substituted for IT, or pentyloxy or hexyloxy, when R1xstands With1-C4alkyl,

provided that R6xdoesn't mean phenylbutyraldehyde, when either R5xdenotes H, or R1xdenotes methyl, or its pharmaceutically acceptable salt.

the compounds described in WO 02/06268 A1, for example the compound of formula VII

in which R1dand R2deach independently of one another denotes H or aminosidine group;

R3ddenotes hydrogen, hydroxyamino group or a group of the formula

R 4dmeans (ness.)alkyl;

nddenotes an integer from 1 to 6;

Xddenotes ethylene, vinile, ethynylene, a group of formula-D-CH2in which D denotes a carbonyl, -CH(OH)-, O, S or N), aryl or aryl having up to three substituents selected from the following group a;

Ydrepresents a simple bond, C1-C10alkylene, C1-C10alkylene with up to three substituents selected from groups a and b, C1-C10alkylen carrying On or S in the middle or at the end of the carbon chain, or C1-C10alkylen carrying On or S in the middle or at the end of the carbon chain, which has up to three substituents selected from groups a and b;

R5ddenotes hydrogen, cycloalkyl, aryl, heterocycle, cycloalkyl with up to three substituents selected from groups a and b, aryl having up to three substituents selected from groups a and b, or a heterocycle having up to three substituents selected from groups a and b;

R6dand R7deach independently of one another denotes H or a Deputy selected from the group a;

R6dand R9deach independently of one another denotes H or

C1-C4alkyl, optionally substituted with halogen;

group a consists of halogen, (ness.)alkyl, halogen(ness.)alkyl, (ness.)alkoxygroup, (ness.)alkit is Gruppo, carboxyl, (ness.)alkoxycarbonyl, the hydroxy-group, aliphatic (ness.)acyl, amino, mono(ness.)alkylamino, di(ness.)alkylamines, aliphatic (ness.)allmenalp, cyano or nitro-group; and "group b" includes cycloalkyl, aryl, heterocycle, each of which optionally has up to three substituents selected from group a; with the proviso that when R5ddenotes hydrogen, Ydno means simple and linear relationship C1-C10alkylen, or its pharmacologically acceptable salt or ester;

- compounds described in JP-14316985 (JP 2002316985), for example a compound of formula VIII

in which R1e, R2e, R3e, R4e, R5e, R6e, R7ene, XeAnd Yehave the values listed in the JP-14316985;

or its pharmacologically acceptable salt or ester;

the compounds described in WO 03/29184 and WO 03/29205, for example the compound of formula IX

in which

Xfdenotes O or S and R1f, R2f, R3fand nfhave the values listed in WO 03/29184 and WO 03/29205,

R4fand R5feach independently of one another denotes H or a group of the formula

in which R8fand R9feach independently of one another denotes N or C1 -C4alkyl, optionally substituted with halogen; for example, 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]propyl-1,3-propandiol or 2-amino-2-[4-(benzyloxyphenyl)-2-chlorophenyl]propyl-1,3-propandiol, or its pharmaceutical salt.

the compounds described in WO 03/062252 A1, for example a compound of the formula X

in which

Ar denotes phenyl or naphthyl; mg and ng each, independently of one another denote 0 or 1; a is selected from COOH, RHO3H2, RHO2N, SO3N, RO(C1-C3alkyl)and 1H-tetrazol-5-yl; R1gand R2geach independently of one another denotes H, halogen, HE, COOH or C1-C4alkyl, optionally substituted with halogen; R3gdenotes N or C1-C4alkyl, optionally substituted with halogen or HE; R4geach independently of one another denotes halogen or optionally substituted with halogen With1-C4alkyl or C1-C3alkoxygroup; and Rgand M have one of the meanings indicated for b and C, respectively, in WO 03/062252 A1;

the compounds described in WO 03/062248 A2, for example the compound of formula XI

in which

Ar denotes phenyl or naphthyl; n denotes 2, 3 or 4; And denotes COOH, 1H-tetrazol-5-yl, RHO3H2, PO2H2, -SO3N or PO(R5h)OH, where R5h is selected from C 1-C4of alkyl, hydroxys1-C4of alkyl, phenyl, -CO-C1-C3alkoxygroup and-CH(OH)phenyl, where phenyl or the phenyl group optionally is substituted; R1hand R2heach independently of one another denotes H, halogen, HE, COOH, or optionally substituted with halogen, C1-C6alkyl or phenyl; R3hdenotes N or C1-C4alkyl, optionally substituted with halogen and/or HE; R4heach independently of one another denotes halogen, HE, COOH, C1-C4alkyl,

S(O)(C1-C3)0.2 or 3alkyl, C1-C3alkoxygroup,3-C6cycloalkanes, aryl or urlcategory, where aryl group optionally can be substituted by 1-3 halogen atoms; and Rgand M each have one of the meanings indicated for b and C, respectively, in WO 03/062248 A2.

According to the following variant of the invention, the agonist of S1P receptor, which is used in combination proposed in the present invention may be a compound which has a selective effect in respect of the S1P1 receptor, such as a connection, which in respect of the S1P1 receptor superior activity against receptor S1P3 at least 20 times, for example 100, 500, 1000 or 2000 times, which was estimated based on the relative value is of EU 50for the S1P1 receptor and values of the EU50for the S1P3 receptor, obtained by analysis of binding 358-γS, the value of EU50the specified connection when binding to the S1P1 receptor was approximately 100 nm or less according to the analysis of binding 358-γS. Representative agonists of the S1P1 receptor is, for example compounds listed in WO 03/061567, the contents of which are incorporated into this description by reference, for example a compound of the formula

or

In each case, when references to a patent application, it is understood that thereby their essence related compounds included in the present description by reference.

Acyl may represent a group Ry-CO-in which Ryrepresents C1-C6alkyl, C3-C6cycloalkyl, phenyl or panels1-C4alkyl. Unless otherwise specified, alkyl, alkoxygroup, alkenyl or quinil can have straight or branched chain.

