RU2538703C2 - Pharmaceutical composition for treating vaginal candidiasis and method for preparing it - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: as an active substance, the composition contains butoconazol, a base that is a combination of a hydrophobic ingredient, a hydrophilic ingredient and an emulsifier, and also a gel-forming polymer. Hydroxypropylstarch phosphate is preferentially used as the gel-forming polymer. A method for preparing the declared composition consists in the fact that a mixture of butoconazol with a portion of the hydrophilic ingredient, the hydrophobic ingredient and emulsifier is added with a dispersion of the gel-forming polymer in the rest of the hydrophilic ingredient; the produced mixture is agitated homogenously with a preserving agent added where it might be necessary.

EFFECT: new pharmaceutical composition is characterised by a high level of antifungal activity, stability both at a storage temperature, and at a use temperature, and good pack extrusion.

14 cl, 2 tbl, 10 ex

Description

The invention relates to medicine and relates to a pharmaceutical composition in the form of a vaginal cream containing a highly effective active substance of antifungal action, and is suitable for the treatment of gynecological diseases.

Vaginal candidiasis (VK) is one of the most common diseases affecting up to 75% of women of childbearing age. The wide spread of vaginal candidiasis is associated with exposure to a woman's body of various environmental factors, a change in the environmental situation, the widespread use of antibiotics and their interaction, which leads to a decrease in the immunological activity of the body.

The drugs used in the treatment of VK are intended for both local and / or systemic use.

Systemic antifungal therapy is prescribed in case of a pronounced clinical picture of VC, a chronic course of the disease, resistance to local therapy, and immunodeficiency (HIV infection). The most effective systemic drugs are azole compounds: fluconazole and itraconazole.

In the uncomplicated course of VK, systemic drugs are used (fluconazole 150 mg once, itraconazole 200 mg 2 times a day for 3 days).

In cases of complicated course of VK, the course of therapy should be doubled, while the duration of use of topical drugs should be 14 days. Systemic antimycotics in all cases of recurrent VC are recommended as the main course of therapy.

In recent years, there has been a decrease in the sensitivity of opportunistic microorganisms to antimycotics. In this regard, new pathogenetically substantiated methods for the treatment of VK and mixed bacterial-fungal infections of the vagina, including the local use of antiseptics, are being developed. Although self-medication with systemic antimycotics is becoming increasingly popular, local therapy remains the most sought-after and safe treatment method.

Among the currently available topical antifungal agents are vaginal suppositories / balls or tablets, as well as special vaginal creams. The choice of a drug in each case should depend on the severity of the clinical course of vaginal candidiasis, the presence of mixed infection, concomitant pathology, predisposing factors.

Active substances include, as a rule, imidazole or polyene antimycotics. The latter include various preparations of nystatin and natamycin. Among imidazoles, clotrimazole preparations are most often used. In addition, there are vaginal forms of mionazole, econazole, isoconazole, omoconazole and other imidazole derivatives. Imidazoles remain the drugs of choice for the treatment of vaginal candidiasis. However, it is recognized that 50% of patients discontinue treatment after experiencing symptom relief. To increase adherence to the treatment regimen, doctors developed a tendency to reduce the time of drug use, and, as a result, miconazole treatment with nitrate and clotrimazole were shortened from the initial 14 days to 7 and 3 days.

Butoconazole nitrate is of interest because of its very acceptable safety profile and proven clinical efficacy. Butoconazole nitrate, an imidazole derivative, has fungicidal activity against fungi Candida, Trichophyton, Microsporum, Epidermophyton and some gram-positive bacteria. Most effective for candidiasis. By blocking the formation of ergosterol from lanosterol in the cell membrane, it increases the permeability of the membrane, which leads to the lysis of the fungal cell. The analyzes showed a wide range of its antifungal effects: it consistently showed high activity against the most important eight varieties of Candida, not belonging to the class albicans. Butoconazole was superior to imidazoles currently used (miconazole, clotrimazole, ketoconazole, terconazole) when inhibiting the growth of C. albicans and Candida pathogenic species not belonging to the genus albicans.

