RU2695995C1 - Vaginal suppository for treating infectious-inflammatory vaginal diseases, and a method for preparing - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutics, namely to a vaginal suppository for treating infectious-inflammatory diseases of the vulva and vagina, particularly vulvar and vaginal diseases caused by Candida fungi, for example, vaginal and vulvovaginal candidiasis, where said vaginal suppository containing an active ingredient – sodium tetraborate, dispersed in the base – fat, which is solid at room temperature, which is a mixture of triglycerides, diglycerides and medium-chain (C₁₆-C₁₈) monoglycerides of fatty acids with hydroxyl number of 40 to 50 mg KOH/g, as well as an emulsifier – polyoxyethylene (20) sorbitan monooleate and an additive preventing melting temperature reduction and time of complete suppository deformation – distilled monoglycerides, and to a method of such suppository manufacturing.

EFFECT: providing a convenient, safe in use and storage stable dosage form of sodium tetraborate providing in its medical application uniform distribution of the drug on the vaginal mucosa.

13 cl, 5 ex, 4 tbl, 1 dwg

Description

Field of Technology:

The present invention relates to the field of medicine and pharmaceuticals, and more particularly, to a vaginal suppository for the treatment of infectious and inflammatory diseases of the vagina associated with excessive growth of infectious fungal pathogens, including Candida spp. and others, and to a method of manufacturing such a suppository.

The prior art:

Infectious and inflammatory diseases of the vagina are a widespread problem. Among infectious and inflammatory diseases of the vagina, candidiasis is of great clinical importance, including vaginal and vulvovaginal candidiasis caused by Candida spp. - a yeast-like fungus that lives in the oral cavity, in the small intestine, on the mucous membrane of the genitals, urinary structures, esophagus and larynx, which normally does not cause pathological conditions in humans, but with a decrease in immunity, which becomes the cause of candidiasis, in particular, vaginal candidiasis. Currently, there is a tendency to increase the incidence of long-term, recurring forms of vaginal and vulvovaginal candidiasis. It was shown that most women at some stage in their life become infected with Candida spp., While 20% of women are asymptomatic carriers of Candida spp., And chronic candidiasis develops in 5-10% of cases (Kongurov N.V., Gerasimova N.M., Vishnevskaya I.F. Actual problems of treatment of urogenital candidiasis // Obstetrics and Gynecology, 2005, No. 4, pp. 50-53; Prilepskaya VN, Bayramova GP Vaginal candidiasis: etiology, clinic, diagnosis, principles therapy. // "Contraception and health", 2002, No. 1, S. 3-8). The most clinically significant pathogen is Candida albicans (also referred to below as C. albicans or simply “mushroom”), however, infection with other Candida species, such as Candida glabrata, Candida tropicans, Candida pseudotropicans, Candida krusei, can also lead to vaginal candidiasis. Candida parakrusei, Candida parapsilosis and Candida guillermondi. Among all the listed Candida species, C. albicans is characterized by the most pronounced enzymatic activity, which is manifested by the ability of C. albicans to produce proteolytic and lipolytic enzymes. This ensures a high adhesive ability of C. albicans and its deep penetration into the cells of the vaginal mucosa (Prilepskaya V.N., Bayramova G.P. Vaginal candidiasis: etiology, clinic, diagnosis, treatment principles. // "Contraception and health", 2002 , No. 1, p. 3-8).

One of the drugs used to treat infectious and inflammatory diseases of the vagina, such as vaginal candidiasis, vaginitis and vulvovaginitis, in particular vaginitis and vulvovaginitis associated with excessive growth of Candida, is sodium tetraborate (Na ₂ B ₄ O ₇ ) - boric sodium salt acid that is readily soluble in glycerol, usually used in the form of pentahydrate (Na ₂ B ₄ O ₇ · 5H ₂ 0) or decahydrate (Na ₂ B ₄ O ₇ · 10H ₂ 0) (hereinafter all three forms are referred to as “sodium tetraborate” for brevity "). Sodium tetraborate is an antiseptic with bacteriostatic and fungistatic activity, effective in candidiasis of the mucous membranes.