When in the compounds of formula I, the carbon chain constituting R1is substituted, preferably it is substituted with halogen, a nitro-group, amino group, hydroxy-group or carboxypropyl. When the carbon chain carries optionally substituted phenylene, carbon chain preferably t is aetsa unsubstituted. When fenelonov group is substituted, preferably it is substituted with halogen, a nitro-group, amino group, methoxy group, hydroxy-group or carboxypropyl.

Preferred compounds of formula I are compounds in which R1stands With13-C20alkyl, optionally substituted by a nitro-group, a halogen, an amino group, a hydroxy-group or carboxypropyl, and more preferably compounds in which R1denotes phenylalkyl, substituted C6-C14alkyl chain, optionally substituted with halogen, and an alkyl group represents C1-C6alkyl, optionally substituted hydroxy-group. More preferably R1indicates finals1-C6alkyl, substituted on the phenyl group, straight or branched, preferably straight With6-C14alkyl chain. With6-C14the alkyl chain may be in ortho-, meta - or para-position, preferably in the para-position.

Preferably R2-R5each represent N.

The preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propandiol. The most preferred agonist of S1P receptor formula I is FTY720, i.e. the 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in the form of pharmaceutically acceptable salts (below us is oasam description designated as compound A), for example in the form of a hydrochloride of the following formula

The preferred compound of formula II is a compound in which R'2-R'5each represent N and m is 4, i.e. the 2-amino-2-{2-[4-(1-oxo-5-fenilpentil)phenyl]ethyl}propane-1,3-diol in free form or in the form of its pharmaceutically acceptable salts (below in the present description, are designated as compound B), for example in the form of hydrochloride.

The preferred compound of formula III is a compound in which W represents CH3, R1-R ' 3 each denote H, Z2represents ethylene, X represents heptyloxy and Y denotes H, i.e. the 2-amino-4-(4-heptyloxy)-2-methylbutanol, in free form or in the form of its pharmaceutically acceptable salts (below in the present description, are designated as compound B), for example in the form of hydrochloride. Most preferred is the R-enantiomer.

The preferred compound of formula IVa is PTY720-phosphate (R2adenotes H, R3AIT denotes, Xandrepresents Oh, R1aand R1bdenote IT). The preferred compound of formula IV is a phosphate compound (R2adenotes H, R3bIT denotes, Xandrepresents Oh, R1aand R1bmean IT, Yadenotes O and R4ameans heptyl). Preferably the m compound of formula V is a phosphate compound B.

The preferred compound of formula V is mono[(R)-2-amino-2-methyl-4-(4-pentyloxide)butyl]ester of phosphoric acid.

The preferred compound of formula VIII is (2R)-2-amino-4-[3-(4-cyclohexylmethyl)benzo[b]Tien-6-yl]-2-methylbutane-1-ol.

When compounds of formulas I-XIII have one or more asymmetric centers in the molecule, under the scope of the invention are subject to various optical isomers and racemates, diastereoisomers and mixtures thereof.

Examples of pharmaceutically acceptable salts of compounds of formulas I-XIII include salts with inorganic acids such as hydrochloride, hydrobromide and sulfate, salts with organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and bansilalpet, or if necessary, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine. Under the scope of the compounds and salts proposed in the present invention fall in the form of a hydrate or solvate.

Binding to S1P receptors can be assessed using the following methods of analysis.

A. Affinity binding of agonists to the receptor S1P with individual human S1P receptors.

Transient transfection of human S1P receptors cell line NECK

CL is coordinated S1P receptors and proteins G1, mixed equal amounts of the four cDNA encoding the receptor EDG, Giα, Gi-β and Gi-γ, and used for transfection of monolayers of the cell line NECK with deposition of calcium phosphate (.Wigler etc., Cell., 11, 1977, p.223 and D.S. Im and others, Mol. Pharmacol., 57, 2000, s). In General, the method was as follows. The mixture of DNA containing 25 μg DNA and 0.25 M CACL2added to HEPES, buffered with 2 mm Na2HPO4. In subconfluent monolayers cell line NECK was made 25 mm chloroquine and then the cells were added to precipitate DNA. After 4 h, the monolayers were washed in phosphate buffered saline and fueled by the media (90% mixture (1:1) modified by way of Dulbecco Wednesday Needle (DMEM:F-12+10% fetal bovine serum). Cells were harvested 48-72 h after addition of DNA by scraping into the buffer, NME (20 mm HEPES, 5 mm MgCl2, 1 mm add, pH 7.4)containing 10% chilled on ice sucrose, and destroyed using a Dounce homogenizer, After centrifugation at 800×g, the supernatant was diluted, NME without adding sucrose and centrifuged at 100000×g for 1 h the Resulting debris re-homogenized and centrifuged at 100000×g for one hour. The crude debris membranes resuspendable in NME with the addition of sucrose, was divided into aliquots and immediately frozen by immersion in liquid nitrogen. is embrane kept at -70°C. The concentration of protein was determined by spectroscopic analysis of protein by the Bradford method.

The analysis of binding γS using membrane preparations of receptor S1P/HEK293

The experiments on the evaluation of the binding γS carried out according to the method described in D.S.Im and others, Mol. Pharmacol., 57, 2000, s. Mediated by ligand binding γS with G-proteins was evaluated in the buffer to bind GTP (50 mm HEPES, 100 mm NaCl, 10 mm MgCl2, pH 7.5) with 25 μg of the preparation of the membranes obtained from the subject to transient transfection of the cell line NECK. The ligand was added to the membranes in the presence of 10 µm and GDF

0.1 nm [35S] γS (1200 CI/mmol) and incubated at 30°C for 30 minutes Associated γS was separated from unbound by using the harvester Brandel (Gaithersburg, stmaryrd) and counted using a liquid scintillation counter.

