Stable formulation from phenylalanine derivatives

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns pharmaceutical composition for treatment of the diseases associated with urokinase activator of plasminogen (u-PA) and/or with receptor of activator of urokinase plasminogen (u-PAR), containing: (i) amidino-, hydroxyamidino-, guanydino- and/or hydroxyguanydinophenylalanine derivative as an active material, (ii) mixed alcohol and polyol, and (iii) aqueous phase containing buffer solution. There is also disclosed stabilisation method of pharmaceutical composition.

EFFECT: physical and chemical stability.

25 cl, 6 dwg, 1 tbl, 9 ex

 

The prior art to which the invention relates.

The invention relates to an improved stable pharmaceutical compositions of phenylalanine derivatives and their use as inhibitors of urokinase, in particular, in the treatment of malignant tumors and tumor metastasis.

The level of technology

The ability of solid tumors to spread and metastasis in tissue associated with the dissolution or reorganization of the extracellular matrix (tumor stroma by tumor cells or with its capacity for penetration into the basement membrane. And although (Pato-) biochemical relationship has not yet been elucidated, however, significant is the role of the plasminogen activator urokinase (uPA) and urokinase receptor (uPAR). uPA induces proteolytic cleavage plasminogen with the formation of plasmin. The plasmin, in turn, is a protease with a broad spectrum of action, which is able to directly cleave components of the extracellular matrix, such as fibrin, fibronectin, laminin, and protein skeleton proteoglycans. In addition, plasmin can activate the "latent" metalloprotease and inactive proferment activator and preactuator plasminogen urokinase (pro-uPA).

Tumor cells and non-cancerous cells of the tumor stroma synthesize and secrete farms is ntative inactive proferment pro-uPA. Proteases, such as plasmin or cathepsin In and L, split pro-uPA in the limited proteolysis with the formation of the active serine protease HMW-uPA (HMW=high molecular weight: high molecular weight). Pro-uPA and active protease HMW-uPA associated with surface receptor cells uPAR (CD87). The plasminogen is also associated with a specific receptor on the plasma membrane of tumor cells, resulting in focusing and strengthening the activation of plasminogen in the immediate vicinity of the tumor cells. Therefore, invasive cells receive as a result of this the possibility of destruction of the extracellular matrix without the need to remove the lower layers through proteolysis required for directional movement.

In different dedicated cell biology studies it was shown that a special meaning is associated with the cell system of plasminogen activator within cascade reaction pathways associated with tumor systems proteolysis (Wilhelm and others, The Urokinase/Urokinase receptor system: A new target for cancer therapy. See: Schmitt m, Graeff H., Kindermann G. (edited by): Prospects in Diagnosis and Treatment of Cancer. International Congress Series, Excerpta Medica 1050, Amsterdam, Elsevier (1994), str-156). For example, cultures of cancer cells human colon was noted that their ability to penetrate the extracellular matrix depends on the degree of saturation of the receptor active uPA uPA (Hollas, etc., Dance Res. 51 (1991), str-3695). Also on the model of cell cultures decreased invasive potential of the cells in the case when the proteolytic activity of uPA was decreased by PAI-1 (Cajot, and others, Proc. Natl. Acad. Sci. USA 87 (1990), str-6943) or PAI-2 (Baker and others, Cancer Res. 50 (1990), str-4684). A comparable effect was achieved by inhibition of binding of uPA from the cell surface by blocking the receptor with proteoliticeski inactive variants uPA (Cohen and others, Blood 78 (1991), str-487; Kobayashi and others, Br. J. Cancer 67 (1993), str-544). Also transfection of epidermal cancer cells by plasmids, which causes the expression of desensitization of the transcript in relation to the part of uPAR, results in suppression of the synthesis of uPAR to reduce the invasiveness of these cells (Kook, EMBO J. 13 (1994), str-3991). Acting against uPA and PAI-1 antibodies reduce the invasive potential of lung cancer cells in vitro (Lieu and other, Int. J. Cancer 60 (1995), SCR-506).

The effect of plasminogen activator in the process of metastasis was confirmed in animal models of tumors. So, for example, was almost completely prevented the formation of metastases in the lungs chick embryos caused cancer in human cells, through the introduction of antibodies against uPA (Ossowski and Reich, Cell 35 (1983), SCR-619). Metastatic human cancer cells were transliterowany the expression plasmid, codero is awsa proteoliticeski inactive, but binding uPAR uPA mutants. In the mouse model, it was found that cancer cells synthesizing inactive uPA, after their injections caused the formation of significantly fewer metastases compared with nitrostilbene cells (Crowley and others, Proc. Natl. Acad. Sci. USA 90 (1993), str-51025). After the introduction of antisense uPA of oligonucleotides was observed, in addition, the delay intraperitoneal spread of cancer cells of human ovarian in "Nude" mice (Wilhelm and others, Clin. Exp.Metast. 13 (1995), str-302).

In recent years there has been a widespread research clinical relevance factors activator plasmid (uPA, uPAR, PAI-1, PAI-2) to predict patients with solid tumors. The content of uPA antigen in different tumors (e.g., tumors of the breast, ovary, stomach, lungs, kidneys, etc. has been effective predictive factor in survival with no recurrence and death (see, for example, Schmitt and others, J. Obstet. Gynaecol. 21 (1995), p.151-165); Jaenicke and others, Breast Cancer Res. Treat. 24 (1993), page 195-208; Kuhn and others, Gynecol. Oncol. 55 (1994), str-409; Nekarda and others, Lancet 343 (1994), str; Pedersen and others, Cancer Res. 54 (1994), str-4675). Also correlated with low forecast increased concentration of uPAR in cancer tissues of the lung (Pedersen and others, as well as the above mentioned authors) and breast (Duggan and others, Int. J. Cancer 61 (1995), str-600; Ronne, etc., Breast Cancer Res. Treat. 33 (1995), str-207) as well as in cancer of the stomach, as in the tumor tissue (Heiss and others, J. Clin. Oncol. 13 (1995), str-2093)and in tumor cells scattered in the bone marrow (Heiss and other, Nature Medicine, 1 (1995), str-1039).

It was also found that derivatives of 3-amidinopropane, substituted in position 2 of the phenyl residue, are selective and effective in vivo inhibitors against uPA (EP 1098651). The use of these compounds in the experiment with animals occurred in the form of aqueous solutions.

In WO 02/074756 and WO 03/103644 disclosed the use of other inhibitors of urokinase on the basis of phenylalanine, as well as the use of derivatives of 3-guanidinopentanoic as inhibitors of urokinase.

During the first clinical trials of these compounds revealed that their introduction in the form of aqueous mannitol, for example, D-mannitol, without the addition of organic solvents and propylene glycol/ethanol, as well as containing salt solutions is fraught with disadvantages. So, for example, or in solutions of salt, or in the case of the use of mannitol to give isotonicity unable to obtain the stable concentrated solution of active substances which were not deposited would not form a precipitate. For example, in a five percent solution of mannitol after long-term storage, a precipitate of the added active substances. Also was not suitable to the position, consisting of pure organic solvents, as the active substance does not possess the necessary chemical resistance and predisposed to decay. So, after about 1.5 months starts the decomposition of the active substance through a transition of amidine in the ester, and the solution of the active substance becomes unusable.

