Stabilized pharmaceutic composition in its lyophilized form

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the present innovation deals with new stabilized pharmaceutical composition in its lyophilized form including the compound of formula I

as an active ingredient and lactose disaccharide as a stabilizing agent. The present pharmaceutical compositions are of high stability at storage. As for active ingredient it is not destroyed in the course of time.

EFFECT: higher efficiency.

10 cl, 15 ex, 6 tbl

 

The technical field

The present invention relates to a stabilized pharmaceutical composition in lyophilized form containing cyclic polypeptide compound. More specifically, the present invention relates to a stabilized pharmaceutical composition in lyophilized form containing cyclic polypeptide compound or its pharmaceutically acceptable salt and stabilizer.

The cyclic polypeptide compound of the present invention represented by the General formula (I):

where R1represents a hydrogen atom or acyl group, and R2and R3are the same or different, a hydrogen atom or a hydroxyl group. The compound has antimicrobial activity, in particular fungicidal activity and inhibiting β-1,3-glucosidase action, and is useful for prevention and treatment of infectious diseases of various kinds, including pneumocystosis, for example, pneumonia, caused carinii.

Prior

Among the cyclic polypeptide compounds represented by the above formula (I), the compound wherein R1represents a hydrogen atom, and R2and R3represent a hydroxyl group, and a compound where R1, R2and R3represent hydrogen atoms, on ucaut fermentation, disclosed in European patent No. 0462531, and methods disclosed in WO 97/32975 and WO 97/47738. Connection, where R1represents an acyl group, and the method thereof disclosed in U.S. patent No. 5376634 and 5569646 and WO 96/11210 and WO 99/40108.

The cyclic polypeptide compound (I) and their salts are usually unstable to light, moisture, acids, heat and the like. Therefore, the desirable development of pharmaceutical preparations, in which the cyclic polypeptide compounds and their salts are stable.

Disclosure of inventions

The present invention provides a stabilized pharmaceutical composition in lyophilized form containing cyclic polypeptide compound (I) or its pharmaceutically acceptable salt and stabilizer.

Next is explained the term "acyl group" R1in the formula (I)representing a cyclic polypeptide compound of the present invention. In the context of the present description, the term "lower" means having one to six carbon atoms, unless otherwise specified.

As examples of the acyl group can be mentioned aliphatic acyl group, aromatic acyl group, an aromatic-aliphatic acyl group and heterocyclic acyl groups derived from aliphatic, aromatic, aromatic-aliphatic and geterotsiklicheskikh acids.

Examples of aliphatic acyl groups include lower or higher alcoholnye groups such as formyl, acetyl, propanol, butanol, 2-methylpropanol, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanoic, emosanal etc.; cycloalkenyl groups such as cyclopentenyl and cyclohexanol; lower alkoxycarbonyl groups such as methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxybenzoyl, heptyloxybiphenyl etc.; lower alkanesulfonyl group such as methanesulfonyl, econsultancy etc.; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and so on and so forth.

Examples of aromatic acyl groups include aroline group such as benzoyl, toluoyl, naphtol and the like.

Examples of aromatic-aliphatic acyl groups include ar(lower)alcoholnye group such as phenyl (C1-C6)alkanoyl (for example, phenylacetyl, phenylpropanol, phenylmethanol, phenylethanol, phenylmethanol, phenylhexanoic etc), naphthyl(C1-C6) alkanoyl (for example, naphthylacetyl, afterrepair, afterburner etc) and the like;

ar(lower)alkenone gr is PPI such as phenyl(C3-C6)alkanoyl (for example, phenylpropenoyl, phenylmethanol, phenylmethanol, phenylmethanol, phenylhexanoic etc), naphthyl(C3-C6)alkanoyl (for example, afterproperties, afterburner etc) and the like;

ar(lower)alkoxycarbonyl group such as phenyl-(C1-C6)alkoxycarbonyl (for example, benzyloxycarbonyl etc), fluorenyl(C1-C6)alkoxycarbonyl (for example, fluorenylmethoxycarbonyl etc) and the like;

aryloxyalkyl groups such as phenoxycarbonyl, mattoxicator etc.;

aryloxy(lower)alcoholnye groups such as phenoxyacetyl, phenoxypropionyl etc.;

arylcarbamoyl groups such as phenylcarbamoyl etc.;

alltournament groups such as phenylthiocarbamoyl etc.;

killiecrankie groups such as phenylglyoxylic, afterpotential etc.;

arylsulfonyl group which may be optionally substituted lower alkyl group, such as phenylsulfonyl, p-tamilselvan and so on and so forth.