The composition proposed in the invention preferably contains from 0.01 to 20 wt.% agonist of S1P receptor, more preferably from 0.1 to 10 wt.%, for example from 0.5 to 5 wt.% in terms of the weight of the entire composition.

The sugar alcohol may act as a diluent, carrier, excipient or agent for increasing the volume and it is convenient to use mannitol, ▫ maltitol, Inositol, xylitol or lactic, preferably almost nephrostolithotomy alcohol, for example mannitol (D-mannitol). You can use sugar alcohol individually or use a mixture of two or more sugar alcohols, for example a mixture of mannitol and xylitol, for example in a ratio of from 1:1 to 4:1.

In the most preferred embodiment of the invention, the sugar alcohol is prepared from the spray dried compositions, for example compositions of mannitol, which has a large specific surface area. The use of a composition of mannitol of this type can contribute to ensuring homogeneous distribution of the receptor agonist S1P in the mannitol in the composition. Large surface area can be obtained by producing the drug, a sugar alcohol such as mannitol, consisting of particles that have a smaller average size and/or a more rough surface of each particle. It was found also that the use of spray dried sugar alcohol such as mannitol, with an average particle size of 300 μm or less can improve the compressibility and hardness of the tablets produced from the composition.

Preferably, the specific surface area of one particle of the preparation of a sugar alcohol such as mannitol, is from 1 to 7, for example from 2 to 6 or from 3 to 5 m2/, Suitable drug mannitol may have an average particle size from 100 to 300, for example from 150 to 250 μm, and nasypnoe the density from 0.4 to 0.6, for example, from 0.45 to 0.55 g/ml Suitable mannitol with a large surface area is Parteck M200, marketed by the company E.Merck.

The composition preferably contains from 75 to 99.99 wt.% sugar alcohol, more preferably from 85 to 99.9, for example from 90 to 99.5 wt.% in terms of the weight of the entire composition.

The composition preferably also contains a lubricant. Suitable oiling agents are stearic acid, magnesium stearate, calcium stearate, zinc stearate, glycerylmonostearate, nutritionalvalue, canola oil, hydrogenated vegetable oil, such as hydrogenated castor oil (for example, Cutina® or Lubriwax® 101), mineral oil, nutriceuticals, magnesium oxide, colloidal silicon dioxide, silicone fluid, polyethylene glycol, polyvinyl alcohol, sodium benzoate, talc, poloxamer or a mixture of any of the above substances. Preferably the lubricant is a stearate, hydrogenated castor oil or mineral oil. Less preferred as lubricant are colloidal silicon dioxide, and polyethylene glycol.

The composition preferably contains from 0.01 to 5 wt.% sizing, more preferably from 1 to 3, for example, about 2 wt.% in terms of the weight of the entire composition.

The composition can sod is neigh one or more other excipients, such as carriers, binders or diluents. In particular, the composition may contain microcrystalline cellulose (e.g. Avicel®), methylcellulose, hydroxypropylcellulose, hypromellose, starch (e.g. corn starch) or dicalcium phosphate, preferably in quantities of from 0.1 to 90, for example from 1 to 30 wt.% in terms of the weight of the entire composition. If you use a binder, such as microcrystalline cellulose, methylcellulose, hydroxypropylcellulose, hypromellose, it is preferably included in an amount of from 1 to 8, for example from 3 to 6 wt.% in terms of the weight of the entire composition. Application of the binder increases the strength of the granules of the drug, which is very important for fine granules. Microcrystalline cellulose and methylcellulose most preferably used in the case when high hardness of tablets and/or a longer disintegration time. Hydroxypropylcellulose preferably used in the case when you want a faster disintegration. If necessary, you can also add xylitol as an additional binding agent, for example, in addition to microcrystalline cellulose, for example in amounts up to 20 wt.% in terms of sugar alcohol such as xylitol.

In one variant now the invention, the composition further comprises a stabilizer, preferably glycine-HCl or sodium bicarbonate. The stabilizer may be present in amounts, for example from 0.1 to 30, preferably from 1 to 20 wt.%.

The composition may be in the form of powder, granules or pellets or in the form of a standard dose, for example in the form of tablets or capsules. The composition proposed in the present invention are well adapted to be encapsulated in the shell, intended for oral administration of capsules primarily in hard gelatin shell.

Alternatively, the composition can be compressed into tablets. On the tablet optionally may be coated with, for example, talc or polysaccharides (e.g. cellulose), or coating hydroxypropylmethylcellulose.

If a pharmaceutical capsule is a standard dose, it is convenient that each standard dose contains from 0.5 to 10 mg agonist of S1P receptor.

The composition proposed in the invention can have good characteristics of stability, as demonstrated in standard tests to assess the stability of, for example, they remain stable during storage over a period of time up to one, two or three years and even longer. Characteristics of stability can be defined, for example, by assessing the degradation products using GHUR analysis after storage for spiral the different periods of time at specific temperatures, for example at 20, 40 or 60°C.

The pharmaceutical composition proposed in the present invention, can be obtained by standard methods, for example using conventional mixing, granulation, coating sugar coating, dissolving or lyophilization. Procedures that can be used for this purpose are known in the art, such as they are described in L.Lachman and others, theory and Practice of Industrial Pharmacy, 3rd ed., 1986, H.Sucker and others, Pharmazeutische Technology, published by Thieme, 1991, Hagers Handbuch der pharmazeutischen Praxis, 4th ed., the publishing house Springer, 1971 and Remington''s Pharmaceutical Sciences, 13th ed., published by Mack Publ. Co., 1970 or later editions.

One of the objects of the present invention is a method of obtaining a pharmaceutical composition, which is that

(a) mixed agonist of S1P receptor with a sugar alcohol;

(b) ground and/or granularit the mixture obtained in stage (a); and

(C) mixed ground and/or granulated mixture obtained in stage (b), with sizing.

Using this method, you receive the drugs that have a high level of content and uniformity of the mixture (i.e. almost homogeneous distribution of agonist S1P receptor in the composition), the required time of dissolution and stability.

