Curative agent

FIELD: medicine, medicinal agents, pharmacy.

SUBSTANCE: invention relates to a medicinal agent made as ointment, gel, vaginal or rectal suppository and designated for treatment of candidomycosis and comprising ketoconazole or fluconazole (variants) in the dose 0.01-0.4 g/1 g of agent, and recombinant alpha-interferon in the dose 150000-3000000 IU/g (for rectal and vaginal suppository) and 5-50000 IU/g (for ointment and gel). Invention provides the development of agent with prolonged effect as ointment, gel, vaginal or rectal suppository showing good penetrating capacity and possessing an antimycotic effect.

EFFECT: valuable medicinal and pharmaceutical properties of agent.

14 cl, 4 tbl, 6 ex

 

The invention relates to medicine and pharmaceutical industry and for the creation of dosage forms containing the drugs interferon and antimycotic drugs imidazole group (ketoconazole or fluconazole), and can be used for the treatment of combined fungal infections. Examples of such conditions include mycosis, developing as a consequence of prolonged use of broad-spectrum antibiotics, which leads to the violation of the correlations in the normal microflora of the human body and the development of dysbiosis, and also by reducing the protective forces of an organism resulting from long-term assignment of certain drugs (corticosteroids, immunosuppressants).

Well-known domestic genetically engineered human interferon alpha-2 (Interfax α-2), which has a pronounced biological activity in cultured human cells /1/. For clinical purposes in the Russian Federation issued several dosage forms of the drug: intranasal (ME 100 vials), inhalation (100000 ME in the ampoule), candles with interferon (0,5-10·106ME on a candle) /1-5/. The last of these dosage form (trade name "Viferon") unlike other drugs interferon additionally contains a complex of vitamins, antioxidants E and C. a Logical continuation of this paragraph is eparate became ointment "Viferon", in which as well as candles, in addition to the main active substance is a genetically engineered human if α-2 - there are vitamins E and C /6/.

Known therapeutic agent containing alpha - or beta-, or gamma-interferon, acyclovir, immunomodulator, vitamins, anti-inflammatory drug, an antimicrobial agent, stabilizer biological, physico-chemical properties and/or resistance to microbial contamination, antioxidant, topical anesthetic drug and pharmaceutically acceptable additives target, and possess antiviral, antibacterial, anti-inflammatory, detoxifying, local anesthetic action. The drug may be in the form of ointment, gel, suppository, paste, cream, liniment, tablets /7/.

It is known that imidazole compound - ketoconazole and fluconazole are now the main effective antifungal agents, taking a more lasting place among the various antimicotic. For clinical purposes produced several dosage forms of the above drugs: a solution for intravenous injection (2 mg of fluconazole per 1 ml of solution), capsules (50 mg, 100 mg and 150 mg of fluconazole per capsule), powder for preparation of suspension for oral administration (50 mg and 200 mg of fluconazole on 5 ml of the prepared suspensions), tablets (200 mg is ketoconazole on the pill), vaginal suppositories (400 mg of ketoconazole by suppository), the cream in a tube (20 mg of ketoconazole in 1 d), and shampoo (20 mg of ketoconazole in 1 ml) /8/.

The technical result of the invention is to provide means prolonged action as ointment, gel, vaginal and rectal suppository on the basis of recombinant interferon, ensuring good penetration ability and possessing antiviral, antibacterial, antifungal, detoxifying effect.

To achieve the technical result remedy containing alpha-interferon and pharmaceutically acceptable additives target, according to the invention additionally contains ketoconazole or fluconazole).

Remedy contain ketoconazole or fluconazole) from 0.01 to 0.4 g per 1 g of product.

It also contains vitamins, selected from the group of vitamin E and vitamin C in the amount of 0.0001-0.06 g per 1 g of product.

As vitamin E. it contains alpha-tocopherol.

As vitamin C it contains ascorbic acid or its calcium salt.

Therapeutic agent further comprises the amino acid methionine as an antioxidant and detoxifying agent in the amount of 0.0001-0.001 g to 1 g of product.

It additionally contains a stabilizer biological physicist the-chemical properties, selected from the group of: albumin human serum, glycerol in amount is 0.0002 to 0.2 g per 1 g of product.

Therapeutic agent contains the stabilizer of resistance to microbial contamination, selected from the group: sodium tetraborate, ethyl alcohol in a quantity of 0.0001 to 0.1,

As pharmaceutically acceptable target additives it contains one or more ingredients from the group of additives, including soklin, tallow, cocoa butter, petrolatum, lanolin, polyethylene oxide, carboxymethyl cellulose, peach oil.