RU 2320322 describes a vaginal drug delivery system with an almost neutral pH value, comprising an emulsion with an almost neutral pH value, containing globules having two phases: an internal water-soluble phase and an external water-insoluble phase or film. The delivery system includes a therapeutically active drug, which is an antifungal agent selected from the group consisting of butoconazole nitrate, clotrimazole, ketoconazole nitrate, miconisole, polyene antifungal drugs, and others. However, the known composition is characterized by a rather complicated manufacturing technology.

In the patent of the Russian Federation No. 2379027 a composition is described which is an emulsion with a high content of a dispersed phase, comprising an active substance, 4.0 wt.% Or less propylene glycol, one or more pharmaceutically acceptable excipients that promote the release of the active substance in the vaginal cavity. A delivery system in the form of a cream with butoconazole nitrate (2% content) is specifically described. The known composition is intended for the treatment of fungal infections of the vaginal cavity of a woman. As an example of a delivery system, a composition is described that includes an active ingredient (butoconazole nitrate), a hydrophobic component (mineral oil, microcrystalline wax, hydrophobic silicon dioxide), a hydrophilic component (propylene glycol, water, an aqueous solution of sorbitol), an emulsifier (glyceryl monoisostearate, polyglyceryl-3 oleate), preservative (methylparaben, propylparaben).

US20110251141 describes a pharmaceutical composition comprising a combination of the antifungal component of butoconazole or a salt thereof and another active ingredient (clindamycin phosphate, metronidazole). As auxiliary ingredients, the known composition contains a hydrophobic component (mineral oil, microcrystalline wax), a hydrophilic component (water, an aqueous solution of sorbitol), an emulsifier (glyceryl monoisostearate, PEG-30 dipolyhydroxystearate), a preservative (methyl paraben, propyl paraben). However, the known compositions do not provide sufficient prolongation of the action of the active ingredient of butoconazole nitrate, as is achieved by the well-known composition of butoconazole [Vidal Handbook. Medicines in Russia: A Handbook. M .: AstraFarmService, 2007, p. 1003, Ginofort preparation]. In the known composition, the prolongation of the action of the drug is achieved by a hydrophobic base, which provides high adhesion (stickiness) to the walls of the vagina, as a result of which the cream does not leak from it for several days. However, this composition has significant negative aspects: firstly, the drug is very difficult to wash from the vagina; secondly, butoconazole is in this base in the form of a suspension; this requires the use of micronized powder of butoconazole, otherwise large particles with a size of 100-250 microns are present in the suspension, and the drug does not always withstand the test for homogeneity according to the State Pharmacopoeia; thirdly, it is very difficult to wash production equipment from such a composition.

The objective of the present invention is to create a pharmaceutical composition in the form of a vaginal cream containing an antifungal substance (butoconazole nitrate), on a modified basis, which ensures the effectiveness and duration of action of the drug, as well as the development of a method for producing the composition.

To solve this problem, a pharmaceutical composition is proposed that includes butoconazole or its salt in an effective amount as an active ingredient, and a base that is a combination of hydrophobic and hydrophilic components and an emulsifier, characterized in that it additionally contains a gel-forming polymer and does not contain another active ingredient.

Butoconazole belongs to the imidazole group. It has fungicidal activity against fungi Candida, Trichophyton, Microsporum, Epidermophyton and some gram-positive bacteria. In a preferred embodiment, the composition comprises butoconazole in the form of a nitrate. Preferably, the composition contains 2 g / per 100 g of butoconazole composition.

In a preferred embodiment, the composition has the following ratio of components, g / 100 g of the composition:

Butoconazole Nitrate 1.0-3.0, Gelling polymer 2.0-14.0 The basis Rest

As the gelling polymer, a cellulose derivative is used, for example methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose or modified starch, for example hydroxypropyl starch phosphate, or various red cross-linked copolymers Pemulen. " “Carbopolis homopolymers” are polymers of acrylic acid with allyl sucrose or allyl pentaerythritol. “Carbopol copolymers” and “Pemulenes” are acrylic acid polymers modified with a long chain (C10-C30) of alkyl acrylates and crosslinked with allyl pentaerythritol, preferably a gelling polymer in an amount of g / 100 g of the composition: 3-12. It is preferable to use phosphate as the gelling agent of hydroxypropyl starch in an amount of, preferably g / 100 g of the composition: 6-9.