In WO 2004/011004 described composition for the stabilization of aqueous solutions containing an inhibitor of urokinase on the basis of phenylalanine in the form of so-called liposomes, mixed micelles, composed of different phospholipids. However, this form of stabilization is not sufficient for all applications, in particular, after recovery using physiological buffer solutions chemical resistance of the composition with the content of the liposomes was not sufficient.

During the preliminary experiments on the creation of new compositions was found very high solubility of the active substance N-α-(2,4,6-triisopropylphenylsulfonyl)-3-amiden-(L)-phenylalanine-4-ethoxy-carbonyldiimidazole (WX-UK1) polyols, for example, dialah, as well as in mixtures of polyol, alcohol, and water (table 1).

These data show that the mixture of the polyol and / or alcohol, such as propylene glycol (PG) and ethanol (EtoH), are good solvents for liquid compositions. Additionally, both of these solvents are suitable for parenteral what about the introduction of active substances.

When storing different compositions, for example,

a) WX-UK1, 60 mg/ml in a mixture of propylene glycol/ethanol/water, 40/10/50,

b) WX-UK1, 50 mg/ml in a mixture of propylene glycol/ethanol/water, 40/10/50,

c) WX-UK1, 40 mg/ml in a mixture of propylene glycol/ethanol/water, 40/10/50,

d) WX-UK1, 20 mg/ml in a mixture of propylene glycol/ethanol/water, 10/10/80,

e) WX-UK1, 4 mg/ml in water (control track),

f) WX-UK1, 4 mg/ml in 5%D-mannitol (control track),

at a temperature of from two to eight degrees Celsius (2-8°C), it was found that in compositions (e) and (f) after a few hours, a precipitate in the form of needle crystals. Through four (4) days of storage at a temperature of from two to eight degrees Celsius (2-8°C) composition (d) was formed precipitate similar appearance.

In compositions (a) and (b) after storage for 16 and 22 days at a temperature of from two to eight degrees Celsius (2-8°C), the precipitate was absent.

In the study of stability at 2-8°C, 25°C / 60% relative humidity and 40°C / 75% relative humidity, the composition (C) was found at a temperature less than 40°C in 6 weeks, about 4%, 8 weeks, about 23%, and 12 weeks for about 38% of impurities compared to about 0.5% at the beginning of the study. Simultaneously, the pH of the composition for 12 weeks increased from 5.1 to 8.7 (figure 1).

The increase in pH is probably due to the collapse of the WX-U1. Figure 2 shows a possible decomposition of the active substance WX-UK1 in aquatic environments: at the first stage of WX-UK1 is decomposed with formation of the corresponding amide WX-UK1, and results in the release of ammonia, catch, of course, the audience WX-UK1 as the hydrochloride in the form of ammonium chloride. In the second stage of the collapse of the amide WX-UK1 reacts with alcohol with the allocation of additional ammonia and the formation of the corresponding ether complex WX-UK1. Excretion of ammonia and probably leads to an increase in pH.

Thanks to the knowledge about the process of disintegration have been taken into account mainly anhydrous compositions to prevent decomposition of the active substance is water. However, the relatively high viscosity of pure organic solvents creates in everyday clinical practice, difficulties in handling viscous flow concentrates. In addition, the high hygroscopic polyols causes the absorption of water, which again leads to the dissolution of the active substance. Also hardly achieved and buffering by using organic buffer solutions, such as triethanolamine/HCl, a piperazine/HCl, propionic acid/propionate, which not all are physiologically acceptable.

Experiments on the stabilization of aqueous solutions by the addition of surfactants, such as Pluronic F68 or Tween 80, or the camera is of catalysts, as, for example, albumin human serum, were unsuccessful. Additive co-solvents, for example, poliatilenglikola, as well as the composition of the active substances in mixed micelles containing bile salt gluconolactone and phospholipid phosphatidylcholine eggs, did not attach sufficient durability.

Therefore there was a need for new pharmaceutical compositions with a content of active substances from the groups of amidine and/or guanidine, which have physical and chemical resistance, can be portioned and/or in the form of a concentrate to store and easy to apply during the preparation of stable pharmaceutical preparations, for example saline solution infusion, which is persistent through appropriate means to give isotonicity, compatible and highly effective.

Disclosure of inventions

This problem is solved according to the invention by a pharmaceutical composition according to claim 1 claims, including (i) derived amidino-, hydroxyamide-, guanidino and/or hydroxybenzylideneamino as the active substance, (ii) an alcohol or polyol or a mixture thereof and (iii) the aqueous phase with the buffer solution.

As the active substance is preferably used a derivative of phenylalanine, which is an effective inhibitor of the m semipretioase, in particular, urokinase. Preferred active substances are compounds of amidinohydrolase and guanidinopentanoic disclosed in EP-a-1 098 651, WO 02/074756 and WO 03/103644. Also preferred are compounds of gidroksiaminopirimidinov and hydroxybenzonitriles described in PCT/ER/005682. As active substances for the pharmaceutical compositions according to the invention are, in particular, derivatives of 3-amidinopropane or 3-guanidinopentanoic novel inhibitors of urokinase General formula I:

which are present in the form of Ruzimatov compounds in the form of L - or D-configurations, thus:

X means a group of amidine or guanidine or hydroxyamine or hydroxyguanidine,

R1means:

(a) HE or or4and R4means optionally substituted, e.g. by hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo and/or by halogen, branched or non-branched (C1-C8) alkyl, (C3-C8)cycloalkyl or aralkyl, for example, benzyl or phenylethyl,

b) a group of the formula:

where R5and R6means any compatible with the overall structure remains, in particular,

(i) R5and R6mean N,

(ii) R5means N, R6means optionally substituted, for the example, by hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo, or/and halogen branched or non-branched (C1-C8) alkyl, aralkyl, for example, benzyl or phenylethyl, or (C5-C8) cycloalkyl,

(iii) R5and R6denote, independently of one another, optionally substituted, e.g. by hydroxyl and/or halogen unbranched or branched (C1-C4) alkyl, or

(iv) R5means N, R6means-NH2or, in particular, substituted aryl or heteroaryl the amino group,

(v) R5means H or optionally substituted, e.g. by hydroxyl and/or halogen unbranched or branched (C1-C4) alkyl, R6means the balance of amino acids, for example, α-, β - or ω-carboxylic or sulfonic acids, or a residue of a peptide, for example, up to 50 amino acid or a residue of the polypeptide, for example, a length of from more than 50 to 1000 amino acids,

(C) a group of the formula:

in which m represents the number 1 or 2 and in which one or more methylene groups is optionally substituted, for example, a residue hydroxyl, carboxyl, (C1-C4) alkyl or aralkyl, for example, benzyl or phenylethyl, and group (C) is racemic, D-or L-configuration, R7has the meaning given for R punctaj (a), (b) and (f),