A solution of sodium tetraborate in glycerin is well known in the art ("Sodium tetraborate. Solution for local use 20%" - "Register of Russian Medicines", 11/13/2013, URL: https://www.rlsnet.ru/tn_index_id_4830.htm) used to treat infectious and inflammatory diseases of the vagina associated with excessive growth of Candida fungi, including for the treatment of vaginal candidiasis. A solution of sodium tetraborate in glycerin is applied topically by wetting with a specified solution of a cotton swab, followed by treatment with a specified cotton swab of the affected areas of the mucous membrane of the vulva and vagina. The sodium tetraborate solution used in this way removes the mycelium of the fungus from the mucous membranes, disrupts the process of attachment of the fungus to the mucous membranes and inhibits its reproduction.

A solution of sodium tetraborate, as well as solutions of other antiseptic drugs used topically to treat vaginal candidiasis, is rapidly eliminated from the surface of the mucous membrane, as a result, the total time of interaction of the drug with the vaginal mucosa decreases. In addition, among the drawbacks of the sodium tetraborate solution, it is worth noting the low accuracy of the dosage of the active substance, as well as the uneven distribution of the vaginal mucosa due to the areas that are difficult to process with a cotton swab located in the crypts of the vaginal mucosa. The presence of such inaccessible areas of the mucosa makes it necessary to repeatedly treat the affected areas, while, preferably, such treatment should be carried out by medical personnel, and not by the patient herself, which may create additional obstacles to the regular use of this drug. Otherwise, the fungal mycelium can persist in the crypts of the vaginal mucosa, which subsequently leads to a relapse of the disease.

In this regard, the urgent task of providing topical agents for the treatment of infectious and inflammatory diseases of the vulva and vagina, primarily for the treatment of infectious and inflammatory diseases of the vulva and vagina associated with excessive growth of Candida, which would ensure uniform distribution of the drug throughout the vaginal mucosa and the high bioavailability of the active substance of suppositories.

This problem can be fundamentally solved using such a topical dosage form as vaginal suppositories (Tikhonov A.I., Yarnyh T.G. "Drug Technology" (textbook for students of pharmaceutical universities and faculties; translated from Ukrainian), edited academician of the Academy of Sciences of Ukraine A.I. Tikhonov, NFAA publishing house, Golden Pages, 2002, pp. 408-410; hereinafter referred to as Tikhonov A.I., Yarnyh T.G., 2002). By definition, suppositories are a solid dosage form at room temperature containing one or more active substances, dissolved or dispersed in a suitable basis, intended for administration into the body cavity and melting (dissolving, disintegrating) at body temperature when introduced into the body cavity ( The State Pharmacopoeia of the Russian Federation of the XIII edition (hereinafter referred to as the State Pharmacopoeia of the Russian Federation XIII), OFS 1.4.1.0013.15 "Suppositories").

It is known from the prior art that Vakos XT (Czech Republic), a topical agent for the treatment of vaginal diseases associated with excessive growth of vaginal microflora - Candida fungi, is made in the form of vaginal balls (globules), which are a type of vaginal suppository (see: Tikhonov A.I., Yarnyh T.G., 2002, p. 408), intended for local (vaginal) use and containing 600 mg of sodium tetraborate decahydrate as the active principle ("GLOBULUS CUM NATRIO TETRABORICO 0.6 CSC. Příbalová informace: informace pro uživat ele ", 02/09/2015, URL: www.sukl.cz/modules/medication/download.php?file=PI84981.pdf&type=pi l ). A method of manufacturing these globules by the manufacturer is not disclosed. The time of complete deformation of the globules during their use, the release profile of sodium tetraborate from the globules, and the bioavailability of sodium tetraborate in these globules are also unknown.

These globules are made using a gelatin-glycerin base and contain, in addition to the specified base and active component, preservatives - methylparaben and propylparaben, as well as purified water.

Although gelatin-glycerol suppository bases are often used for the manufacture of vaginal suppositories due to their inherent mechanical plasticity, such bases have numerous disadvantages, among which, first of all, low microbiological stability and high susceptibility of such gelatin-glycerin suppository basis of microbial contamination (see. , for example: Zyubr TI, Vasiliev IB Soft dosage forms: a teaching aid. - GOU VPO IGMU Roszdrav, Irkutsk, 2008, p. 44).