Examples of heterocyclic acyl groups include heterocyclic carbonyl group such as tenor, furoyl, nicotinoyl etc.;

heterocyclic(lower)alcoholnye groups such as heterocyclic acetyl, heterocyclic propanol, heterocyclics the rd butanol, heterocyclic pentanoyl, heterocyclic hexanoyl etc.;

heterocyclic(lower)alkenone groups such as heterocyclic propanol, heterocyclic butanol, heterocyclic pentanoyl, heterocyclic hexanoyl etc.;

heterocyclic glycerol and the like.

Acyl group, the radical R1may have one or more suitable substituent(s). Among the above examples of acyl groups, arolina group which may have one or more suitable substituent(s), is especially preferred.

Examples of suitable substituents in the acyl group include heterocyclic group, substituted aryl group having lower alkoxygroup, heterocyclic group, substituted aryl group having lower alkoxy(lower)alkoxygroup, heterocyclics group, substituted aryl group having lower alkoxy(higher)alkoxygroup, heterocyclic group, substituted aryl group having cyclo(lower)alkyloxy, heterocyclic group, substituted aryl group having a heterocyclic group, heterocyclic group, substituted cyclo(lower)alkyl group having cyclo(lower)alkyl group, heterocyclic group, substituted aryl group having aryl group, substituted dissimulate(lower)alkoxy and a heterocyclic group, substituted aryl group having a heterocyclic group, a substituted cyclo(lower)alkyl group.

Among these examples, preferred are unsaturated 3-8-membered heterophilically group containing one or two atoms of oxygen and one to three atoms(a) nitrogen and substituted phenyl having (C4-C6) alkoxy, unsaturated condensed heterocyclic group containing one or two atoms(a) sulfur and one to three atoms(a) nitrogen and substituted phenyl having (C4-C6)alkoxy, unsaturated 3-8-membered heterophilically group containing one or two atoms(a) sulfur and one to three atoms(a) nitrogen and substituted phenyl having (C1-C4) alkoxy (C4-C6) alkoxy, unsaturated 3-8-membered heterophilically group containing one or two atoms(a) sulfur and one to three atoms(a) nitrogen and substituted phenyl having (C1-C4) alkoxy (C7-C14) alkoxy, saturated 3 to 8-membered heterophilically group containing one to four atoms(a) nitrogen and substituted phenyl having (C1-C4)alkoxy(C7-C14)alkoxy, unsaturated condensed heterocyclic group containing one or two atoms(a) sulfur and one to three atoms(a) nitrogen and substituted phenyl having cyclo(C4-C6)alkyloxy, unsaturated condensed heterocyclic group containing one or two atoms(a) sulfur and one to three atoms(a) nitrogen and substituted phenyl, saturated 3 to 8-membered heterophilically group containing one or two atoms of oxygen and one to three atoms(a) nitrogen, saturated 3 to 8-membered heterophilically group having one to four atoms(a) nitrogen and substituted cyclo (C4-C6) alkyl having cyclo (C4-C6) alkyl, unsaturated 3-8-membered heterophilically group having one or two atoms(a) sulfur and one to three atoms(a) nitrogen and substituted with phenyl having phenyl substituted C1-C4)alkoxy(C1-C4) alkoxy, unsaturated 3-8-membered heterophilically group containing one or two atoms(a) sulfur and one to three atoms(a) nitrogen and substituted with phenyl having saturated 3 to 8-membered heterogenities group that contains one to four atoms(a) nitrogen and substituted cyclo(C4-C6)alkyl and unsaturated condensed heterocyclic group containing one or two atoms(a) sulfur and one to three atoms(a) nitrogen and substituted with phenyl having saturated 3 to 8-membered heterogenities group that contains one to four atoms(a) nitrogen and is cyclo (C4-C6) alkyl.