(d) a group of the formula:

in which p=r=1, p=1, r=2 or R=2, r=1, and in which one or more methylene groups is optionally substituted, for example, hydroxyl, carboxyl,

(C1-C4) alkyl or Uralkali balance, for example, benzyl or venilation, R7has the value specified for R1in paragraphs (a), (b) and (f),

(e) group piperidyl, which is optionally substituted in one of the positions 2, 3 or 4, for example, the residue (C1-C4) alkyl, a residue (C1-C3) alkoxy or a residue hydroxyl, and optionally heterocyclizations ring of formula (C), (d) and (e) optionally condensed with an aromatic or cycloaliphatic ring, preferably a phenyl or cyclohexyl, in position 2, 3 or 3, 4 relative to the heteroatom,

(f) a group of the formula:

in which R8means:

(i) optionally substituted, for example, (C1-C6) alkyl, (C1-C3) alkoxy, hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo or halogen (C1-C6) alkyl residue, such as, for example, etoxycarbonyl, or aryl residue, such as, for example, phenyl, p-halogenfrei, naphthyl,

(ii) saturated or unsaturated, branched or unbranched OS is atok (C 1-C6) alkoxy or

(iii) the balance phenoxy or benzyloxycarbonyl, optionally substituted, for example, (C1-C8) alkyl, (C1-C3) alkoxy, hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo or halogen,

(g) acyl residue of the formula MOR, and X means:

(i) H, optionally substituted, e.g. by hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo, or/and halogen unbranched or branched alkyl residue, preferably a residue (C1-C6) alkyl, in particular methyl,

(ii) optionally substituted, for example, (C1-C6) alkyl, (C1-C3) alkoxy, hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo, or/and halogen aryl or heteroaryl residue, such as, for example, phenyl, p-halogenfrei, thienyl or

(iii) optionally substituted, e.g. by hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo, or/ halogeno the rest of cycloalkyl, preferably the residue (3-C10) cycloalkyl,

(h) alkyl residue, for example, benzyl or phenylethyl, in which the aromatic residue substituted if necessary, for example, a halogen atom, a group (C1-C6) alkyl, (C1-C3) alkoxy, hydroxy, cyano, carboxyl, sulfonyl or nitro,

(i) amide residue of carboxylic acid f is rmula-CONR'R", amide residue thiocarbonic acid - CSNR'R" or amide residue of acetic acid-CH2-CONR'R", and

(i) R' and R" denote H,

(ii) R' and R", independently of one another, mean (C1-C4) alkyl,

(iii) R' is H, R" means (C1-C4) alkyl,

(iv) R' is H, R" means aryl, for example phenyl or

(v) R' and R" form together with the nitrogen atom 5-7-membered heterocyclizations ring, which may carry additional heteroatom, such as N, O or/and S,

(j) the balance of SO2-Y, in which Y means:

(i) (C1-C8) alkyl optionally substituted, e.g. by hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo, or/and halogeno, preferably methyl, trifluoromethyl, trichloromethyl,

(ii) optionally substituted, for example, (C1-C6) alkyl, (C1-C3) alkoxy, hydroxyl, carboxyla, sulfonyl, nitro, piano, oxo and/or by halogen, aryl or heteroaryl, such as, for example, phenyl, 4-were, 2,4,6-trimetilfenil, 2,4,6-triisopropylphenyl, 4-methoxy-2, 3,6-trimetilfenil, 2,2-dimethyl-6-methoxy-chromanol and 2.2.5,7,8-pentamethylchroman, anthrachinone, naphthyl or chinolin or 0-aryl, preferably O-phenyl or O-heteroaryl or

(iii) -NR'r R", and R', R", independently of one another, denote H or (C1-C3) alkyl,

(K) cycloaliphatic ring with 5 to 8 carbon atoms, to the E. optionally substituted, for example, the group (C1-C6) alkyl, (C1-C3) alkoxy, halogen or hydroxy group,

(l) optionally substituted, for example, (C1-C6) alkyl, (C1-C3) alkoxy, hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo or halogen, the rest of heteroaryl, such as, for example, pyridyl or pyrimidyl, or geterotsiklicheskikh residue, for example, N-methylpiperidin,

(m) functional alkyl residue of the formula -(CH2)n-X, while the alkyl chain is unbranched or branched, n=1-8, functional balance of X means:

(i) a hydroxyl group, a hydrogen atom of which is optionally substituted by group (C1-C4) alkyl, a group of aralkyl, for example, benzyl or phenylethylene, aryl group, e.g. phenyl, (C1-C4) hydroxyalkyl, acyl group, CO-alkyl (C1-C6),

(ii) a halogen atom,

(iii) tertiary amino group of formula-N(Alk)2and (C1-C3) alkyl groups are predominantly of the same value, with the nitrogen atom optionally refers to a 5-7 membered geterotsiklicheskikh ring, which is able to bear the additional heteroatom, such as N, O or/and S,

R2means optionally substituted, for example, (C1-C6)alkyl, (C1-C3) alkoxy, hydroxyl, carboxyla, sulfonyl, nitro, cyano, oxo or halogen, phenyl residue such as, for example, phenyl, 4-were, 2,4,6-trimetilfenil, 2,4,6-triisopropylphenyl,4-methoxy-2,3,6-trimetilfenil,

R3means a hydrogen atom or a branched or non-branched (C1-C4) alkyl, n is 0 or 1,

Z denotes N or CR9and R9means a hydrogen atom or a branched or non-branched (C1-C4) alkyl.

The compounds can also serve as a salt, preferably a physiologically compatible salts of acids such as salts of mineral acids, particularly preferred are hydrochloride, Bogorodchany, sulfates, or salts of the corresponding organic acids.

Among described in the General claims of compounds of particular importance are those in which R1corresponds to a group of formula (b), (d) and (f), R2means simple, double or triple substituted by alkyl phenyl residue, in particular, 2,4,6-substituted phenyl residue, for example, the balance of 2,4,6-triisopropylphenyl, n=0. Also preferred are compounds in which Z denotes CH or N.

Of the compounds of formula (I) particularly preferred compounds Na-(2,4,6-triisopropylphenylsulfonyl)-3-amiden-(D,L)-phenylalanine-4-ethoxycarbonylphenyl Nα-(2,4,6-triisopropylphenylsulfonyl)-3-guanidine-(D,L)-phenylalanine-4-ethoxycarbonylphenyl or L-enantiomer or pharmaceutically compatible salts of these compounds.