In addition, gelatin-glycerin suppository bases dry out relatively quickly, liquefy and exfoliate (see ibid.). These factors further limit the possibility of using such bases for the manufacture of vaginal suppositories.

Due to the low microbiological stability of the gelatin-glycerol base, the preservatives used are parabens (derivatives of para-hydroxybenzoic acid), including methylparaben and propylparaben, in the aforementioned globules made by Vakos X.T. Parabens are widely used both in the cosmetic and pharmaceutical industries as preservatives, however, the literature has shown that they are able to induce systemic allergic reactions (immediate hypersensitivity reactions). See, for example, Nagel J.E., Fuscaldo J.T., Fireman P. Paraben allergy. // "Journal of the American Medical Association", 237: 1594-1595, April 1977. In addition, some authors have justified doubts about the safety profile and cumulative effects of parabens that may occur with regular topical use of paraben-containing products, sufficiently studied. See, for example, Karpuzoglu E., Holladay S.D., et al. Parabens: potential impact of low-affinity estrogen receptor binding chemicals on human health. // "Journal of Toxicology and Environmental Health. Part B", 16: 321-335, 2013.

It should also be noted that suppositories made using a gelatin-glycerin base, coming into contact with the mucous membrane of the vagina, absorb water from it and, thus, dehydrate the mucosa, as a result, the irritation of the mucosa only intensifies. Finally, it should be noted that the aforementioned gelatin-glycerin globules with sodium tetraborate are available only on the European market for pharmaceuticals, while they are not available on the Russian market. In this regard, the importance of expanding the arsenal of vaginal suppositories for the treatment of infectious and inflammatory diseases of the vagina, such as vaginal candidiasis, vaginitis and vulvovaginitis, in particular vaginitis and vulvovaginitis associated with excessive growth of Candida, primarily Candida albicans, is effective and safe to use and stable during storage.

It has been shown that the choice of suppository base plays a very important role in the preparation of suppositories with desired properties, for example, a given rate and completeness of release of the active substance from the suppository and a given bioavailability of the active substance (Demina NB. Modern aspects of the production of the dosage form of the suppository. // " Development and registration of medicines "-" Pharmcontract ", 2016, No. 2 (15), pp. 60-69; hereinafter - N. Demina, 2016).

An important alternative to suppositories made using a gelatin-glycerin base are suppositories made using solid fat as the basis, for example, a mixture of triglycerides, diglycerides and monoglycerides of medium chain C ₁₆ -C ₁₈ fatty acids. These mixtures are produced by various manufacturers of auxiliary components for the needs of the pharmaceutical industry, for example, Dynamit Nobel GmbH (Germany) under the trade name "Witepsol" (hereinafter also referred to as vitepsol). Directed esterification of these triglycerides, diglycerides and monoglycerides, carried out upon receipt of vitepsol, allows to obtain a number of suppository bases with desired properties (see: Loyd V. Allen Jr. Suppositories. // "Pharmaceutical Press", London, Great Britain, 2008, p . 31).

Among these commercially available mixtures, it should be noted that the most preferred mixture of triglycerides (65-80%), diglycerides (10-35%) and monoglycerides (1-5%) C ₁₆ -C medium chain fatty acids as the most preferred suppository base for the vaginal suppository of the invention ₁₈ with a hydroxyl number of 40 to 50 mg KOH / g. This mixture is sold under the trade name "Witepsol W35" (hereinafter also referred to as Witepsol W35).

Witepsol W35 is widely used as a base for suppositories (hereinafter also referred to as the “suppository base”), because, due to the high hydroxyl number of triglycerides, diglycerides and monoglycerides that make up Witepsol W35, Witepsol W35 provides high bioavailability of the active substance of suppositories. In addition, the mono- and diglycerides included in the composition of Witepsol W35 slow down the deposition of solid particles of the active substance, promote wetting of the mucous membranes and improve the bioavailability of the active substance of the suppository. Finally, one of the important advantages of Witepsol W35 is that it is characterized by a significant gap between the melting point and crystallization temperature (33.5-35.5 ° C and 27.0-30.0 ° C, respectively), and therefore Witepsol W35 is more elastic under conditions of rapid cooling and hardens more slowly compared to other suppository bases, which also makes Witepsol W35 attractive for use in vaginal suppositories as a suppository base, for example, when creating suspension type suppositories.