Remedy contains antioxidant: citric acid or butylacetyl in the amount of 0.0001-0.001 g to 1 g of product.

It contains an antimicrobial agent: benzoic acid in an amount of 0.0001-0.001 g to 1 g of product.

A therapeutic agent is a liquid or soft medicinal forms.

His soft medicinal forms submitted by the ointment or gel, or suppository, rectal or vaginal.

Its dosage form in the form of a vaginal suppository contains a buffer mixture, supporting the pH of the suppository of 3.0 to 5.0.

The invention is illustrated in the following examples.

Example 1. The technology of obtaining a remedy.

To obtain gel prepare a solution of the stabilizer: albumin human serum, glycerol and sodium tetraborate. Take rest the market antioxidants: methionine, benzoic acid, citric acid and 5%alcohol solution of vitamin E. Add albumin alpha-interferon solution antimycotics ketoconazole or fluconazole) and mix them. These components are mixed with the required pharmaceutically acceptable targeted supplements mentioned above. Ready the product Packed in the required capacity (e.g., tubes), seal and label. These components take the following ratio of 1 g of product (see table 1).

Example 2. For more ointment take the solution antimycotics ketoconazole or fluconazole). Add alpha-interferon and mix them. The resulting solution by rubbing connect with vitamin E and essential pharmaceutically acceptable targeted supplements. Next, as in example 1. These components take the following ratio of 1 g of product (see table 2).

Example 3. To obtain a rectal suppository take a solution of butylacetyl. Then add a solution of antimycotics ketoconazole or fluconazole) and vitamins C and E. Connect with molten necessary pharmaceutically acceptable targeted supplements and add alpha-interferon. The mixture is then poured into molds for candles, cooled and packaged. These components take the following ratio of 1 g of product (see table 3).

PR is measures 4. To obtain a vaginal suppository take a solution of butylacetyl and mixed with solutions of antimycotics ketoconazole or fluconazole) and vitamins C and E. Then add a buffer mixture, supporting the pH of the suppository of 3.0 to 5.0. Connect with molten necessary pharmaceutically acceptable targeted supplements and add alpha-interferon. The mixture is then poured into molds for candles, cooled and packaged. These components take the following ratio of 1 g of product (see table 4).

Received the drug for the treatment of combined fungal infections has the appearance of soft or liquid forms.

The essential features of the proposal is to use a combination of alpha recombinant interferon with antimycotic drug for the prevention of mycosis of various etiologies.

According to the literature data it is known that drugs alpha recombinant interferon is effective for correction of intestinal dysbiosis /3/. On the background of the appointment of these drugs, regardless of disease activity, virtually disappear from the intestinal contents fungi of the genus Candida, significantly reduced seeding in the faeces of Staphylococcus aureus, Klebsiella, Escherichia coli with altered properties. This property drugs alpha recombinant interf what Ron is greatly enhanced by the introduction of a therapeutic agent of ketoconazole or fluconazole), which have direct antifungal effect.

In recent years have increasingly drawn attention to the fact that the use of antifungal drugs imidazole series recommended in combination with Immunostimulants and immunomodulators (because of the damaging effect on the immune system). Thus, their introduction into a dosage form alpha recombinant interferon allows you to obtain a new result - decrease side effects antimycotics, increased antiviral and immunomodulatory activity. The antioxidants included in the combined treatment, stabilize the cell membrane of the organism, increasing their resistance to different damaging agents mushrooms.

Thus, to create a combined therapeutic agent-based dosage forms alpha recombinant interferon, which also includes antimycotics ketoconazole or fluconazole), allows to obtain a new result, namely:

1) to expand the range of therapeutic applications, using a combination therapeutic agent in cases where the use of drugs without antifungal agents little or ineffective;

2) to achieve the same level of antifungal activity as preparations prototype with reduced dose of antimycotics (or to get a higher efficiency at t the th same dose antimycotics);

3) to avoid unwanted side effects inherent in the drugs imidazole series, due to correction from alpha recombinant interferon and antioxidants.