As mentioned above, as the active substances are also suitable appropriate hydroxycodone derivatives amidino and guanidinopentanoic, for example, such as described in PCT/ER/005682, in particular, compounds of General formula II or/and III:

where E means a group consisting of:

where In means-SO2- or-CO-,

X is-NR1or-CHR1,

Z means R4, -OR4or-NH-R4,

Y means-OR2or other2,

R1means independently substituted or unsubstituted-N, (C1-C6) alkyl, (C2-C6) alkenyl or (C3-C6) quinil,

R2means-N, OR1, -COR', -COOR1or CON(R1)2,

R3means-N, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) quinil, substituted or unsubstituted, or-COR6or-COOR6or the remainder of the oligo or polyalkylene, for example, 2-50 (C2-C4) alkylene, for example, the remnants of ethylenoxy,

R4means-N, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) quinil, substituted or unsubstituted, or cyclic residue,

R5means, substituted or nezame the military, -OR6, -N(R6)2, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) quinil,

R6means-N, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) quinil, substituted or unsubstituted, or cyclic residue,

each cyclic residue may bear one or more substituents selected from, for example, (C1-C3) alkyl, -OR6(for example, HE or (C1-C3) alkoxy), halogen, -OH, -NO2, -CN, -COOR6, -N(R6)2, -NR6COR6, -NR6CON(R6)2, -OCOR6,

each alkyl, alkenyl or quinil can be unbranched or branched and bear one or more substituents selected from, for example, halogen (F, Cl, Br, I), -OR6, -OCOR6N(R6)2, -NR6COR6, -COOR6, -NR6COR6or cyclic residue,

or salts of these compounds, and optionally pharmaceutically conventional carriers, diluents and/or excipients.

Preferred are compounds of General formula IV:

where X, R1, R3, R4and R6have the meanings specified above,

or their salts.

The group is located primarily in the pair of the phenyl ring in compounds I and II. About the about preferred are compounds of General formula I, where E means Am.

Compounds according to the invention have a modified function E of amidine or guanidine, mainly function hydroxyguanidine or hydroxyamine. Such modifications were known only in the form of synthesized intermediates in obtaining inhibitors of urokinase-type guanidine or amidin. To date pharmaceutical efficiency was assumed.

Connections can be in the form of salts, mainly physiologically compatible salts of acids, for example mineral acids, particularly preferred are hydrochloride or Bogorodchany, or corresponding salts of organic acids such as organic carboxylic or sulfonic acids, such as, for example, tartratami, mesylates or besylate. Particularly preferred are Bogorodchany. The compounds can be applied in the form of optically pure compounds or as mixtures of enantiomers and/or diastereomers.

Cyclic residues can contain one or more saturated or unsaturated rings. Preferred examples of the cyclic residues can serve cycloalkyl residues, aryl residues, heteroaryl bicyclic residues and residues. Particularly preferred are mono - or bicyclic residues. Cyclic residues contain preimushestvenno is 4-30, in particular 5-10 carbon atoms and heteroatoms as ring atoms, and optionally one or more substituents as described above. Heterocyclic system containing predominantly one or more atoms of oxygen, sulfur and/or nitrogen. Preferred bicyclic ring systems are the systems with the rest.

Alkyl, alkeline and alkyline groups contain predominantly to 4 carbon atoms. R means mainly H or optionally substituted C1-C4) alkyl residue, for example, -CH3or (C1-C6) alcylaryl balance, resulting-CO-X-NR1can mean, for example, the remainder of gizela, Alanya, i.e. phenylalanyl or homophenylalanine. Particularly preferably, R2meant N or (C1-C3) alkyl residue, resulting in Y can mean, for example, (O-C1-C3) alkyl residue or HE. Particularly preferably, R3meant N. In compounds I, R5means preferably other6particularly preferably-NH(C1-C5)-alkyl, unsubstituted or substituted, for example, -NHC2H5or6particularly preferably-O(C1-C3)-alkyl, unsubstituted or substituted, for example, acyloxy or benzyloxy, or O-aryl, for example, phenyloxy. In the compounds II and III, R 6means mainly a hydrogen atom or a (C1-C3) alkyl.

Preferred are compounds, in which the structural element Z implies R4while R4means an alkyl residue with cyclic Deputy, for example, optionally substituted phenyl residue or a bicyclic residue, such as, for example,

or

Particularly preferred compounds are compounds in which R4means substituted or unsubstituted (C1-C3) alcylaryl residue, for example, benzyl residue, which may be optionally substituted in the meta position or para halogen or/and-NO2and the halogen is selected from F, Cl, Br and I, particularly preferred are Cl and Br.

The most preferred compounds are:

N-α-(2,4,6-triisopropylphenyl-sulfonyl)-3-hydroxyamide-(L)-phenylalanine-4-ethoxy-carbonlimited (WX-671);

N-α-(2,4,6-triisopropyl-phenylsulfonyl)-3-hydroxyamide-(D)-phenylalanine-4-ethoxycarbonylphenyl;

N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyamide-(D,L)-phenylalanine-4-ethoxycarbonylphenyl;

N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidine-(L)-phenylalanine-4-ethoxycarbonylphenyl (WX-683);

N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidine-(D)-Fe is jalanin-4-ethoxycarbonylphenyl;

N-α-(2,4,b-triisopropylphenylsulfonyl)-3-hydroxyguanidine-(D,L)-phenylalanine-4-ethoxycarbonylphenyl;

N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidine-(L)-phenylalanine-4-arylaminomethylidene (WX-685);

N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidine-(D)-phenylalanine-4-arylaminomethylidene;

N-α-(2,4,6-triisopropylphenylsulfonyl)-3-hydroxyguanidine-(D,L)-phenylalanine-4-arylaminomethylidene;

Benzylmethyl-(D)-Ser-Glu-(4-hydroxyguanidine)amide (WX-678);

4-chlorobenzenesulfonyl-(S)-Ser-N-Me-Ala-(4-hydroxyguanidine)amide,

4-chlorobenzenesulfonyl-(S)-Ser-Glu-(4-hydroxyguanidine)amide,

Benzylmethyl-(D)-Ser-N-Me-Glu-(4-hydroxyguanidine)amide,

4-chlorobenzenesulfonyl-(D)-Ser-Ala-(4-hydroxyguanidine)amide,

and also their salts, for example Bogorodchany, such as WX-671.HSO4.

Compositions according to the invention contain a therapeutically effective amount of the active substance based on a derivative of phenylalanine, physiologically compatible amounts of alcohol and/or polyol, an aqueous phase with a buffer components, and optionally means to give isotonicity and other auxiliary substances, alone or in mixtures or combinations.

Compositions according to the invention contain the active substance in the amount of 0.5-10 weight., preferably 1-9 wt.%, particularly preferably 2-5 wt.%, the total weight of the composition.

Preferably, the active substance contained in concentrations up to 100 mg/ml, preferably up to 80 mg/ml, preferably up to 60 mg/ml, preferably up to 50 mg/ml, more preferably up to 40 mg/ml, even more preferably up to about 30 mg/ml, even more preferably up to about 20 mg/ml, even more preferably up to about 10 mg/ml, even more preferably up to about 4 mg/ml, even more preferably up to about 1 mg/ml, mainly up to about 0.1 mg/ml If necessary, the composition may further be diluted before use.

Alcohol or polyol in the sense of the present invention includes a physiologically compatible one - or polyhydric alcohols. Under the polyol is a polyhydric alcohol. In particular, they can serve as a diatomic alcohol (diol) or a trivalent alcohol (triol) and / or a polyhydric alcohol.

As a monohydroxy alcohol is preferable, for example, ethanol. However, there may be used, and other physiologically compatible alcohols.

As polyols can be used, in particular, physiologically compatible diols and triola is preferred triol, such as glycerol. According to the invention are also acceptable glycols. Examples of the latter can service the th glycol, propylene glycol, polietilenglikol.