From an article by Blinova O.A., Kondratieva N.A., Ryuminoy T.E. and Korosteleva S.A. Biopharmaceutical studies of suppositories for the treatment of vaginal candidiasis. // "Pharmacy", 2009, No. 4, pp. 31-34 (hereinafter - Blinova O.A. et al., 2009) are known as the closest analogue of the claimed invention, vaginal suppositories for the treatment of vaginal candidiasis, containing as active substances sodium tetraborate and, optionally, the Neomycon plant extract, including extracts of calendula, chamomile, celandine, violet and common cuff, described in the prior art by Kondratieva N.A., Blinova O.A., Smirnova M.M. . and others. Development of the composition of the collection for the treatment of vaginal candidiasis. - "Medicine and Health" - Materials of the II international exhibition "Pharmacy and Health" (November 9-12, 2005), Perm, 2005, pp. 34-35 (hereinafter - O. Blinova et al., 2009 ) Vaginal suppositories according to Blinova O.A. et al., 2009 were made using Witepsol W35 or Witepsol W35 in combination with glycerin as a suppository base, or using a gelatin-glycerin base similar to the globule base manufactured by Vakos X.T. (Czech). The quantitative content of sodium tetraborate and base in vaginal suppositories, as well as the technology for producing such suppositories, according to an article by O. Blinova et al., 2009 is not disclosed.

According to Blinova O.A. et al., 2009, to improve the dispersion of sodium tetraborate in a suppository base and to obtain a stable disperse system, a T-2 emulsifier was used. Issues related to the safety of using T-2 emulsifier as part of drugs are poorly understood, and in most countries it is not approved for use as part of drugs. The correct choice of emulsifier, which provides a uniform distribution of the active substance of the suppository over the suppository mass, however, is very important for obtaining suppositories with predetermined properties (Demina NB, 2016). In addition, the work of Blinova O.A. et al., 2009 does not address the problems associated with the possible precipitation of the active substance of the suppository and with the possible cracking of the finished suppository.

Finally, Blinova O.A. et al., 2009 do not disclose the optimal quantitative ratio of sodium tetraborate and the base, as well as the optimal quantitative ratio of the base and emulsifier, while the quantitative ratio of the active substance and the base can significantly affect the properties of suppositories, in particular, the release of the active substance and its bioavailability . Thus, these factors impede the implementation of the proposed Blinova O.A. et al., 2009 Suppositories in Clinical Practice.

The objective of the present invention is, therefore, the creation of effective and convenient vaginal suppositories, safe to use and stable during storage, intended for the treatment of infectious and inflammatory diseases of the vagina, in particular for the treatment of vaginal and vulvovaginal candidiasis containing sodium tetraborate as an active substance, providing, in their medical use, a uniform distribution of the active substance over the vaginal mucosa and high bioavailability of the active still.

Another objective of the present invention is closely related to this task, the task of developing a simple and economical method of manufacturing such vaginal suppositories, which allows to obtain vaginal suppositories that are stable during storage, containing sodium tetraborate as the active substance, providing high bioavailability of the active substance.

The technical results of the invention are to provide a drug in the form of vaginal suppositories with sodium tetraborate, intended for the treatment of infectious and inflammatory diseases of the vulva and vagina, characterized by high microbiological stability, despite the absence of preservatives, and to ensure a more uniform distribution and high bioavailability of the active substance - tetraborate sodium - on the mucous membrane of the vagina with local (vaginal) use of these suppositories ev, as well as expanding the arsenal of topical preparations intended for the treatment of infectious and inflammatory diseases of the vagina, in particular, such as vaginal candidiasis, vaginitis and vulvovaginitis, in particular (without limitation), vaginitis and vulvovaginitis associated with excessive growth of Candida fungi .