In special analyses it has been shown that going beyond the stated values of the components of therapeutic agent in the reduction causes a decrease in specific activity, and increase leads to a deterioration of the organoleptic properties of the drug without amplification of specific activity. When studying the influence of components of the treatment to the antifungal effect of ketoconazole and fluconazole has been shown that the above components in the stated concentrations did not affect the expression of ketoconazole and fluconazole in their fungicidal activity. Was not also identified possible actions antimycotics, as well as other components of the drug in the selected concentrations on the antiviral activity of human recombinant interferon α-2 in vitro. In the study of toxic effects of components of the treatment to the culture of diploid cells human fibroblasts strain M-27 was shown that the higher the concentration of the component remedies cause toxic effects on the cells.

The effectiveness of a therapeutic agent (for example, rectal and vaginal suppositories) studies which were doulas clinically in two groups of patients: Candida intestinal dysbiosis (20 people) and vaginal candidiasis (16 people). We analyzed the clinical and anamnestic data were performed microbiological and immunological research.

Candles were appointed 1-2 times a day. Safety and reactogenicity of the drug was determined by the variance in the General condition of the patients (analysis of blood and urine, fever, General feeling). therapeutic effect was evaluated in terms of the vanishing culture of the fungus from feces and vaginal secretions and intensity of clinical signs of relapse. Conclusions about the immunomodulatory activity of the claimed therapeutic agents was done based on the study of the immune status of patients before and after treatment. The duration of treatment were different depending on the type and severity of pathology.

Example 1. Patient C., 25 years old, complained of nagging abdominal pain and abnormal discharge from the genital tract (Beli cheesy of harkter); low grade fever. Clinically identified Candida colpitis. The laboratory smear of vaginal secretions detected individual colonies of Candida albicans. The diagnosis of vaginal candidiasis with ureaplasmosis. Treatment with ketoconazole tablets concomitantly with antibiotic therapy was ineffective. The patient is recommended vaginal suppositories containing:

Genetically engineered interferon Alfa-2, ME 500000
Ketoconazole or fluconazole), g0,2
Antioxidant:
Butylacetyl, g0,0003
Pharmaceutically acceptable
targeted supplements, gthe rest of it.

Suppositories were administered vaginally 2 times a day for 7 days. On the 2nd day started fading pain, decreased temperature, to 5 days of treatment disappeared pathological discharge from the genital tract. Conducted after 7 days from the beginning of the drug culture in the presence of smear vaginal discharge C.albicans gave a negative result. The absence of clinical symtomatic combined with the normalization of the immune system. The patient was tracked during the year. Recurrence no.

Example 2. Patient K., 28 years. After prolonged use of broad-spectrum antibiotics are complaints of nausea, flatulence, diarrhea. When cultural study of the feces was established that the presence in the composition of intestinal microflora fungi C.albicans in Association with strains of Staphylococcus and Klebsiella with high diagnostic titers. Diagnosed with Candida intestinal dysbiosis. The patient is recommended rectal suppositories, containing:

Genetically engineered interferon Alfa-2, IU/g500000
Ketoconazole or fluconazole), g0,1
Vitamins:
vitamin E, g0,06
vitamin C, g0,015
Antioxidant:
butylacetyl, g0,0003
Pharmaceutically acceptable
targeted supplements, gthe rest of it.

Suppositories were administered rectally 1 time a day for 5 days. The disappearance of the subjective sensations of the patient has already occurred on the first day of application of therapeutic agent. Held on the fifth day from the beginning of treatment culture study showed there was no Kale patient fungi C.albicans in Association with Staphylococcus aureus. Diagnostic titer of the microorganism Klebsiella sp. after treatment, consistent with the normal balance of microflora that inhabit the human gut.

Thus, the data presented demonstrate the importance of the qualitative and quantitative composition of the claimed therapeutic agent.

Compared with the prototype of the claimed therapeutic agent has a higher efficiency and a wider range of actions as part of the means of alpha-interferon can reduce the side effects of antimycotics, it has antiviral and antibacterial activity. The distinctive properties of therapeutic agents allow it to be used simultaneously in order and antifungal prophylaxis in patients with reduced protective forces of an organism resulting from long-term assignment of certain drugs (broad-spectrum antibiotics, corticosteroids, immunosuppressants).

Use of the claimed therapeutic agents in complex therapy of combined fungal infections makes it highly economical, since it allows to achieve the desired therapeutic effect when you use one instead of several drugs, containing smaller amounts of antimycotics than in the case of the prototype.

Table 1.
Genetically engineered interferon Alfa-2, IU/g5-50000
Ketoconazole or fluconazole), g0,01-0,2
Vitamins:
vitamin E, g0,0001-0,001
methionine, g0,0001-0,001
Antioxidant:
citric acid, g0,0001-0,001
Stabilizer:
albumin si is oratory human is 0.0002-0,005
glycerin0,2-2
benzoic acid0,0001-0,001
sodium tetraborate0,001-0,01
ethyl alcohol0,001-0,1
Pharmaceutically acceptable
targeted supplements, gthe rest of it.