Among them, particularly preferred are isoxazolidine group substituted by phenyl having pentyloxy, imidazothiazole group substituted by phenyl having pentyloxy, thiadiazolyl group substituted by phenyl having metox is hexyloxy, thiadiazolyl group substituted by phenyl having ethoxyacrylate, thiadiazolyl group substituted by phenyl having methoxyethoxy, imidazothiazole group substituted by phenyl having cyclohexyloxy, imidazothiazole group substituted by phenyl having dimethylmorpholine, piperazinilnom group substituted by phenyl having methoxyethoxy, piperazinilnom group substituted by phenyl having ethoxyacrylate, piperazinilnom group substituted with cyclohexyl having cyclohexyl, thiadiazolyl group substituted by phenyl having phenyl substituted methoxyethoxy, thiadiazolyl group substituted by phenyl having phenyl substituted methoxybutan, thiadiazolyl group substituted by phenyl having phenyl substituted ethoxypropane, imidazothiazole group substituted by phenyl having piperazinil, substituted cyclohexyl, imidazothiazole group substituted by phenyl having piperazinil, substituted cyclohexyl, and the like.

Accordingly, particularly suitable examples of the acyl group R1can be benzoline group having isoxazolyl substituted with phenyl having pentyloxy, benzoline group having imidazothiazoles substituted with phenyl having pentyloxy, benzoline group having thiadiazolyl, substituted what anilam, having methoxyacetate, benzoline group having thiadiazolyl, substituted phenyl, with ethoxyacrylate, benzoline group having thiadiazolyl, substituted phenyl, with methoxyethoxy, benzoline group having imidazothiazoles, substituted phenyl, with cyclohexyloxy, benzoline group having imidazothiazoles, substituted phenyl, with dimethylmorpholine, benzoline group having piperazinil, substituted phenyl, with methoxyethoxy, benzoline group having piperazinil, substituted phenyl, with ethoxyacrylate, benzoline group having piperazinil substituted with cyclohexyl having cyclohexyl, benzoline group having thiadiazolyl substituted with phenyl having phenyl substituted methoxyethoxy, benzoline group having thiadiazolyl substituted with phenyl having phenyl substituted methoxybutan, benzoline group having thiadiazolyl substituted with phenyl having phenyl substituted ethoxypropane, benzoline group having imidazothiazoles, substituted phenyl having piperazinil, substituted cyclohexyl, benzoline group having imidazothiazoles, substituted phenyl having piperazinil, substituted cyclohexyl, and the like.

Particularly preferred examples of the acyl groups, R1the form of the AMI:

The cyclic polypeptide compound (I)having the above-mentioned acyl group, can be obtained from compounds having a hydrogen atom as R1and a hydroxyl group as R2and R3or compounds having hydrogen atoms as R1, R2and R3according to U.S. patent No. 5376634 and 5569646 and WO 96/11210 and WO 99/40108.

Suitable salt of the cyclic polypeptide compound (I) are soluble in water and pharmaceutically acceptable salts, including salts, bases, and acid-salt additive. Such salts can be obtained by processing the cyclic polypeptide compound (I) is the appropriate base or acid in the usual way.

As salts of the bases may be mentioned salts of inorganic bases such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), salts of alkaline earth metals (e.g. calcium salt, magnesium salt etc), ammonium salts and the like; salts of organic bases such as salts of organic amines (for example, salts of triethylamine, salt diisopropylethylamine, pyridine salts, picoline salts, ethanolamine salt, triethanolamine salt, salt DICYCLOHEXYL the amine, salt N,N'-dibenziletilendiaminom etc) and the like.

As the acid additive salts may be mentioned the acid additive salts of inorganic acids (for example, hydrochloride, hydrobromide, sulfates, phosphates, etc.) and acid additive salts of organic carboxylic or sulfonic acids (e.g., formate, acetate, triptoreline, maleate, tartratami, fumarate, methanesulfonate, bansilalpet, toluensulfonate etc). In addition, you can also mention the salt of the basic or acidic amino acid (e.g. arginine salt, aspartic acid, glutamic acid and so on).

The cyclic polypeptide compound (I) of the present invention also include the possible conformers and a couple or more stereoisomers such as geometrical isomers and optical isomers which may exist due to asymmetric carbon atoms.

Preferred cyclic polypeptide compound (I) represented by the following formulas (II)-(VI):

Most preferred is a compound represented by formula (II).

The number of cyclic polypeptide compound (I) or its pharmaceutically acceptable with the and, contained in the composition for a single standard dose of the present invention is 0.1 to 400 mg, more preferably 1-200 mg, even more preferably 10-100 mg, especially 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 75, 80, 85, 90, 95 and 100 mg.

As the stabilizer, there can be mentioned polysaccharides, disaccharides, sodium chloride and combinations thereof.