Alcohol and/or polyol is contained in the pharmaceutical compositions according to the invention in such quantity that the component was about 20-60%, preferably 40-60%, more preferably 45-55%, most preferably about 50% of the total volume of the composition.

Particularly preferred is a mixture of polyol and alcohol. The ratio between the polyol and the alcohol is preferably 2:1 to 10:1, more preferably 3:1 to 8:1, even more preferably 4:1 to 6:1 and most preferably 4:1.

This mixture is a predominantly a mixture of glycol and ethanol. Particularly preferred is a mixture of propylene glycol and ethanol, and polyethylene glycol and ethanol.

The aqueous phase containing buffer is selected mainly from the group of physiologically compatible buffer solutions, in particular from acetate, citrate, phosphate and other buffer solutions, the preferred component of the buffer is sodium acetate. However, there may be used other acetate buffers, such as buffers from potassium acetate or calcium acetate. Average person able to select a buffer from the physiologically compatible buffers, in particular acetate.

Preferably, the aqueous phase is present in an amount up to 70% of the total volume of the composition, preferably to 60%, more preferably up to about 50%. Needless to say, if necessary, the pharmaceutical composition may be diluted before use. It is preferable to dilute the composition immediately before use mainly using substances to give isotonicity or isotonic fluid, and therefore it is preferable to prepare the corresponding isotonic solution for infusion or injection.

The concentration of the buffer solution is mainly up to 1000 mm, preferably up to 500 mm, more preferably up to 250 mm, more preferably up to 200 mm and even more preferably up to about 100 mm.

Additionally, the composition according to the invention may contain a means to give isotonicity and/or other excipients that specialist known.

Means for imparting isotonicity is mostly sugar or primarily a means selected from, for example, glucose, ribose, sucrose, sorbitol, mannitol, lactose, dextrose, trehalose, glycerol and mixtures thereof. Preferably, the means for imparting isotonicity was present in the form of a solution. It is preferable to apply the tool to give isotonicity in approximately 1-10%, preferably 2-7%, particularly preferably 5%-aqueous solution of Particularly preferred is a glucose solution.

In addition, compositions according to the invention can contain auxiliary substances, which can easily be determined.

Also preferably, the composition according to the invention at least its aqueous phase had a pH of 3.5 and 9.0, preferably 4-7, particularly preferably of 4.5 to 5.5.

The composition according to the invention can be administered in different ways, for example, in the form of liquid composition is parenterally, in the form of a funds infusion, intramuscularly, intravenously, subcutaneously, etc.

Mainly the composition is administered intravenously or intramuscularly. The necessary excipients expert in this field can easily determine.

If necessary, the composition according to the invention can be used in combination with other active substances, for example, a cytostatic or cytotoxic agents, such as doxorubicin, CIS-platinum, 5-fluoro-upall or antibodies and peptides.

The composition according to the invention can be used for parenteral purposes, for example, for intravenous or intramuscular injection or infusion. Daily dose is mainly 5-250 mg, particularly preferably 20-120 mg by subcutaneous or intramuscular injection and 10-500 mg, particularly preferably 50-250 mg intravenously, respectively, with an average of the ECE body 70 kg The introduction is mainly from once per day to once per week.

Another object of the invention is a concentrate composition according to the invention, the active ingredient in the concentrate makes up to 100 mg/ml, preferably up to 80 mg/ml, more preferably up to 50 mg/ml and even more preferably up to about 40 mg/ml Concentration of the buffer is mainly up to 1000 mm, preferably up to 500 mm, more preferably up to 250 mm, even more preferably up to about 100 mm.

Particularly preferred is a concentrate, in which the active substance is 40 mg/ml when the concentration of the buffer solution 100 mm.

Concentrates and compositions according to the invention can be stored without significant reduction in the purity and content of the active substance for a long time, usually at a temperature of from two to 8 degrees Celsius (2-8°C), but also at elevated temperatures, for example at 40°C.

Connection of active substances intended for the treatment of diseases associated with pathological overexpression of uPA and/or receptor plasminogen activator urokinase (uPAR). For example, they are capable of highly efficient to delay the growth and spread of malignant tumors, and metastasis of tumors. However, if necessary, the uPA inhibitors may when enetica together with other anticancer drugs or other treatment modalities, for example, radiation or surgery. In addition, the inhibitors are effective against diseases associated with other uPA and/or uPAR.

These compounds can greatly delay the growth and spread of malignant tumors, for example, the spread of tumors in cancer of the pancreas, the tumor growth in breast cancer and metastasis of tumors.

In addition, the inhibitors according to the invention are effective in other diseases associated with uPA, for example, in the treatment of diseases such as arthritis, inflammation, osteoporosis, retinopathy, for example, age-related degenerative changes in the macula, to prevent the formation of bubbles in the skin disease Pemphigus vulgaris.

The introduction is mostly together, for example, in the form of prior and/or subsequent treatment, and simultaneously with treatment with surgery, radiation or chemical therapy.

Another object of the invention is the use of the concentrate according to the invention for preparation of a solution of the active substance for injection or infusion by diluting the appropriate tool to give isotonicity, and is mainly used 5%glucose solution at a concentration of active substance before occhialino to 1 mg/ml

The composition according to the invention is used for the treatment due to urokinase diseases, in particular, in the treatment of tumors, for example, in the treatment of breast carcinoma and carcinoma of the pancreas or/and in the formation of metastasis.

Another object of the invention is a method of stabilizing pharmaceutical compositions containing a compound with a group of amidine, hydroxyamide, guanidine and/or hydroxyguanidine, mainly derivatives of amidine and/or guanidine-phenylalanine or hydroxycodone, a sufficient amount of polyol or alcohol or their mixture and the aqueous phase with the contents of the buffer solution. It is preferable to additionally introduce the tool to give isotonicity.

Alcohol, polyol, buffer solution and a means to give isotonicity applied as described above.

As the active substance is used mainly derived amidino and/or guanidino-phenylalanine, which is an effective inhibitor of urokinase, as described above.

Below the invention is explained in more details with examples, which are not restrictive.

A brief description of the drawings and tables

Table 1 shows the maximum solubility of the active substance WX-UK1 in different solvents and their mixtures.

Figure 1 - curve purity active the th substance WX-UK1 and pH at a temperature of 40°C in a mixture of propylene glycol, ethanol and water (4/1/5);

figure 2 - potential mechanism of dissolution of the active substance WX-UK1 in aqueous solution;

figure 3 - dependence of the decay of the active substance WX-UK1 from pH at 60°C is observed within 48 hours;

figure 4 - resistance of individual compositions with a content of active substance WX-UK1 at 60°C;

5 is a resistance of the compositions with a content of active substance WX-UK1 buffer compared to the solution without buffer;

6 is a degree of purity and the content of the active substance WX-UK1 in the compositions during storage for 5 months at 40°C.