Table 2.
Genetically engineered interferon Alfa-2, IU/g5-50000
Ketoconazole or fluconazole), g0,01-0,2
Vitamin:
vitamin E, g0,04-0,06
Pharmaceutically acceptable
targeted supplements, gthe rest of it.

Table 3.
Genetically engineered interferon Alfa-2, IU/g150000-3000000
Ketoconazole or fluconazole), g0,01-0,2
Vitamins:
vitamin E, g0,04-0,06
vitamin C, g0,015-0,025
Antioxidant:
butylacetyl, g0,0001-0,001
Pharmaceutically acceptable
targeted supplements, gthe rest of it.

Table 4.
Genetically engineered interferon Alfa-2, ME150000-3000000
Ketoconazole or fluconazole), g0,2-0,4
Antioxidant:
Butylacetyl, g0,0001-0,001
Pharmaceutically acceptable
targeted supplements, gthe rest of it.

The list of references.

1. Bryukhanova L.K. and other Pediatrics, 1982, No. 7, p.55-57.

2. Bugaev, NP and others In kN.: Viral hepatitis. M., 1987, s-173.

3. Gadzhialieva MM Pathogenetic basis of application of preparations of interferon - (Viferon) for pyelonephritis in children. The dissertation on competition of a scientific degree of candidate of medical Sciences. M., 2001, pp.92-98.

4. Linnik L. F., and others In kN.: Experimental studies in ophthalmology. M., 1986, p.132-134.

5. Malinovskaya CENTURIES and other Issues of Virology, 1989, No. 2, s-183.

6. Parfenov CENTURIES and other Antibiotics and chemotherapy, 1990, t.35, No. 9, ñ.38-41.

7. Description remedy. RU, patent 2187332 C1, a 61 K 38/21, 2002

8. Drugs in Russia: a Handbook. M., 2004, 1488 S.

1. A therapeutic agent for the treatment is of candidomycosis, containing ketoconazole and pharmaceutically acceptable additives target made in the form of ointment, gel, rectal or vaginal suppository, characterized in that it contains ketoconazole in an amount of 0.01-0.4 g per 1 g of the agent, and optionally contains alpha-interferon, provided that if the tool is made in the form of ointments and gels, alpha-interferon is contained in the number 5-50000 IU/g, and if the tool is made in the form of rectal and vaginal suppositories, number 150000-3000000 IU/g

2. A therapeutic agent for the treatment of mycosis containing fluconazole and pharmaceutically acceptable additives target made in the form of ointment, gel, rectal or vaginal suppository, characterized in that it contains fluconazole in an amount of 0.01-0.4 g per 1 g of the agent, and optionally contains alpha-interferon, provided that if the tool is made in the form of ointments and gels, alpha-interferon is contained in the number 5-50000 IU/g, and if the tool is made in the form of rectal and vaginal suppositories, number 150000-3000000 IU/g

3. A therapeutic agent according to claim 1, characterized in that it additionally contains vitamins, selected from the group of vitamin E and vitamin C in the amount of 0.0001-0.06 g per 1 g of product.

4. A therapeutic agent according to claim 2, characterized in, is that it additionally contains vitamins, selected from the group of vitamin E and vitamin C in the amount of 0.0001-0.06 g per 1 g of product.

5. A therapeutic agent according to claim 3 or 4, characterized in that as the vitamin E it contains alpha-tocopherol.

6. A therapeutic agent according to claim 3 or 4, characterized in that the quality of the vitamin C it contains ascorbic acid.

7. A therapeutic agent according to claim 3 or 4, characterized in that the quality of the vitamin C it contains calcium salt of ascorbic acid.

8. A therapeutic agent according to claim 1 or 2, characterized in that it further comprises the amino acid methionine as an antioxidant and detoxifying agent in the amount of 0.0001-0.001 g to 1 g of product.

9. A therapeutic agent according to claim 1 or 2, characterized in that it additionally contains a stabilizer biological, physico-chemical properties selected from the group of: albumin human serum, glycerol in amount is 0.0002 to 0.2 g per 1 g of product.