Examples of the polysaccharide is dextran, starch, cellulose, and hyaluronic acid; and examples of the disaccharide is lactose, maltose and sucrose. The disaccharide or polysaccharide contained in the pharmaceutical compositions of the present invention, can be α-monohydrate, α-anhydride, β-anhydride, or a combination.

The amount of stabilizer used in the pharmaceutical compositions of the present invention, should be at least sufficient to stabilize the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt in the composition. To stabilize the cyclic polypeptide compound (I) is sufficient at least one part by weight of the stabilizer relative to one part by weight of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt in the composition. The stabilizer can also serve as a carrier or excipient. Thus, the amount of stabilizer does not have the specified upper limit and can be defined by considering the mass or volume of the composition relative to the standard dose of a compound and the like. However, this amount preferably is 0.4 to 50 parts by weight, more preferably 0.6 to 20 parts by weight, even more preferably 0.8 to 10 parts by weight relative to one part by weight of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt, although it varies depending on the type and used amount of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salts, its formulation and/or the like. In particular, more preferably, if used 1 to 20 parts, more preferably 2-10 parts by weight of a disaccharide with respect to one part by weight of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt. In particular, it is preferable if you use 0.6 to 20 parts, more preferred 0.8 to 10 parts by weight of sodium chloride relative to one part by weight of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt.

The pharmaceutical composition of the present invention can be obtained by methods known in this field, using, if necessary, additives. As the links mentioned Basic Lecture on Development of Pharmaceuticals XI 20 Production of Pharmaceuticals (second volume) (edited by Kyosuke Tsuda and Hisashi Nogami and published by Chizyo Shoten). Liofilizarea the percent composition can be obtained by preparing an aqueous solution of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt and a stabilizer, optional when adding a pH regulator (anhydrous citric acid, sodium hydroxide etc)as required to achieve pH 4.0 and 7.5, preferably pH 4.5 to 7.0 and then by lyophilization of the resulting solution in the ampoule in the usual way. Thus, a stabilized pharmaceutical composition in lyophilized form, when dissolved in purified water, preferably gives a solution with pH 4.0 and 7.5, more preferably with pH from 4.5 to 7.0. Preferably, the thus obtained composition in dried form was closed and kept in the dark. The freeze-dried composition can be loaded into each ampoule in the form of a solution before lyophilization or in the form of dried powder after lyophilization.

Because of the cyclic polypeptide compound is not satisfactorily stable to moisture, it is necessary to freeze-dried composition of the present invention contained 3,4% by weight or less of water, preferably to 3.0%, more preferably of 2.0%.

Typically, the stabilized pharmaceutical composition in lyophilized form, dissolve in isotonic sodium chloride as required, and is used in the form of injection solution. The pharmaceutical composition of the present invention can be used as an injectable drug for which t is aboutsa some manipulation before use.

The best way of carrying out the invention

Further, the present invention is described in more detail using examples and examples of tests that should not be considered as limiting the scope of the invention. In the examples, the compounds of formulas (II)to(VI) shown as compound (II)-(VI), respectively.

Example 1

The compound (II) 25 g

Lactose 200 g

Anhydrous citric acid in a suitable number

Sodium hydroxide in a suitable number

Lactose was dissolved in purified water (2000 ml) by heating below 50°C. After cooling below 20°to a solution of lactose was added the compound (II)avoiding allocation of bubbles with gentle stirring. After adding a 2% aqueous solution of citric acid (9.5 ml) to the solution was added a 0.4% aqueous solution of sodium hydroxide (approximately 24 ml) to bring the pH to 5.5 with further dilution with purified water to obtain a specified amount (2500 ml). The resulting solution was divided into 1000 vials with a capacity of 10 ml 2.5 ml ampoule. The solution in the respective ampoules liofilizirovanny when using lyophilizate (RL-603BS, manufactured by Kyowa Shinku, Co., Ltd.) the usual way to obtain a lyophilized compositions, each containing 25 mg of compound (II).

Example 2

Lyophilized compositions, each containing 50 mg of compound (II)receive such disposala, as in example 1, except that the amount used of the compound (II) was 50,

Example 3

Lyophilized compositions, each containing 25 mg of compound (II), receive the same manner as in example 1, except that instead of lactose using 150 g of maltose.