Before carrying out stage (a) receptor agonist S1P, i.e. the hydrochloride of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-is Iola, optional you can finely grind and/or pre-sifted through a sieve with a mesh size of 400 to 500 microns for removal of lumps. Stage of mixing (a) can be done by mixing agonist of S1P receptor and sugar alcohol such as mannitol, in any suitable mixer or blender within, for example, 100-400 rpm.

The method can be carried out by dry mixing the components. In this embodiment of the invention at the stage of mixing (b) can be skipped obtained in stage (a) the mixture through a sieve, preferably having a size of holes from 400 to 500 μm. At stage (a) of the method can be carried out stage of mixing the total number of receptor agonist S1P first with a small amount of the sugar alcohol component, for example, from 5 to 25 wt.% of the total weight of the sugar alcohol, for preparation of the premix. Then the premix add the rest of sugar alcohol. Stage (a) may also include stage added to a mixture solution of a binder such as methylcellulose and/or xylitol, for example in aqueous solution. Alternatively, the binder added to the mixture in dry form and at the stage of granulation water is added.

Milled mixture obtained in stage (b), it is not necessarily possible to mix before mixing with the lubricant. Before mixing the lubricant, n the example magnesium stearate, preferably sieved, for example, through a sieve with openings of 800 to 900 microns.

Alternatively, use the method of wet granulation. In this embodiment of the invention, the agonist of S1P receptor preferably first mixed in a dry state with the desired sugar alcohol such as mannitol, and then the mixture of sugar alcohol/agonist of S1P receptor mixed in a dry state with a binder such as hydroxypropylcellulose or hypromellose. Then add water and mix granularit, for example using automatic pellet mill. Then the granulate is dried and milled.

Optionally, in stage (C) to the mixture obtained in stage (b), you can add an additional amount of the binder.

The method may include the additional step tabletting or encapsulation of the mixture obtained in stage (b), for example, hard gelatin capsule using an automatic kapsulirujushchej device. Capsules can be painted or marked to give an individual appearance and for quick recognition. The use of dyes can serve both to improve the appearance and identification of capsules. Dyes suitable for use in the pharmaceutical industry typically include carotenoids, iron oxides and hlorophyll. Preferably the capsules offered in the invention, labeled using the code.

The pharmaceutical composition proposed in the present invention can be applied either individually or in combination with other active substances for the treatment and prevention of conditions such as described in US 5604229, WO 97/24112, WO 01/01978, US 6004565, US 6274629 and JP-14316985, the contents of which are incorporated into this description by reference.

The pharmaceutical compositions can be used primarily for

a) treatment and prevention of transplant rejection of an organ or tissue, for example, for the treatment of recipients of heart transplants, lung, combined transplants, heart-lung, liver, kidney, pancreatic, skin or corneal, and to prevent the reaction of graft-versus-host that sometimes occurs after bone marrow transplantation; primarily for the treatment of acute or chronic rejection of ALLO - and xenograft or transplantation insulinproducing cells, such as islet cells of the pancreas;

b) treatment and prevention of autoimmune disease or inflammatory conditions such as multiple sclerosis, arthritis (e.g. rheumatoid arthritis), inflammatory bowel disease, hepatitis, etc.

in the treatment and prevention of viral is about myocarditis and viral diseases, associated with viral myocarditis, including hepatitis and AIDS.

Therefore, the following objects of the present invention are the following

1. The above composition is intended for treating or preventing the above diseases or conditions.

2. The method of treatment of an individual in need of immunomodulation, namely, that the individual is administered an effective amount of the above composition.

3. A method of treating or preventing the above diseases or conditions, namely, that the individual enter the above composition.

4. The application of the above pharmaceutical compositions for the preparation of a medicinal product intended for the prevention or treatment of the above diseases or conditions.

Below the invention is described with reference to the following specific embodiments of the invention.

Example 1

Sift through a fine sieve connection And, for example, hydrochloride 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720) and of 116.7 g of sifted compounds mixed with 9683,3 g mannitol (Parteck M200, firm Emags). The mixture is then milled in a device of the type Frewitt MGI (firm Key International Inc. USA) using sieves with number 30 mesh. Magnesium stearate is sifted through a sieve with 20 mesh. and 200 g of sifted connection smeshivautsya mixture FTY720/mannitol, getting the composition of the product.

Then the composition of the product is pressed using a tablet press using punch size 7 mm with obtaining tablets with a weight of 120 mg, each of which contains:

The connection And, for example FTY720*1.4 mg
Mannitol M200to 116.2 mg
Magnesium stearate2.4 mg
Only120 mg
* 1 mg compounds And free-form equivalent of 1.12 mg FTY720

Example 2

In the following example, repeat the process described in example 1, except that instead of magnesium stearate used Cutina® (hydrogenated castor oil).

Example 3

Connection And, e.g. FTY720, and mannitol (Parteck M200, company E. Merck) each separately sieved with a # 18 mesh. 1.9 grams sifted FTY720 mixed with 40 g of sifted mannitol mixer at 32 rpm for 120 rpm. The mixture is then PTY720/mannitol sieved with a No. 35 mesh.

The sifted mixture FTY720/mannitol contribute to the granulator along with 340,1 g mannitol and 12 g of hydroxypropylcellulose. The mixture is stirred for 3 m is N. Then water is added at a rate of 100 ml/min and the mixture granularit within 2 minutes Granulate is transferred to a tray dryer and dried at 50°C for 150 minutes

The mixture is then milled in a device of the type Frewitt MGI using a sieve with a size of 35 mesh. Sift magnesium stearate and 6 g of sifted compounds are mixed within 90 rpm at 32 rpm with a mixture of FTY720/mannitol to obtain the composition of the product, having an almost uniform distribution of agonist S1P receptor in the mannitol in the mixture.

Then the composition of the product is filled with kapsulirujushchej device type Hoflinger & Karg 400 hard gelatin shell size 3. Each capsule make 120 mg of the composition of the product.