Examples

Example 1. The dependence of the decay of the active substance from pH

To study the dependence of dissolution of the active substance (WX-UK1) from three different pH at 60°C in 1 ml of a mixture of ethanol/water (1:1 in volume ratio) was dissolved 2.5 mg WX-UK1. The solution was distributed between the three vessels in aliquot parts. One aliquot share brought to pH 2 by addition of 20 μl of hydrochloric acid 1 N, the second aliquot share brought to pH 11 by addition of 20 μl of caustic liquor 2 N and the third aliquot share retained at neutral pH. After incubation for a certain period of time (0, 5, 12, 48 hours) the solution was analyzed by liquid chromatography with high resolution and display of fortitude. It was found that during the analyzed period of time WX-UK1 maintain what took place stable at acidic pH values. However, at neutral and basic pH values, the collapse of WX-UK1 was moderate to rapid (figure 3).

Example 2. The resistance of the active substance in the composition with the content of the polyol and ethanol

To 40 mg of the active substance WX-UK1 sequentially added 0.4 ml of propylene glycol (PG) and 0.1 ml of ethanol. The solution was poured 0.3 ml of water and stirred until such time as the active substance WX-UK1 is not dissolved and the solution did not become weak opalescence. Then added the remaining water (about 0.2 ml). Then the solution was kept at 40°C and analyzed it on the pH and the degree of purity after 2, 4, 6, 8 and 12 weeks. For this purpose, 250 μl of a solution with a content of WX-UK1 was transferred to volumetric flask of 100 ml and added to the level of the mixture of water/acetonitrile (50:50 in volume) (concentration: about 0.1 mg/ml WX-UK1). Then by liquid chromatography with high resolution and display resistance analyzed 20 ál of this solution. Analysis on the pH of the solution of the active substance WX-UK1 was conducted potentiometric method at 20-25°C. it Was found that the active substance WX-UK1 splits the faster, the higher the pH value of the solution.

Example 3. Alternative buffer composition with the content of WX-UK1

There were prepared solutions (a)-(e) 5 ml each. Then, these solutions have stood at 60°C and analyzed the pH and the degree purely the s solutions through 0, 12, 24, 48 hours. For this purpose, 250 μl of a solution with a content of WX-UK1 was transferred to volumetric flask of 100 ml and added to the level of the mixture of water/acetonitrile (50:50 in volume) (concentration: about 0.1 mg/ml WX-UK1). Then 20 ál of this solution WX-UK1 was analyzed by liquid chromatography with high resolution and display of fortitude.

a) 1 mg/ml of WX-UK1 in water (pH);

b) 40 mg/l WX-UK1 in a mixture of propylene glycol/ethanol/water, 4:1:5 (pH);

c) 40 mg/ml of WX-UK1 in a mixture of anhydrous 1,2-propandiol/ethanol;

d) 40 mg/ml of WX-UK1 in a mixture of propylene glycol/ethanol/ sodium citrate, 40 mm, 4:1:5 (the pH value was set equal to its value in solution (b));

e) 40 mg/ml of WX-UK1 in a mixture of propylene glycol/ethanol/ buffer of sodium acetate, 40 mm, 4:1:5 (the pH value was set equal to its value in solution (b)).

For preparation of buffer of sodium citrate 80 mm (pH, as indicated above), 1.68 g of citric acid monohydrate was introduced in 8 ml of sodium hydroxide IN and added water to 100 ml. pH was asked sodium hydroxide 80 mm. A buffer of 1 mm was prepared by dilution in a ratio of 1/80 with a subsequent job LV.

Sodium acetate and sodium citrate were selected at pH 5 as parenterale compatible system for giving buffering composition with the active substance WX-UK1, which was tested for chemical and physical resistance compared to the composition without the buffer and betw the ne composition. Phosphate buffering into account was not accepted, as from previous studies it was known that the solutions of WX-UK1, with the addition of a phosphate buffer, a precipitate may form. Research on resistance was carried out at 60°C to achieve rapid dissolution of the active substance WX-UK1. In the solution of WX-UK1 with citrate buffer quickly formed precipitate, in addition to durability, the solution was also investigated and purity of the active substance WX-UK1. Due to the lack of physical stability of the solution with a buffer of sodium citrate, as well as due to insufficient chemical resistance of the investigated composition study on the resistance of these compositions was interrupted after four days. Most physical and chemical resistance expressed by the composition with the active substance WX-UK1 and a buffer of sodium acetate. Analyzed the active substance WX-UK1 with the definition of the reaction surface in percent using the method of liquid chromatography with high resolution and display resistance (figure 4).

Example 4. Resistance mortars with a buffer of sodium acetate

On the basis of the results obtained have chosen sodium acetate with different both molarity and pH 5 as a parenteral compatible system for giving buffering composition of WX-UK1, while additionally tested for chemical resistance compared to a composition without the buffer. Research the Finance for resistance was carried out at 60°C to ensure rapid disintegration of WX-UK1 (figure 5). Analyzed the active substance WX-UK1 with the definition of the reaction surface in percent using the method of liquid chromatography with high resolution and display of fortitude.

The result: thanks to the buffering composition of the dissolution of the active substance WX-UK1 can be significantly delayed.

Example 5. The study of stability of the composition with a buffer of sodium acetate for several months

Preparation of buffer of sodium acetate 200 mm

821 mg of sodium acetate were dissolved in 50 ml of water, asked pH 5 by addition of concentrated acetic acid and was filtered prepared buffer solution via syringe microphony filter Millex GV 0.22 μm.

The preparation of the composition of WX-UK1 buffer of sodium acetate 100 mm

960 mg WX-UK1 was placed in a vessel, added 9.6 ml of propylene glycol and 2.4 ml of ethanol. The solution complements the addition of 7 ml of a solution of sodium acetate 200 mm and stirred until the transition of the active substance WX-UK1 in solution and acquire the solution weak opalescence. Then added the residual quantity (5 ml) buffer their sodium acetate. The solutions were divided into aliquot parts of 1 ml each and stored at 40°C. Analysis for purity and content of WX-UK1 in solution were carried out, respectively, by 2, 4, 6, 8 and 12 weeks. For this purpose, 250 μl of a solution of WX-UK1 was transferred into a measuring flask with a capacity of 100 ml and added to otmed is a mixture of water/acetonitrile (50:50 in volume) (concentration: about 0.1 mg/ml WX-UK1). 20 µl of the diluted solution WX-UK1 was analyzed by liquid chromatography with high resolution and display of fortitude.

The content of the active substance WX-UK1 was determined in comparison with two standard solutions of WX-UK1 by the following formula:

,

where AreaPL- the surface of the test solution (WX-UK1 Peak) [mAU*s]

AreaSt1- the surface of a standard solution I (WX-UK1 Peak) [mAU*s]

AreaSt2- the surface of a standard solution II (WX-UK1 Peak) [mAU*s]

WSt1- hanging of a standard solution I [mg]

WSt2- hanging of a standard solution II [mg]

WithSt- concentration in the standard solution [%]

VPL- the volume of solution for injection [ml].

Figure 6 shows the time-purity compositions and their content of active substances WX-UK1. It can be seen that the purity and content of WX-UK1 in combination with the buffer remain very stable in contrast to the composition without the buffer (6).