The introduction of a gelling polymer into the composition promotes the formation of a stable cream both at storage temperature (25 ° C) and at application temperature (37 ° C). At the same time, the selected concentration of the substance provides the necessary rheological properties of the cream and preserves the consistency even when the temperature rises to 40 ° C. At the same time, the composition is stable during storage and good extrusion of the finished dosage form from the package (tube), which is very important for the convenience of patients.

As a carrier base, a modified hydrophilic base is proposed, represented by an emulsion of the first kind, which in combination with a water-soluble polymer provides a gel-like consistency at body temperature and bioadhesion of the drug to the vaginal mucosa, which prevents its flow. Preferably, the base has the following composition, g / per 100 g of composition:

Hydrophobic component 3.0-17.0 Hydrophilic component 50.0-90.0 Emulsifier 3.0-15.0

Isopropyl myristate, which is a solvent of butoconazole, more preferably in the amount of 6-9 g / 100 g of the composition, isopropyl palmitate, cetostearyl isonanoate may also be used as a hydrophobic component in the composition, the following excipients may be used instead or in combination with them: octyl dodecanol , ethylhexyl octanoate, cocoyl caprylocaprate, oleyl oleate.

The hydrophilic component is preferably a combination of propylene glycol and water, which more preferably contains a pH corrector. Alternatively, other polyhydric alcohols can be used, such as glycols, for example, butylene glycol, glycerin, macrogols, in particular polyethylene oxides of the general formula H (O-CH2-CH2) _n OH, preferably polyethylene oxides with an average molecular weight of 375-6000, more preferably with an average molecular weight 1000-4000, or mixtures of these compounds. To adjust the pH, alkali metal hydroxides are used, preferably sodium hydroxide, amines, for example trometamol or diethylamine, can also be used.

The preferred ratio of the components of the hydrophilic component, g / 100 g of the composition:

Propylene glycol 2.0-15.0 PH corrector up to pH 3.5-6.5 Purified water 48.0 - 75.0

Preferably, the pH of the composition is in the range of 4.5-6.5, due to which butoconazole is in the composition in dissolved form, which ensures uniform distribution in the mass, and also increases its effectiveness.

To ensure colloidal stability of the emulsion, emulsifiers of the 1st and 2nd kind are introduced into the composition, the total content of which is more preferably from 3.7 to 12.3 g / 100 g of the composition. In this case, macrogol 20 cetostearyl ether and cetostearyl alcohol are preferably used in the following ratio, g / 100 g of the composition:

Macrogol 20 cetostearyl ether 1-3,5 Cetostearyl alcohol 4.7-6.8

In a preferred embodiment, the composition comprises a preservative. One of the conditions that determine the quality and safety of drugs for local use is the effectiveness of antimicrobial preservatives. As antimicrobial preservatives, methyl parahydroxybenzoate, propyl parahydroxybenzoate, phenoxyethanol are used in an amount of 0.3-1.0 g / 100 g of the composition. Preferably, phenoxyethanol in an amount of 0.45-0.9 g / 100 g of the composition. Preferably in combination with ethylhexylglycerin, which increases the antimicrobial activity of phenoxyethanol. Preferably in a ratio of 9: 1.

The claimed ratio of ingredients found experimentally and is optimal.

The proposed pharmaceutical composition is in the form of a soft dosage form, preferably in the form of an emulsion gel cream, and is a complex dispersed system that is both an emulsion (oil / water) and a solution (relative to the active ingredient). The proposed composition is characterized by a uniform distribution and a minimum particle size of the hydrophobic component of the emulsion.

The introduction of butoconazole ensures the simultaneous achievement of antifungal and antibacterial action. As already noted, butoconazole is present in the composition in dissolved form, which ensures uniform distribution in the mass, and also increases the effectiveness of the therapeutic effect.