Thus, each capsule contains:

FTY720*0.56 mg
Mannitol M200114,04 mg
Hydroxypropylcellulose3.6 mg
Magnesium stearate1.8 mg
Only120 mg

Example 4

In the following example, repeat the process described in example 3, except that instead of magnesium stearate used Cutina® (hydrog dozirovanno castor oil).

Example 5

In the following example, repeat the process described in example 3, except that instead of hydroxypropylcellulose use hypromellose.

Example 6A

Finely ground connection And, e.g. FTY720, sieved using a sieve with a mesh size of 400 microns (40 mesh.). 58,35 g sifted compounds mixed with 4841,65 g mannitol (Parteck M200, firm Emags) in bunker type mixer Bohle volume of 25 l for 240 rpm. The mixture is then milled in a device of the type Frewitt MGI using sieves with openings of 400 μm and grind the mixture is stirred for another time. Sift magnesium stearate and 100 g of sifted product mixed with PTY720/mannitol to obtain the composition of the product, having an almost uniform distribution of agonist S1P receptor in the mannitol in the mixture.

Then the composition of the product is filled with kapsulirujushchej device type Hoflinger & Karg 400 hard gelatin shell size 3. Each capsule make 120 mg of the composition of the product. Thus, each capsule contains:

FTY720*1.4 mg
Mannitol M200to 116.2 mg
Magnesium stearate2.4 mg
Only120 mg

Example 6b

In an alternative embodiment of the invention, the capsules are made using the components and amounts listed in example 6A, but first FTY720 is mixed with 14 mg of mannitol (before sieving). The mixture is then sieved as described above. Then the sifted mixture is mixed with the remaining part of mannitol and add magnesium stearate, followed by additional mixing and filling of capsules.

Examples 7 and 8

In the following examples capsules get according to the method described in example 6, except that each capsule contains the following amounts of each component:

Example 7Example 8
FTY720*2.8 mg5.6 mg
Mannitol M200114,8 mg112 mg
Magnesium stearate2.4 mg2.4 mg
Only120 mg120 mg

Examples 9-11

In the following examples capsules get the method according to, in examples 6-8, except that in each case, the stearate is replaced by Cutina® (hydrogenated castor oil).

Examples 12-22

In the following examples capsules or tablets receive according to the method described in examples 1-11, except that in each case instead of FTY720 use of the hydrochloride of 2-amino-2-{2-[4-(1-oxo-5-fenilpentil)phenyl]ethyl} propane-1,3-diol.

Examples 23 and 24

Capsules containing the following ingredients, obtained by weighing each component and mixing in a mortar, after which the mixture is filled capsules:

Example 23Example 24
FTY7205 mg1 mg
D-mannitol83,7 mg117 mg
Corn starch24 mg-
Avicel® PPH10112 mg-
Hydroxypropylcellulose0.3 mg7 mg
Talc 3 mg3 mg
Lubri wax® 1012 mg2 mg
Only130 mg130 mg

Examples 25-27

Get a pharmaceutical composition containing the following ingredients:

Example 25Example 26Example 27

FTY7205 g10 g100 g
D-mannitol991 g986 g897 g
The methylcellulose SM-254 g4 g3 g
Only1000 g1000 g1000 g

FTY720 and part D-mannitol, the mass of which is equal to two masses FTY720, is mixed in the mixer type Microspeed Mixer MS-5 (firm Palmer, USA) for 2 min at 1200 rpm To the mixture remaining is the art of D-mannitol and mix for another 2 minutes From the hopper add 80 or 60 ml of a 5%solution of methylcellulose SM-25 and granularit in the same conditions. The mixture ekstragiruyut through a sieve with openings of 0.4 mm using an extruder type RG-5. Extruded product is dried at 65°C in the granulator, fluidized bed type STREA I (firm Patheon, Canada) and then sieved through a sieve with No. 24 mesh. Remove fine particles which passed through a sieve with 60 mesh. The obtained pellets filled capsules using a machine for filling capsules of the type Zuma (100 mg per capsule).

Examples 28-31

Get tablets containing the following ingredients (in mg):

Example 28Example 29Example 30Example 31
FTY7201111
D-mannitol62,362,362,062,0
Xylitol*26,7 (5,4)26,7 (5,4)26,626,6
The methylcellulose--0,40,4
Microcrystalline cellulose24,0-24,0-
Nizkozameshhennoj hydroxypropylcellulose-24,0-24,0
Hydrogenated wt lo6,06,06,06,0
Only120,0120,0120,0120,0
* specified in brackets the number of xylitol used as binders

FTY720, D-mannitol and xylitol contribute to the granulator fluidized bed (model MP-01, Powrex company), mixed for 5 min and granularit in the sprayed solution of the binder, after which dried up until the outlet temperature reaches 40°C. the granulation Conditions below. Wyssen the nd powder passed through a sieve of 24 mesh., add to a certain amount of filler and sizing and mixed in the mixer (Tubular Mixer, a firm WAB) for three minutes to obtain a powder intended for pressing.

The resulting powder was pressed using a tablet press machine (type Cleanpress correct 12 HUK, firm Kikushui Seasakusho) using punch size 7 mm (inner diameter) ×7.5 mm R when compression force 9800 N.