The objective of the invention is solved, and the technical results are achieved through the use of a solid fat base (hereinafter also referred to as solid fat) in a vaginal suppository according to the invention, wherein a mixture of medium chain triglycerides, diglycerides and monoglycerides (C ₁₆ -C ₁₈ ) fatty is used as said solid fat acids with a hydroxyl number of 40 to 50 mg KOH / g, and also due to the inclusion of distilled monoglycerides in the composition of these vaginal suppositories as an additive, which increases the decrease in the melting temperature and the time of complete deformation of the suppository, and polyoxyethylene (20) sorbitan monooleate, hereinafter also referred to as polysorbate 80 or Tween ^® 80, as an emulsifier. The use of distilled monoglycerides in addition to the emulsifier - polysorbate 80 - further improves the technological properties of suppositories, in particular, prevents cracking of suppositories and precipitation of the active substance of suppositories.

The objective of the invention relating to a method of manufacturing a vaginal suppository is solved, and technical results are achieved due to the fact that, in accordance with the specified method, perform the following sequence of actions:

a) dissolve a weighed portion of sodium tetraborate in glycerin, previously heated to a temperature of + 50-60 ° C, followed by stirring the resulting mixture until a clear solution is obtained, followed by filtration of the resulting solution;

b) jointly melt samples of solid fat and monoglycerides distilled at a temperature of + 75-80 ° C and with constant stirring, followed by filtration of the obtained melt;

c) add to the melt obtained in step (b) a portion of polyoxyethylene (20) sorbitan monooleate, followed by stirring, thereby obtaining a mixture;

g) cool the mixture obtained in step (c) to a temperature of + 55-60 ° C;

d) combine the specified cooled mixture with the solution obtained in step (a), followed by stirring them at a temperature of + 55-60 ° C until a homogeneous suppository mass is obtained;

f) cool the suppository mass obtained in step (e) to a temperature of + 42-45 ° C with constant stirring;

g) the suppository mass cooled in step (e) is poured into molds, followed by cooling of the indicated suppository mass until it solidifies, to obtain vaginal suppositories.

After step (g), if necessary, they mark the finished vaginal suppositories (including, without limitation, the manufacturer’s logo, dosage, batch number and expiration date of the suppositories), and then pack them sequentially first in the primary and then in secondary packaging.

Thanks to the proposed method for the manufacture of vaginal suppositories, a simple, economical and efficient technology for the method of manufacturing vaginal suppositories with sodium tetraborate is provided, while this manufacturing method ensures the stability of the suppositories during their manufacture and subsequent storage.

Preferred Embodiments

According to preferred (non-limiting) embodiments of the invention, infectious and inflammatory diseases of the vulva or vagina are infectious and inflammatory diseases of the vulva or vagina caused by excessive growth of Candida fungi. More preferably (without limitation), infectious and inflammatory diseases of the vulva or vagina are infectious and inflammatory diseases of the vulva or vagina caused by excessive growth of one or more of the following species of Candida: Candida albicans, Candida glabrata, Candida tropicans, Candida pseudotropicans, Candida krusei, Candida parakrusei, Candida parapsilosis and Candida guillermondi. Preferably (without limitation), the disease can be vaginal or vulvovaginal candidiasis caused by overgrowth of one or more of the above types of Candida.

According to preferred (non-limiting) embodiments of the invention, Witepsol W is used as the base, a mixture of triglycerides, diglycerides and monoglycerides of saturated medium chain (C ₁₆ -C ₁₈ ) fatty acids with a hydroxyl number of 40 to 50 mg KOH / g. According to to the most preferred (non-limiting) embodiments of the invention, Witepsol W35 is used as the base.

Preferably, but not limited to these preferred embodiments, the vaginal suppositories according to the invention contain from 0.25 g to 0.55 g of active ingredient per 1 g of the mass of the suppository. Most preferably, but also without limitation to these most preferred embodiments, the vaginal suppositories according to the invention contain 0.268 g or 0.536 g of active ingredient per 1 g of the mass of the suppository.

It is also preferable, but not limited to these embodiments, the vaginal suppositories according to the invention contain from 0.005 g to 0.025 g of monoglycerides distilled per 1 g of the mass of the suppository. In more preferred embodiments of the invention, but without limitation to these embodiments, the vaginal suppositories according to the invention contain from 0.01 g to 0.015 g of monoglycerides distilled per 1 g of the mass of the suppository. Most preferably, but not limited to these embodiments, the vaginal suppositories according to the invention contain 0.01 g, or 0.0125 g, or 0.015 g of monoglycerides distilled per 1 g of the mass of the suppository.