10. A therapeutic agent according to claim 1 or 2, characterized in that it further comprises a biasing resistance to microbial contamination, selected from the group: sodium tetraborate, ethyl alcohol in a quantity of 0.0001 to 0.1,

11. A therapeutic agent according to claim 1 or 2, characterized in that as a pharmaceutically acceptable target additives it contains one or more ingredients from the group of additives, including soklin, tallow, cocoa mass is about, petrolatum, lanolin, polyethylene oxide, carboxymethyl cellulose, peach oil.

12. A therapeutic agent according to claim 1 or 2, characterized in that it additionally contains an antioxidant: citric acid or butylacetyl in the amount of 0.0001-0.001 g to 1 g of product.

13. A therapeutic agent according to claim 1 or 2, characterized in that it further comprises an antimicrobial agent: benzoic acid in an amount of 0.0001-0.001 g to 1 g of product.

14. A therapeutic agent according to claim 1, characterized in that its dosage form in the form of a vaginal suppository contains a buffer mixture, supporting the pH of the suppository of 3.0 to 5.0.



 

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6 cl, 6 dwg, 9 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

The invention relates to benzimidazole derivative of the formula (I)

or its pharmaceutically acceptable salt, where Rrepresents a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents a group of formula-CO2R2where R2is hydroxyalkyl, alkoxyalkyl or toolboxitem, Rrepresents a group of the formula

where o is 0 or 1, n is 0, 1 or 2, X represents N or CH, Y is O, NR11or CHR11where R11represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl, or acyl, or a group of the formula -(alkyl)p-CN, -(alkyl)p-aryl, -(alkyl)p-O-aryl, -(alkyl)p-O-aralkyl, -(alkyl)p"heterocycle", -(alkyl)p-CO2"heterocycle" or -(alkyl-CO2)s-(alkyl)t-COR5and , in these formulas, R, s and t independently of each other 0 or 1, "heterocycle" represents a 5 the n heteroatom, represents a nitrogen, oxygen or sulfur, and which may substituted once or more than once, by substituents selected from the group consisting of halogen, alkyl and oxo, R5represents a hydroxy, alkoxy, hydroxy-C1-8-alkoxy, C1-8-alkoxyalkane, Tiltonsville, aryl, or aralkyl, or a group of the formula-NR6R7or-O-alkyl-NR6R7and , in these formulas, R6and R7independently of one another represent hydrogen or alkyl, and R14and R15independently of one another represent hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, carboxyl or acyl; or where R' is a group of formula -(ALK)q-R1where (ALK) represents alkyl, alkenyl or quinil, q is 0 or 1, R1represents fornillo group; and Rrepresents -(alkyl)m-CO2R8where m is 0 or 1, R8represents a group of formula -(alkyl)p-NR9R10where R is 0 or 1, and R9and R10together with the nitrogen atom to which they are attached, form a piperazinilnom group, possibly substituted by acyl

The invention relates to new arylpiperazine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, esters, where Y is O; Q is CH; X, Z and Z' each independently represent CH or N; m=0-1; n=0-4; R1and R2independently selected from H, F, Cl, Br, OCH3OC2H5, OCH2CF3CH3WITH2H5, CF3isopropylate; R3represents H; R4and R5represent H or phenyl, except that R1represents H, R2represents H, Cl or CF3, R3, R4and R5=N, Y=0, and Q=CH, if m=0 and n=1; and also except that R1represents H, R2is OCH3, R3, R4and R5=H, Y=0, Q=CH, if m=0 and n=2

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc
The invention relates to medicine, namely to the treatment of infectious diseases, and for the treatment of recurrent herpes

The invention relates to medicine, in particular tuberculosis and for the treatment of drug-resistant tuberculosis

FIELD: medicine, gynecology.

SUBSTANCE: one should carry out intrauterine photohemotherapy with the help of special equipment for 45-50 min, 5 seances. Moreover, for interrupting acute manifestations of vaginal candidosis it is necessary to conduct therapy with antimycotic preparations once daily for 3 d, and since the 3d-4th d one should perform intrauterine photohemotherapy every other day at the mode "II", after photohemotherapy it is useful to continue antimycotic vaginal therapy for 3 d more. For treating chronic, relapsing forms of vaginal candidosis therapy with antimycotic preparations should be fulfilled locally every other day by alternating it with intrauterine photohemotherapy at modes "II" and "III". In 1.5-2 mo after the course of therapy it is suggested to carry out repeated course of intrauterine photohemotherapy at the mode "III", every other day, 5 seances.

EFFECT: higher efficiency of therapy.

1 cl, 1 ex

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