Pharmacological studies have shown that the proposed composition is not inferior to the comparison drugs in the effectiveness of the therapeutic effect. The results of a study of the antimicrobial activity of the inventive cream with butoconazole by diffusion into agar are shown in table 1.

Table 1 Microorganism test Diameter of growth inhibition zones (mm) S. aureus ATCC 6538 P 10.60 ± 0.11 S. aureus 1925 11.05 ± 0.10 S. aureus 1722 10.10 ± 0.04 S. aureus 620 9.70 ± 0.04 S.saprophyticus ATCC 15305 11.08 ± 0.10 M.luteus ATCC 9341 11.40 ± 0.13 C.xerosis 1911 12.15 ± 0.14 C.albicans ATCC 885-653 20.88 ± 0.06 C.tropicalis VKPGu-547 / Y-1003 19.80 ± 0.27 C.pseudotropicalis VKPGu-601/33 22.43 ± 0.29 C.parapsilosis VKPGu-488/10 22.58 ± 0.24 C.neoformans VKPGu-881 / VKMu-753 17.03 ± 0.08

The antifungal effect of the claimed composition was observed in relation to all strains of yeast-like fungi used in experimental studies.

The acute, subacute toxicity, locally irritating and sensitizing effect of this composition with butoconazole nitrate was studied.

The results of the study of acute toxicity indicate that with an intravaginal route of administration to female rats at a dose of 12.0 g / kg, the developed composition does not have a toxic effect on the general condition and dynamics of body weight of animals, does not cause changes in biochemical parameters of blood serum, does not change the relative mass of internal organs rats.

The results obtained in a subacute experiment (within two weeks) indicate that intravaginal administration of the developed composition to rats in doses of 2.0 g / kg and 4.0 g / kg does not have a toxic effect on the general condition, behavior, weight gain of animals, on the electrophysiological activity of the myocardium, peripheral blood counts, the functional state of the central nervous system, liver and kidneys of rats.

According to the results of pathomorphological studies, it was found that a cream with butoconazole during subacute exposure does not change such an indicator as the relative mass of the internal organs of rats. After exposure to the test drug, there are no morphological signs of damage to the vital organs of animals.

Vaginal cream 2% does not show a locally irritating effect, which is histologically confirmed, and does not have a sensitizing effect.

The choice of ingredients and their ratio significantly affects the method of obtaining the drug.

A method of obtaining the claimed composition is that a dispersion of a gel-forming polymer in the remaining part of the hydrophilic component is added to the mixture of butoconazole with a part of the hydrophilic component, the hydrophobic component and the emulsifier and the resulting mixture is mixed until homogeneous, adding a preservative if necessary. In a preferred embodiment of the method, a solution of butoconazole is prepared in an emulsion obtained by adding emulsifiers and a hydrophobic component to a mixture of butoconazole and propylene glycol. It is more preferable to adjust the pH of the resulting emulsion to prevent crystallization of the active substance during production and storage.

A typical example. The active ingredient (butoconazole nitrate) is mixed with propylene glycol at a temperature of 65-75 ° C and an emulsifier (combination of macrogol 20 cetostearyl ether and cetostearyl alcohol), a hydrophobic component (isopropyl myristate) are added, if necessary, adjust the pH (10% sodium hydroxide solution), mix thoroughly and added to the dispersion of a gel-forming polymer (hydroxypropyl starch phosphate in water), homogenized. Then a preservative is added, homogenized and the resulting cream is cooled to room temperature. A homogeneous cream of white or almost white color is obtained, which is packaged in tubes.