Example 6. Preparation of compositions with a content of WX-UK1 (40 mg/ml) according to the following scheme:

WX-UK140 mg
Propylene glycol0.4 ml
Ethanol absolute0.1 ml
Waterto 1 ml

A portion of the active substance WX-UK1 was placed in a vessel and added propylene glycol and then ethanol. In the resulting solution was poured 0.3 ml of water and stirred until the transition WX-UK1 in solution and acquiring them weak opalescence. Then added the remaining amount of water.

Example 7. The preparation of compositions of WX-UK1 (40 mg/ml) with a buffer of sodium acetate according to the following scheme:

WX-UK140 mg
Propylene glycol0.4 ml
Ethanol, absolute0.1 ml
Buffer from acetate
sodium (200 mm)to 1 ml

A portion of the active substance WX-UK1 was placed in a vessel and added propylene glycol and then ethanol. In the resulting solution was injected with 0.3 ml of sodium acetate 200 mm and stirred until a complete transition of WX-UK1 in solution and acquiring them weak opalescence. Then added the residual quantity of acetate buffer.

Example 8. Method of liquid chromatography with high resolution and display resistance to verify the stability of the compositions with a content of WX-UK1

Equipment and conditionsInstallation for liquid chromatography high-resolutionAgilent 1100 LUNA C8(2), 5 μm, 250 mm, 4.6 mm ID or
Type of column:Kromasil 100 C18,5 μm, 250 mm, 4 mm ID
The wavelength of detection:ultraviolet light 205 nm
The temperature of the dispenser:4°C
The temperature of the column:40°C
Volume of injection:20 ál
System type:gradient
Speed expiration:1 ml/min
Duration:44 min
Solvent is: Buffer, pH=5,00±0,05
A: (sodium phosphate 25 mm)
In: acetonitrile
Gradient:Time minA, %In, %
07525
302872
311090
361090
377525
447525
End
Used materials:Water for chromatography; the gradient in degrees;
acetonitrile for chromatography; phosphoric acid with a content of 85% ultra-pure di-vodonagrevatel sodium for analysis (>99.99 percent).
The buffer of phosphate 25 mm pH=5,00±0,05 (3,55 g Na2HPO4added water to 1000 ml. pH 5,00±0,05 asked with N3PO4).
Sample preparation: Test
tion solution
WX-UK1:
25 μl (40 mg/ml) concentrate WX-UK1 diluted 975 ál of a mixture of water/acetonitrile (50:50 in volume), 100 µl of the diluted solution was diluted with 900 μl of a mixture of water/acetonitrile (50:50 in volume) (the final concentration is about 0.1 mg/ml WX-UK1).

Example 9. Method of liquid chromatography and high resolution mass spectrometry for the determination of the decay products of the compositions with a content of WX-UK1

Equipment and conditions:Installation for liquid chromatography high resolution.Waters Alliance: 2695 Separation Module; 2487 UV-VIS Detektor Micromass ZQ: Single Quadrupol MS-Detektor
Detector for mass spectroscopy
Type of column:Symmetry 18 of 3.5 μm to 2.1×100 mm
The wavelength of detection:Ultraviolet light 215 nm
The temperature of the dispenser:4°C
The temperature of the column:35°C
Volume of injection:20 ál
System type:gradient
Speed expiration:0.5 ml/min
Duration:16 min
NH4Ac-buffer/CAN 72/25
Solvent:And:
(volume ratio) NH4Ac-buffer/CAN 30/70
In:
(in volume)
From: methanol
Gradient:Time minA,%In,%S with %
010000
1001000
1102080
1202020
1310000
1610000
End
Used materials:Water for chromatography (gradient in degrees);
acetonitrile for chromatography (gradient in degrees);
methanol (IHVR, the gradient in degrees);
ice vinegar (ultrapure);
ammonium acetate (IHVR, the gradient in degrees);
NH4Ac 50 mm: 3,85 g NH4Ac brought up to 1000 ml by addition of water. The pH was set equal to 5 ice cold vinegar.

table 1
SolventsThe solubility of WX-UK1, mg/ml
Water5,2
5%glucose D6,6
a 0.9%solution of NaCl1,3
Propylene glycol>100
The polyethylene glycol 400>100
10%solution of propylene glycol in water16
40%solution of polyethylene glycol in water78
10%solution of ethanol in water22
Propylene glycol/ethanol/water, 60/15/25>108
Propylene glycol/ethanol/water, 40/10/50,>100
Propylene glycol/ethanol/water, 20/5/7547
Propylene glycol/ethanol/water, 10/10/8038

1. Pharmaceutical composition for treatment of diseases associated with urokinase-plasminogen activator (u-PA) and/or receptor activator of plasmas is of novena urokinase type (u-PAR), contains:
(i) derived amidino-, hydroxyamide-, guanidino and/or hydroxybenzylideneamino as active substances,
(ii) a mixture of alcohol and polyol and
(iii) the aqueous phase containing buffer solution.

2. The pharmaceutical composition according to claim 1, where the disease is associated with urokinase-plasminogen activator (u-PA) and/or receptor activator of plasminogen urokinase type (u-PAR) is associated with pathological overexpression of urokinase plasminogen activator (u-PA) and/or receptor activator of plasminogen urokinase type (u-PAR).

3. The pharmaceutical composition according to claim 1, in which the buffer solution is acetate.

4. The pharmaceutical composition according to claim 3, in which the buffer solution is a solution of sodium acetate.

5. The pharmaceutical composition according to any one of the preceding paragraphs, in which the concentration of the buffer solution up to 1000 mm.

6. The pharmaceutical composition according to any one of claims 1 to 4, in which the alcohol used is ethanol.

7. The pharmaceutical composition according to any one of claims 1 to 4, in which the polyol is selected from glycerol, propylene glycol and polyethylene glycol.

8. The pharmaceutical composition according to any one of claims 1 to 4, in which alcohol and/or polyol is contained in an amount up to about 20-60% of the total composition.

9. The pharmaceutical composition according to any one of claims 1, in which component (ii) is a mixture of polyol and alcohol in the ratio of 2:1 to 10:1.

10. The pharmaceutical composition according to any one of claims 1 to 4, which additionally contains means for imparting isotonicity and/or other excipients or combinations thereof.

11. The pharmaceutical composition according to any one of claims 1 to 4, in which the means for imparting isotonicity selected from the group consisting of glucose, ribose, sucrose, sorbitol, lactose, dextrose, trehalose, glycerol, mannitol and mixtures thereof.

12. The pharmaceutical composition according to claim 11 in which the means for imparting isotonicity represents 1-10%, in particular 5%solution.

13. The pharmaceutical composition according to any one of claims 1 to 4, in which the pH value at room temperature is from about 4.0 to about 7.0 and preferably from about 4.5 to about 5.5.