Example 4

Lyophilized compositions, each containing 50 mg of compound (II), receive the same manner as in example 1, except that the amount used of the compound (II) was 50 g instead of 25 g, and instead of lactose using 250 g of sucrose.

Example 5

Lyophilized compositions, each containing 25 mg of compound (II), receive the same manner as in example 1, except that instead of lactose using 25 g of sodium chloride.

Example 6

Lyophilized compositions, each containing 10 mg of compound (II), receive the same manner as in example 1, except that the amount used of the compound (II) was 10 g instead of 25 g, and instead of lactose using 100 g of dextran.

Example 7

Lyophilized compositions, each containing 25 mg of compound (III)receive the same manner as in example 1, except that use 25 g of compound (III) instead of compound (II), and instead of lactose using 200 g of maltose.

Example 8

Lyophilized compositions, each which contains 10 mg of the compound (IV), receive the same manner as in example 1, except using 10 g of the compound (IV) instead of compound (II), and the amount of lactose 100 g instead of 200,

Example 9

Lyophilized compositions, each containing 50 mg of compound (V)receive the same manner as in example 1, except that use 50 g of compound (V) instead of compound (II), and instead use lactose 50 g of sodium chloride.

Example 10

Lyophilized compositions, each containing 10 mg of compound (VI), receive the same manner as in example 1, except using 10 g of compound (VI) instead of compound (II), and instead use lactose 100 g of dextran.

Example 1 test

The influence of the stabilizer in a stable lyophilized compositions of compound (II)

10 mg of the compound (II) and, as a stabilizer, 100 mg of lactose, or 9 mg of sodium chloride was completely dissolved in 1 ml of water. The obtained solutions liofilizirovanny and kept at 70°glass ampoules. After nine days of the obtained compositions was investigated by their appearance, the residual amount of compound (II) and other indicators. As a control, used a solution of compound (II) without any stabilizers. The results are presented in table 1.

Example 2 IP is itani

Similar experiments conducted in the same manner as in example 1, tests, except that, as a stabilizer used 100 mg of maltose, 50 mg of sucrose or 50 mg of glucose. The results are presented in table 2.

As obvious from tables 1 and 2 lyophilized composition of compound (II) and lactose, sodium chloride, maltose or sucrose was significantly more stable in comparison with those that do not contain any stabilizers or contain other stabilizers.

Example 3 test

The dependence of the stability of lyophilised compositions of compound (II) from the amount of added lactose

Experiments conducted in the same manner as in example 1, tests, except that, as a stabilizer was added 20 mg, 50 mg, 100 mg or 200 mg of lactose. Table 3 presents the results of tests to monitor the appearance of the compositions, the residual amount of compound (II), the appearance of the recovered solutions of compositions in 1 ml of water, and the like. In this regard, it takes 15 seconds to recover songs in 1 ml of water.

* Color, transparency and pH of the recovered solutions of compositions in 1 ml of water.

As is obvious from table 3, the lyophilized composition of 10 mg of compound (II) and various amounts of lactose is not them who are any problems with their stability.

Example 4 testing

The stability of lyophilised compositions 200 mg of lactose and the compound (II) in the ampoule.

Experiments conducted in the same manner as in example 1, tests, except that used 12.5 mg, 25 mg, 50 mg, 75 mg or 100 mg of compound (II) with 200 mg of lactose. Table 4 presents the results of the experiments on the residual amount of compound (II) obtained in the compositions and the like. Considering all songs, their appearance is a white mass, the reduction time of the dissolution was 15 seconds, and as for the color and transparency of the recovered solutions of the compositions, they were colorless and transparent.

* pH of the recovered solutions of compositions in 5 ml of purified water

As evident from table 4, all of the lyophilized compositions were stable.

Example 5 testing

Stability studies

The pharmaceutical compositions obtained in examples 1 and 2 were stored at room temperature. After 18 months, the residual proportion of the compound (II) was 98% in all compositions.

Example 6 test

The dependence of the stability of lyophilised compositions of compound (II) from the value of pH of the composition prior to lyophilization

10 mg of the compound (II) and, as a stabilizer, 100 mg of lactose was completely dissolved in 1 ml of citrate-NaOH is the buffer, having different pH values between 4,0-7,0. The resulting solutions having different pH values, liofilizirovanny and maintained at 70°glass ampoules. After nine days of the obtained composition were investigated on their pH and the residual amount of compound (II). The results are presented in table 5.