The granulation conditions:

the adjustment parameter
Downloadable quantity1170
The amount of intake air50 m3/min
The suction air temperature75°C
The flow rate of the spray solution15 ml/min
Pressure spray air15 N/cm2
The amount of sprayed air30 l/min
The volume of solution binder351 ml

Examples 32-39

Get pills soderjaschegosya ingredients (in mg):

1. Solid pharmaceutical composition suitable for oral administration that contains
(a) agonist S1P receptor; and
(b) a sugar alcohol,
in which agonist of S1P receptor selected from
the compounds of formula I

in which R1denotes a straight or branched (C12-C22)-carbon chain
moreover, the chain can carry the bond or heteroatom selected from a double bond, a triple bond, O, S, NR6where R6denotes H, alkyl, aralkyl, acyl or alkoxycarbonyl, and carbonyl, and/or
may have as a substituent alkoxygroup, alkenylacyl, alkyloxy, aralkylated, acyl, alkylamino, allylthiourea, allmenalp, alkoxycarbonyl, alkoxycarbonylmethyl, alloctype, allylcarbamate, a nitrogroup, halogen, amino, hydroxyimino, the hydroxy-group or carboxypropyl; or R1does
phenylalkyl, in which alkyl denotes a straight or branched (C6-C20)carbon chain; or
phenylalkyl, in which alkyl denotes a straight or branched (C1-C30)-carbon chain, where phenylalkyl substituted
straight or branched (C6-C20)carbon chain optionally substituted with halogen,
With6-C20alkoxygroup who sing with a straight or branched chain, optionally substituted with halogen,
With6-C20alkenylacyl straight or branched chain,
vinylalcohol, halogenocarboxylic, generalkonsulat, phenoxyethoxy or tenoxicam, cycloalkyl, substituted C6-C20the alkyl,
heteroallyl, substituted C6-C20the alkyl,
heterocyclic6-C20the alkyl, or
the heterocyclic alkyl, substituted C6-C20the alkyl and where the alkyl group may bear
in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinil, sulfonyl or NR6where R6has the above values, and
as Deputy alkoxygroup, alkenylacyl, alkyloxy, aralkylated, acyl, alkylamino, allylthiourea, allmenalp, alkoxycarbonyl, alkoxycarbonylmethyl, alloctype, allylcarbamate, the nitro-group, a halogen, an amino group, a hydroxy-group or carboxypropyl; R2, R3, R4and R5each independently of the other represents H, C1-C4alkyl or acyl, or its pharmaceutically acceptable salt.

2. The composition according to claim 1, in which the agonist S1P receptor selected from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt.

3. The composition according to claim 2, the which Sol presents hydrochloride.

4. Composition according to one of claims 1 to 3, in which the sugar alcohol is nephroscopes sugar alcohol or mixtures thereof.

5. The composition according to claim 4, in which the sugar alcohol is a mannitol.

6. Composition according to one of claims 1 to 5, optionally containing a lubricant.

7. The composition according to claim 6, in which the lubricant is a stearate.

8. Composition according to one of claims 1 to 7, which contains from 0.01 to 20 wt.% agonist of S1P receptor.

9. Composition according to one of claims 1 to 8, containing from 0.5 to 5 wt.% agonist of S1P receptor.

10. Composition according to one of claims 1 to 9, which contains from 75 to 99.99 wt.% sugar alcohol.

11. Composition according to one of claims 1 to 10, containing from 90 to 99.5 wt.% sugar alcohol.

12. Composition according to one of p-11, which contains from 0.01 to 5 wt.% the sizing.

13. Composition according to one of p-9, containing from 1.5 to 2.5 wt.% the sizing.

14. Composition according to one of claims 1 to 13, in which the agonist S1P receptor is crushed.

15. Composition according to one of claims 1 to 14, in which the agonist S1P receptor is pre-sifted through a sieve with cell sizes from 400 to 500 μm.

16. Composition according to one of claims 1 to 15, in the form of tablets or capsules.

17. Composition according to one of claims 1 to 16, intended for use in the manufacture of medicines to counter the surveillance or treatment of transplant rejection of organ or tissue the reaction of graft-versus-host, autoimmune diseases, inflammatory conditions, viral myocarditis and viral diseases associated with viral myocarditis.

18. Composition according to one of claims 1 to 16, intended for use in the manufacture of medicinal products for the treatment of multiple sclerosis.



 

Same patents:
Solid medication // 2357757

FIELD: pharmacology.

SUBSTANCE: invention relates to pharmacon immediately dealing with preparation of a solid medication for treatment of diabetes and its sequela. The medication contains metformin or a salt thereof, pioglitazone or a salt thereof, homogenously dispersed, as well as target admixtures. The ratio of the average particle size of metformin or the salt thereof to the average particle size of pioglitazone or the salt thereof varies from 2.23:1 to 8.06:1.

EFFECT: provision for high homogeneity and dissolution degree of the active ingredient.

5 cl, 3 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry and concerns method for making antiulcer and antacid tablets containing an active material made of hairgrass rhizome and buckthorn bark, as well as base bismuth nitrate, base magnesium carbonate, sodium hydrocarbonate and microcrystalline cellulose, all being mixed with humid granulation and pelletisation. Herewith the active material is polyextracted buckthorn bark and hairgrass rhizome resulted from multistage counter-current extraction of hairgrass rhizome and buckthorn bark in specific environment followed by graduation of the extract.

EFFECT: method allows for tablets made of standardised extractive complexes of natural raw materials with low microbial semination, high biological activity of components, improved biological availability and stability.

2 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmacology and medicine and concerns a pharmaceutical composition for treatment or prevention of vascular pathological condition, diabetes, obesity or low-sterol plasma concentration in mammals containing sterol absorption inhibitor of formula (II), lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium salt, sodium lauryl sulphate and magnesium stearate.

EFFECT: invention provides improved solubility of the composition.

21 cl, 4 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to solid formulation betahistine dihydrochloride containing lactose, microcrystalline cellulose, copolymer vinylpyrrolidone and vinyl acetate, as well as stearic acid and/or its salts as additives in ratio as specified in the patent claim, and to production procedure of the present formulation.

EFFECT: solid formulation under the invention is characterised with good disintergration and high strength.

6 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to pharmacy. There is disclosed new preparation. Controlled-release Proxodolol is prepared effectively and conveniently with applying one or more mixed swelling or gelling components, an active component and pharmaceutically acceptable filler. It is preferential to apply a tableted preparation containing Proxodolol dosed 120 mg, hypromellose and pharmaceutically acceptable fillers, e.g. microcrystalline cellulose, calcium stearate and aerosil. New pharmaceutical forms with a suitable Proxodolol release profile allow reducing number of daily dosages while concentration of active component is constant within a therapeutic dose.