Specific embodiments of the invention are presented in table 2. In examples 4-6, hydroxypropyl methylcellulose is used as a gelling polymer, in examples 7.8, carboxymethyl cellulose and in examples 9-10, hydroxypropyl cellulose. In examples 2, 7, isopropyl palmitate is used as a hydrophobic component, in examples 3 and 9, cetostearyl isonanoate is used, and in example 4, a combination of isopropyl myristate and octyldodecanol is used in equal proportions. In example 2, butylene glycol is used instead of propylene glycol and potassium hydroxide is used as a pH corrector, polyethylene glycol (polyethylene oxide 6000) is used in example 3 and trometamol is used as a pH corrector. Obtained in examples 1, 2, 3, 4, the pharmaceutical composition meets the regulatory requirements (in appearance, uniformity, microbiological purity and other indicators), is stable during storage and has a shelf life of more than 2 years.

table 2 Ingredients Content, g / per 100 g of composition Examples one 2 3 four 5 Butoconazole Nitrate 2.0 1,0 2.0 3.0 2.2 Gelling polymer 8.0 2.0 14.0 13.0 6.0 Hydrophobic component 3.0 6.0 17.0 8.0 9.0 Hydrophilic component 78.0 82.5 51.0 70.1 74.22 Emulsifier 8.0 8.0 16,0 5.5 7.8 Preservative 1,0 0.5 - 0.4 0.78 Ingredients Content, g / per 100 g of composition Examples 6 7 8 9 10 Butoconazole Nitrate 1.85 1,0 2.05 2.15 2 Gelling polymer 8.8 2.0 13.0 6.8 7.7 Hydrophobic component 6.5 4.0 8.3 8.7 7.8 Hydrophilic component 73.86 90.0 82.82 68.18 73.83 Emulsifier 8.1 3.0 7.8 8.1 8.0 Preservative 0.89 - 0.67 0.5 0.67

Claims (14)

1. The pharmaceutical composition in the form of a soft dosage form, which includes as an active substance butoconazole or its salt in an effective amount and a base, which is a combination of a hydrophobic component, a hydrophilic component and an emulsifier, characterized in that it further comprises a gelling polymer and does not contain another active ingredient . 2. The pharmaceutical composition according to claim 1, characterized in that it contains nitrate as the active substance of butoconazole. 3. The pharmaceutical composition according to claim 2, characterized in that it contains ingredients in the following ratio, g / 100 g of the composition:
Butoconazole Nitrate 1.0-3.0 Gelling polymer 2.0-14.0 The basis Rest 4. The pharmaceutical composition according to claim 3, characterized in that it contains the ingredients of the base in the following ratio, g / 100 g of the composition:
Hydrophobic component 3.0-17.0 Hydrophilic component 50.0-90.0 Emulsifier 3.0-16.0 5. The pharmaceutical composition according to claim 4, characterized in that it contains propylene glycol, water and a pH corrector as a hydrophilic component. 6. The pharmaceutical composition according to claim 5, characterized in that it contains propylene glycol, water and a pH corrector in the following ratio, g / per 100 g of composition:
Propylene glycol 2.0-15.0 Purified water 48.0-75.0 PH corrector Up to pH 3.0-6.5 7. The pharmaceutical composition according to claim 6, characterized in that it contains isopropyl myristate as a hydrophobic component. 8. The pharmaceutical composition according to claim 7, characterized in that it contains, as an emulsifier, a combination of macrogol 20 cetostearyl ether and cetostearyl alcohol. 9. The pharmaceutical composition according to claim 8, characterized in that it contains macrogol 20 cetostearyl ether and cetostearyl alcohol in the following ratio, g / 100 g of composition:
Macrogol 20 cetostearyl ether 1-3,5 Cetostearyl alcohol 4.7-6.8 10. The pharmaceutical composition according to claim 1, characterized in that it further comprises a preservative. 11. The pharmaceutical composition of claim 10, characterized in that it contains as a preservative a combination of phenoxyethanol and ethylhexylglycerol. 12. The pharmaceutical composition according to claim 11, characterized in that it contains phenoxyethanol and ethylhexylglycerol in a ratio of 9: 1. 13. The method of obtaining the composition described in claims 1-12, wherein a dispersion of a gel-forming polymer in the remaining part of the hydrophilic component is added to a mixture of butoconazole with a part of the hydrophilic component and an emulsifier and the resulting mixture is mixed until homogeneous, adding a preservative if necessary. 14. The method according to item 13, in which butoconazole nitrate is mixed with propylene glycol and an emulsion of butoconazole nitrate is obtained in the presence of a pH corrector.