As is evident from table 5, the pharmaceutical composition of the present invention is stable after freeze-drying of a solution containing the compound (II), at least at pH 4,0-7,0, preferably at pH 4,5-7,0.

Example 7 testing

The dependence of the stability of lyophilised compositions of compound (II) from the water content in the composition

10 mg of the compound (II) and, as a stabilizer, 50 mg of lactose was completely dissolved in 1 ml of water. The obtained solutions liofilizirovanny and maintained at 70°glass ampoules. After nine days of the obtained compositions were tested for their pH, water content and the residual amount of compound (II). The results are presented in table 6.

As is obvious from table 6, the pharmaceutical composition of the present invention is a stable, containing about 3.5%, more specifically of 3.4% by weight or less of water.

In accordance with the present invention, it is proposed composition, whether fileserving form in the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt is stabilized by a stabilizer such as a polysaccharide, disaccharide, and sodium chloride.

The mechanism of stabilization of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt stabilizer such as a polysaccharide, disaccharide and sodium chloride, are still unknown, but it may be that the stabilizer adsorbs water in the freeze-dried sediments, and that the stabilizer is used for uniform distribution of the compound or its pharmaceutically acceptable salt in the composition.

The cyclic polypeptide compound (I) possesses antifungal activity, particularly against the following fungi:

Acremonium;

Absidia (e.g., Absidia corymbifera and so on);

Aspergillus (e.g., Aspergillus clavatus, Aspergillusflavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus versicolor, and so on);

Blastomyces (e.g., Blastomyces dermatitidis, etc.);

Candida (e.g., Candida albicans, Candida glabrata, Candida guilliemondii, Candida kefyr, Candida krusei, Candida parapsilosis, Candida stellatoides, Candida tropicalis, Candida utilis, etc.);

Cladosporium (for example, Cladosporium trichoides, and so on);

Coccidioides (e.g., Coccidioides immitis, etc.);

Cryptococcus (e.g., Cryptococcus neoformans, etc.);

Cunninghamella (e.g., Cunninghamella elegans, etc.);

Dematophyte;

Exophiala (e.g., Exophiala dermatitidis, Exophiala spinifera, etc.);

Epidermophyton (e.g., Epidermophyton floccosum, etc.);

Fonscaea (for example, Fonsecaea pedrosoi, etc.);

Fusarium (e.g., Fusarium solani, etc.);

Geotrichum (e.g., Geotrichum candiddum etc.);

Histoplasma (e.g., Histoplasma capsulatum var. capsulatum, etc.);

Malassezia (e.g., Malassezia furfur, etc.);

Microsporum (e.g., Microsporum canis, Microsporum gypseum, etc.);

Mucor;

Paracoccidioides (e.g., Paracoccidioides brasiliensis, etc.);

Penicillium (e.g., Penicillium marneffei, etc.);

Phialophora;

Pneumocystis (e.g., Pneumocystis carinii, etc.);

Pseudallescheria (e.g., Pseudallescheria boydii, etc.);

Rhizopus (for example, Rhizopus microsporus var. rhizopodiformis, Rhizopus oryzae, etc.);

Saccharomyces (e.g., Saccharomyces cerevisiae, etc.);

Scopulariopsis;

Sporothrix (e.g., Sporothrix schenchii etc.);

Trichophyton (e.g., Trichophyton mentagrophytes, Trichophyton rubrum, etc.);

Trichosporon (for example, Trichosporon asahii, Trichosporon cutaneum, and so on).

It is well known that these fungi cause various infectious diseases on the skin, the hair, the nails, the mucous membrane of the oral cavity, gastrointestinal tract, bronchi, lungs, endocardium, brain, brain membranes, organs of the urinary tract, vagina, mouth, eyes, blood and lymph, kidney, bronchi, heart, external auditory canal, bone, nasal cavity, paranasal cavity, spleen, liver, subcutaneous tissue, lymph duct, stomach and intestine, joints, muscles, tendons, interstitial plasma cells in the lungs and so next.

Therefore, the cyclic polypeptide joint is (I) of the present invention are suitable for the prevention and treatment of various infectious diseases such as dermatomycosis (for example, Trichophyton etc), pityriasis versicolor, candidiasis, cryptococcosis, geotechs, trichosporon, aspergillosis, penicillin, Fusarium, sagamiko, sporotrichosis, chronomics, coccidioidomycosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, pseudoallescheria, mycetoma, fungal keratitis, atomikos, Pneumatics etc).