EFFECT: stable kinetic indicators of active material delivery.

8 cl, 5 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns auxiliary binding substances for manufacturing drop-shaped tablets and to preparation of drop-shaped tablets. Auxiliary binding substances according to claimed invention are selected from group which consists of monosaccharide, oligosaccharide, polysaccharide, sugar ester, sugar of alcohol structure, alpha-hydroxy acid, higher fatty acid derivative, higher aliphatic alcohol, polyol, urea and poly(ethyleneoxide) derivative.

EFFECT: claimed invention reduces toxicity caused by polyethylene glycol, improves drop-shaped tablet quality and accelerates development of drop-shaped tablets.

20 cl, 68 ex, 2 tbl

FIELD: pharmacology.

SUBSTANCE: invention relates to method of preliminary physical processing of clarithromycin, whose application results in such modification of technologically important physical properties of active substance which allows to obtain medicinal form with more stable profile of active substance release during all term of medication storage life in comparison with profile of release from similar composition but without preliminary processing. Claimed method includes moistening of clarithromicin or mixture of clarithromycin with other excipients with light solvent or mixture of solvents, in which clarithromycin solubility constitutes approximately less than 0.1 g/l, with further drying. Claimed invention also relates to pharmaceutical composition containing clarithromycin, processed in accordance with claimed method, and application of film covering which contains combination of low-molecular polymer representing cellulose ester, having viscosity approximately 6 mPa*s, and highly-molecular polymer, representing cellulose ester, which has viscosity approximately 15 mPa*s, for covering tablet cores, containing clarithromycin, processed in accordance with claimed method.

EFFECT: medicinal form with more stable profile of active substance release.

18 cl, 5 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to medicinal form protected against non-intended use. Protected against non-intended use thermally formed without extrusion medicinal form, which together with one or two active substances (A), which are potential object of their non-medicinal use, as well as with physiologically compatible auxiliary substances (B) contains definite synthetic or natural polymer (C) and optionally wax (D), component (C) and possibly present component (D) are contained in medicinal form in definite amounts. Method of preparing medicinal form, in which without application of extruder components (A), (B), (C) and possibly used component (D) are mixed together, and also with them or if necessary separately possibly used components (a)-(f) are mixed with addition of component (C) and possibly used component (D), and from obtained mixture or from obtained mixtures, in some cases after its, or respectively their granulation, by applying force with preliminary or simultaneous heat impact medicinal form is formed. Medicinal form obtained by definite method.

EFFECT: efficient protection against non-intended use.

29 cl, 1 dwg, 8 ex

FIELD: pharmacology.

SUBSTANCE: invention relates to field of pharmacology and concerns compositions of ready combined tablets. Composition of ready combined tablets includes g: aspirin 0.24; phenacetin 0.18; caffeine 0.03; sugar in powder 0.1; citrus skin 0.45.

EFFECT: by pharmacological action composition of ready combined tablets is close to "Citramon", but in contrast to it is enriched with vitamins of B group, vitamin C, organic acids, essential oils, pectic substances.

FIELD: pharmacology.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to production of medications used in case of upper airways diseases (rhinitis, pharyngitis, laryngitis, tracheitis); in case of neuralgia (myalgia, artralgia, migraine, cardioneurosis), stenocardia (light forms), itching dermatosis. Medication contains: menthol, eucalyptus oil, lump sugar, sodium salt of carboxymethylcellulose, talc, stearic acid or its salts, additionally containing black mint oil and aerosyl with definite component ratio. Also claimed is method of obtaining said medication.

EFFECT: increase of tablet strength, increase of tablet disintegration time.

2 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to urgent surgery, and can be used in treatment of closed pancreas injuries ensured by examination performed in admission to hospital. If there are two signed detected, including increase of glucose in blood 10 mmol/l and higher in combination with hyperamylasemia 300 standard units and more; pancreas expansion with lower parenchyma echogenicity diagnosed by ultrasound; pancreas haemorrhage; observed effusion in omental bursa at amylase activity 2 times exceeding that of blood, certain mixture is perfused into retroperitoneal parapancreatic fat. The mixture contains 0.25% Novocaine solution 250 ml, Trasylol 150 units, 0.1% Dimedrol solution 1.0 ml, heparin 5000 units, 2.0% Papaverine solution 2.0 ml and Cephepime 1.0 g. Perfusion is to lower amylase content is blood to 200 standard units. Besides omental bursa is sanitised with 5% ε-aminocapronic acid solution.

EFFECT: method improves clinical effectiveness for the patients suffering from closed pancreas injuries and prevents heavy complications including traumatic omentobursitis, peritonitis, parapancreatitis and retroperitoneal phlegmons without direct organ surgery.

2 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine and pharmaceutics, and application of 4-hydroxytamoxifen in medicine preparation for treatment of benignant breast tumours, where the indicated medication takes form suitable for subcutaneous injection, and 4-hydroxytamoxifen is used in the form of hydroalcohol composition including isopropylmyristat as permeability amplification agent, water carrier, alcohol carrier and gelatinising agent.

EFFECT: enhanced permeability of 4-hydroxytamoxifen.

16 cl, 2 dwg, 7 tbl, 3 ex

FIELD: medicine, obstetrics.

SUBSTANCE: group of inventions relates to prevention of hemoreological disorders in pregnant women with obliterate forms of hyperandrogenia (HA). For this purpose claimed is medicaton Sulodexide. Medication is administered in dose 600LU i/m 1 time a day during 10 days. After that, peroral introduction is administered in dose 250LU 2 times a day for period not shorter than one month.

EFFECT: method ensures normalisation of uterine-placental blood flow at the background of sclerotic changes in microcirculatory stream, increased fragility of miometrium and placenta vessels, induced by androgen excess in patients of said group, in structural and chronometric isocoagulation.