14. The pharmaceutical composition according to any one of claims 1 to 4, in which the active substance is selected from Nα-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(D,L)-phenylalanine-4-ethoxycarbonylpyrimidine, Nα-(2,4,6-triisopropylphenylsulfonyl)-3-guanidino-(D,L)-phenylalanine-4-ethoxycarbonylpyrimidine or L-enantiomers and pharmaceutically compatible salts of these compounds, in particular, the active substance is selected from Nα-(2,4,6-triisopropylphenylsulfonyl)-3-amidino-(L)-phenylalanine-4-ethoxycarbonylpyrimidine, chloride, water is roadsurface or/and its sulfate salt.

15. The pharmaceutical composition according to any one of claims 1 to 4, in which the concentration of the active substance is up to 100 mg/ml and the concentration of the buffer solution up to 1000 mm.

16. The pharmaceutical composition according to 17, in which the concentration of the active substance is up to 40 mg/ml and the concentration of the buffer solution up to 100 mm.

17. The pharmaceutical composition according to any one of the preceding paragraphs for the treatment of diseases associated with urokinase.

18. The pharmaceutical composition of claims 1 to 17 for the treatment of tumors, prevention of tumors, treatment or/and prevention of the formation of metastases.

19. The pharmaceutical composition according to any one of claims 1 to 17 for the treatment and/or prevention of cancer of the breast, pancreas, and/or formation of metastases.

20. The pharmaceutical composition according to any one of claims 1 to 17 for the treatment and/or prevention of arthritis, inflammation, osteoporosis, retinopathy, for example, age-related degenerative changes in the macula, to prevent the formation of bubbles in the skin disease Pemphigus vulgaris.

21. The pharmaceutical composition according to any one of the preceding paragraphs for preparation of solution for injection in the form of injection or infusion by diluting the appropriate isotonic agent to give isotonicity, the maximum concentration of the active substance is up to 1 m is/ml.

22. The pharmaceutical composition according to item 21, in which the specified isotonic agent is a 1-10%solution of glucose, in particular, 5%glucose solution.

23. The pharmaceutical composition according to any one of claims 1 to 17 in combination with cytostatic or cytotoxic agents.

24. The method of stabilization of the pharmaceutical composition described in claims 1 to 23, comprising adding to the active ingredient, representing a derivative amidino-, hydroxyamide-, guanidino-, and/or hydroxybenzylideneamino, polyol, alcohol, or their mixture and the aqueous phase containing a buffer substance.

25. The method according to 24, in which the polyol mixture and the alcohol is present in amount of about 20-60% relative to the weight of the entire composition and in which the aqueous phase is present in an amount up to 70% relative to the total volume of the composition and in which the buffer has a concentration of up to 1000 mm.



 

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EFFECT: higher mixture safety and tolerance.

39 cl, 29 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: formulation contains N-carbamoyl-methyl-4-phenyl-2-pyrrolidone as active principle and solubilising neutral organic component selected from the group that comprises diamide of carbonic acid, and/or monosaccharides, and/or disaccharides, and/or polyatomic spirits or their homogeneous mixture, with mass relation of N-carbamoyl-methyl-4-phenyl-2-pyrrolidone and specified solubilising component 1:(0.15-5). Method for preparation of pharmaceutical formulation consists in the fact that formulation components are simultaneously and separately evaporated in depressurised gas medium, and produced vapors are cocondensated on the surface of sedimentation cooled down to negative temperature. The second version of method for preparation of pharmaceutical formulation consists in the fact that formulation components are previously dissolved in water, solution is frozen to the temperature of not higher than - 60°C, then frozen solution is sublimated in depressurised gas medium, and adsorbed water remainder is removed in prepared pharmaceutical formulation. Invention provides for preparation of water-soluble pharmaceutical formulation on the basis of N-carbamoyl-methyl-4-phenyl-2-pyrrolidone.

EFFECT: formulation is suitable for preparation of injection, suspension dosage forms.

3 cl, 8 dwg, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: lyophilised preparation forms and solutions CCI-779 are available for production of lyophilised preparation forms CCI-779. The specified solutions consist of CCI-779 and solvent chosen from dimethylsulfoxide, acetonitrile, ethanol, isopropanol, tert-butyl alcohol and their mixtures. Besides, methods of lyophilised preparation forms CCI-779 preparation and restoration are offered.

EFFECT: improved storage stability and preservation of initial activity.

21 cl, 10 ex

FIELD: medicine; pharmacology.

SUBSTANCE: mainly water-free composition for oral or vaginal mucosa lubrication includes at least one polyatomic alcohol and honey as insulation agent. Invention also concerns methods of the composition application for lubrication, active component introduction and dysmenorrhea prevention or treatment. Methods involve application of mainly water-free lubricating composition including at least one polyatomic alcohol and insulation agent selected from honey and isopropylpalmitate, onto oral or vaginal mucosa to produce heating effect.

EFFECT: reduced toxicity and irritation effect.

31 cl, 1 tbl, 9 ex

FIELD: medicine; pharmacology.

SUBSTANCE: semifirm pharmaceutical compositions for local application include ascomycene in solution of carrier including three-componental admixture of dissolvents, component not less than 40% wt from lump of composition and consisting from: i) C3-8-alkanol and-or C1-8-alkandiol; ii) fat alcohol iii) additional dissolvents chosen from the family, containing:) alkyl ether of alkancarboxylic acid and-or alkyl ether alkandincarboxylic acid and-or a hydrophylic additional component and-or a triglyceride. Besides, the invention concerns application of the specified composition and the method of treatment of inflammatory and hyperproliferative diseases of skin and dermal implications of immunologically mediated diseases.

EFFECT: improvement of penetration of active substance.

9 cl, 7 tbl, 26 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical composition containing mixture of (a) active macromolecular reactant and (b) aromatic alcohol absorption intensifier chosen from butylated hydroxytoluene, butylated hydroxyanisole and their analogs and derivatives where aromatic alcohol absorption intensifier is available in weight amount exceeding or equal to those of active macromolecular reactant; and besides, to pharmaceutical composition containing mixture of (a) active macromolecular reactant and, (b) aromatic alcohol absorption intensifier chosen from propyl gallat, butylated hydroxytoluene, butylated hydroxyanisole and their analogs and derivatives where aromatic alcohol absorption intensifier is available in weight amount exceeding or equal to those of active macromolecular reactant and (c) additive solubiliser increasing solubility of aromatic alcohol absorption intensifier in aqueous mediums.

EFFECT: provides intensified molecule absorption including biologically active macromolecules in organism through intestinal wall from intestine lumen respectively.

29 cl, 13 ex, 1 tbl

FIELD: medicine; oncology.

SUBSTANCE: stimulate an apoptosis of the cells by plating in presence of an alcohol water extract of hemlock, dissolved with Hanks's solution in concentration of masses of 0.0001-0.00001 wt %. The alcohol water extract is obtained by infusing of soft fibers and foetuses of hemlock on 70° ethyl alcohol.

EFFECT: effective stimulation of apoptosis at low concentration of an accessible and cheap preparation.

2 cl, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and pharmaceutics and concerns combined anti-tuberculosis composition in form of solid medicinal form including as active components riphampicin, levofloxacin, isoniazide, pyrazinamide and pyridoxine hydrochloride.

EFFECT: increased treatment efficiency.

8 cl, 1 tbl, 6 ex

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