Commercial packaging includes the cyclic polypeptide compound (I) of the present invention and the leaflet associated with it, where the leaflet indicates that the pharmaceutical composition can or should be used for the prevention or treatment of infectious diseases.

1. Stabilized pharmaceutical composition in lyophilized form for the prevention or treatment of infectious diseases containing cyclic polypeptide compound of the formula (I)

or its pharmaceutically acceptable salt as the active ingredient and lactose.

2. The composition according to claim 1, which contains 0.4 to 50 parts by weight of lactose in relation to one part by weight of the cyclic polypeptide compound or its pharmaceutically acceptable salt.

3. The composition according to claim 1, which contains 0.1 to 400 mg of the cyclic polypeptide compound or its pharmaceutically acceptable salt in a single standard dose is.

4. The composition according to claim 1, obtained by the stages of dissolution of the cyclic polypeptide compound (I) or its pharmaceutically acceptable salt, lactose and optionally a regulator of pH in the treated water and lyophilization of the solution.

5. The composition according to claim 1, which when dissolved in purified water gives a solution with pH 4.0 and 7.5.

6. The composition according to claim 1, containing 3.4 percent by weight or less of water.

7. The composition according to claim 1, which further comprises a pH regulator.

8. Injectable preparation obtained by dissolving the composition according to claim 1 in isotonic sodium chloride.

9. Commercial package comprising the pharmaceutical composition according to claim 1 and a leaflet associated with it, where the leaflet indicates that the pharmaceutical composition can or should be used for the prevention or treatment of infectious diseases.

10. The method of stabilization of compounds of formula (I) according to claim 1, characterized in that a pharmaceutical composition comprising a compound of formula (I), add lactose.



 

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48 cl, 4 tbl

FIELD: medicine, hematology, pharmacy.

SUBSTANCE: invention relates to the composition of factor VIII composed without addition of albumin and comprising the following excipients of composition in addition to factor VIII: from 4% to 10% of filling agent taken among group consisting of mannitol, glycine and alanine; from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose, arginine; from 1 mM to 5 mM of calcium salt, from 100 mM to 300 mM of NaCl, and buffer agent for pH value maintenance about between 6 and 8. Alternatively, the composition can comprise from 2% to 6% of hydroxyethylstarch; from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose, arginine; from 1 mM to 5 mM of calcium salt, from 100 mM to 300 mM of NaCl, and buffer agent for pH value maintenance between 6 and 8. In additional variant of realization of invention the composition can comprise: from 300 mM to 500 mM of NaCl, from 1% to 4% of stabilizing agent taken among group consisting of sucrose, trehalose, raffinose and arginine; from 1 mM to 5 mM of calcium salt, and buffer agent. The composition provides stability in the absence of albumin or other proteins.

EFFECT: valuable properties of compositions.

35 cl, 11 tbl, 7 ex

The invention relates to new pharmaceutical compositions that contain the basis or agonist of the basis for the treatment of diabetes, slowing of gastric emptying or reduce food intake, and their dosage forms and methods for their introduction

The invention relates to the field of medicine and relates to a stable form of anti-cancer drug containing paclitaxel, and how it is received by dissolving crystalline paclitaxel in a neutral organic solvent selected from the group consisting of acetonitrile, dioxane, ethanol or mixtures thereof, provided that the contents of the individual solvents in the mixture is in the range from 5 to 95%, whereas the water content is in the range from 0 to 60%, optionally filtering the resulting solution, freezing and removal of the solvent by sublimation under reduced pressure at low temperature, and optional separation of dose in terms providing sterility

The invention relates to pharmaceutical industry
The invention relates to lyophilizate with increased dissolution rate, which can be restored without the formation of particles, which is achieved by re-heating of selected solutions in bottles to a temperature of from 30 to 95With directly in the freeze-dryer for 10 min to 4 h

The invention relates to the field of pharmaceutical industry and relates to lyophilized peptide/lipid product
The invention relates to medicine, namely to a restorative or cosmetic surgery and aesthetic dermatology

FIELD: medicine.

SUBSTANCE: preparation comprises echinocandine substance of formula I or its pharmaceutically permissible salt, pharmaceutically permissible micelle-forming surface-active agent and non-toxic aqueous solvent and stabilizing agent.

EFFECT: improved stability and bioaccessibility properties.

48 cl, 4 tbl

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