2 cl, 4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention describes new chemical compound of general structural formula (I), its pharmaceutically acceptable salts or solvates: A-B-C (I) where radicals A, C, R9 are those as specified in the patent claim, R1, R2, R3, R4 independently represent hydrogen or C1-6 alkyl; B stands for -(CH2)n-, where n has an integral value within 1 to 5; where R5 is chosen from the group containing hydrogen, C1-6 alkoxy, CH2NR10R11 CH(CH3)NR10R11 and other values specified in the patent claim, R6 and R7 independently represent hydrogen, C1-6 alkyl; C1-6 alkoxy; halogen; R8 represents hydrogen or C1-6 alkyl; R10, R12 are independently chosen from the group comprising hydrogen, C1-6 alkyl; (CH2)mCOOR13, (CH2)mCON(R13)2 and other values specified in the patent claim where m has an integral value within 1 to 4, R13 stands for hydrogen or C1-6 alkyl, R11 represents C1-6 alkyl; Ar; Ar represents phenyl, pyridyl, oxazolyl, thiazolyl, thienyl, furanyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, banzothiophenyl substituted with one to five substitutes chosen from group: hydrogen, C1-6 alkyl, C1-6 alkoxy, halogen, N(R13)2, OH, NO2, CN, COOR13, CON(R13)2, SO2R13; application of these compounds as thrombin inhibitors and based pharmaceutical compositions.

EFFECT: new compounds can be useful in treatment and prevention of thrombin-dependent recurrent thromboembolism for research.

5 cl, 4 tbl, 6 ex, 2 dwg

FIELD: chemistry.

SUBSTANCE: claimed invention describes novel chemical compounds possessing ability to slow down blood plasma coagulation, of general structural formula (I), its pharmaceutically acceptable salts or solvates: A-B-C (I), where values of radicals A, C, R9 are such as given in invention formula, R1, R2, R3, R4 independently on each other represent hydrogen or C1-6alkyl; B represents -(CH2)n-, where n takes whole values from 1 to 5; where R5 is selected from group containing hydrogen, C1-6alkoxy, CH2NR10R11, CH(CH3)NR10R11 and other values, given in invention formula, R6 and R7 independently represent hydrogen, C1-6alkyl; C1-6alkoxy; halogen; R8 represents hydrogen or C1-6alkyl; R10, R12 independently on each other are selected from group, consisting of hydrogen, C1-6alkyl; (CH2)mCOOR13, (CH2)mCON(R13)2 and other values given in invention formula, where m takes whole values from 1 to 4, R13 represents hydrogen or C1-6alkyl, R11 represents C1-6alkyl; Ar; Ar represents phenyl, pyridyl, oxazolyl, tiazolyl, tienyl, furanyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothiophenyl, substituted from one to five substituents, sele4cted from group: hydrogen, C1-6alkyl, C1-6alkoxy, halogen, N(R13)2, OH, NO2, CN, COOR13, CON(R13)2, SO2R13; application of said compounds as anticoagulants for treatment of thrombotic conditions, based on them pharmaceutical composition and plasma-substituting solution for correction of hypercoagulation disorders.

EFFECT: obtaining novel compounds which can be useful for treatment of thromboembolic complications and prevention of hypercoagulation conditions.

5 cl, 3 tbl, 7 ex, 12 dwg

FIELD: medicine.

SUBSTANCE: present invention relates to the area of medical products, in particular to the weight loss compound, containing an opioid antagonist naltrexone and bupropione in synergistic effective quantities. The way of weight reduction is besides, described at introduction: naltrexone and bupropione or fluoxetine; or nalmephene and fluvoxamine. Also the invention concerns application of the specified combinations for preparation of medicinal agents for weight reduction.

EFFECT: synergistic effect of the specified combinations.

20 cl, 3 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, particularly dermatology, and can be applied in external treatment of fungus diseases of foot nail plate. Method involves application of tizol and Terbisil cream mix at (1-2):(1-3) ratio under adhesive plaster for 10-12 hours twice per day.

EFFECT: efficient treatment at lower cost and in shorter time, elimination of complications.

2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: for preventive vaccination, vaccine injection is preceded with Tilorone therapy. Tilorone is introduced once a day according to dosage regimen as follows: 1st day - 250 mg, 2nd day - 125 mg, further triduan - 125 mg. Course doze is at least 1250 mg.

EFFECT: higher efficiency of preventive vaccination ensured by higher longevity of protective antibody titre and lower rate of postvaccinal complications due to presented maximal immunomodulatory properties of Tilorone introduced at the specified regimen.

3 ex

FIELD: medicine; neurology.

SUBSTANCE: treatment of acute viral facial nerve neuropathy is ensured with complex pathogenetic therapy, excluding glucocorticosteroid hormones from complex. It is accompanied with oral introduction of Amixine once a day and Nurophen 2-3 times a day in effective doses within 2 weeks.

EFFECT: higher efficiency of treatment enabled by activation of virus elimination mechanisms, and anti-inflammatory action stimulating restriction of hyperergic viral response.

3 cl, 1 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: it is suggested to apply 2-methyl-6-isobornyl phenol, 4-methyl-2.6-diisobornyl phenol or 2-(dibutylamino)methyl-4-methyl-6-isobornyl phenol hydrochloride as agents with hemorheological, antiaggregant and antitrombogenic activity.

EFFECT: limitation of erythrocytes aggregation amplification in model of blood hyperviscosity, expressed antiaggregant activity in case of ADP-induced aggregation of platelets and reduction of thrombus mass compared to control in case of blood flow reduction in artery.

5 tbl, 25 ex

FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: one should perform puncturing of epidural space at Th12-L1 level. Through the lumen of puncture needle one should introduce catheter to move it cranially at the depth of 3 cm. After that one should inject 10 ml 05%-marcaine solution to perform repeated injections per 5.0 ml every 4 h during 1-8 d. The effect is achieved due to unloading minor cycle of circulation.

EFFECT: higher efficiency of therapy.

2 ex

Up!