Also in preferred embodiments of the invention, but without limitation to these embodiments, the vaginal suppositories according to the invention contain from 0.01 g to 0.06 g of polyoxyethylene (20) sorbitan monooleate (Tween 80) per 1 g of suppository mass. In more preferred embodiments of the invention, but without limitation to these embodiments, the vaginal suppositories according to the invention contain from 0.01 g to 0.04 g of polyoxyethylene (20) sorbitan monooleate per 1 g of suppository mass. Most preferably, but not limited to these embodiments, the vaginal suppositories according to the invention contain 0.025 g of polyoxyethylene (20) sorbitan monooleate per 1 g of suppository mass.

Finally, in preferred embodiments of the invention, but without limitation to these embodiments, the vaginal suppositories according to the invention contain from 0.40 to 0.70 g of base per 1 g of the mass of the suppository. In more preferred embodiments of the invention, but without limitation to these more preferred embodiments, the vaginal suppositories according to the invention contain from 0.424 g to 0.697 g of base per 1 g of the mass of the suppository. Most preferably, but not limited to these embodiments, the vaginal suppositories according to the invention contain 0.424 g or 0.697 g of the base per 1 g of the mass of the suppository.

The following are examples of the implementation of the present invention, intended only to illustrate the invention, but not to limit the scope of claims.

Example 1

2.68 kg of a 40% solution of sodium tetraborate in glycerin was prepared, preheated to a temperature of + 50-60 ° C, followed by continuous stirring until a clear solution was obtained. The resulting solution was filtered into a container. Samples of Witepsol W35 (2.12 kg) and distilled monoglycerides (0.075 kg) were placed in the reactor, then, having established the temperature regime (+ 76-77 ° С), they were melted with continuous stirring. The obtained melt was filtered into a vessel (vessel II) and transferred to a reactor, then a portion of polysorbate 80 (0.125 kg) was added to the obtained filtrate with continuous stirring for 15 minutes. The resulting mixture was cooled to a temperature of + 57 ° C, then the resulting 40% solution of sodium tetraborate in glycerol was added to this cooled mixture, continuously stirred for 1 hour at a temperature of + 57 ° C, thereby obtaining 5 kg of a homogeneous suppository mass. The resulting homogeneous suppository mass was cooled to a temperature of + 43 ° C with continuous stirring, then poured into suppository forms to obtain separate vaginal suppositories, and left to cool until room temperature reached, which led to the solidification of the suppository mass.

The thus obtained vaginal suppositories according to the invention (1786 pcs.) Were marked with the manufacturer’s logo and dosage, and then the indicated vaginal suppositories were sequentially packaged first in the primary package (blisters) and then in the secondary package.

Example 2

All actions were repeated analogously to example 1, using 1.34 kg of a 40% solution of sodium tetraborate in glycerol, 3.485 kg of Witepsol W35, 0.125 kg of polysorbate 80 and 0.05 kg of distilled monoglycerides, obtaining vaginal suppositories according to the invention (1786 pcs.).

Put a mark on the received vaginal suppositories, indicating the manufacturer’s logo and dosage, and then sequentially pack these vaginal suppositories first in the primary package (blisters) and then in the secondary package.

Example 3

All actions were repeated similarly to examples 1 and 2, using 2.68 kg of a 40% solution of sodium tetraborate in glycerol, 2.133 of Witepsol W35, 0.125 kg of polysorbate 80 and 0.063 kg of distilled monoglycerides, obtaining vaginal suppositories according to the invention (1786 pcs.).

Put a mark on the received vaginal suppositories, indicating the manufacturer’s logo and dosage, and then sequentially pack these vaginal suppositories first in the primary package (blisters) and then in the secondary package.

Example 4

The appearance, organoleptic (smell), and physicochemical properties of the suppositories obtained according to Examples 1-3 were investigated, including the consistency of the suppository, the absence or presence of softening of the suppository at room temperature, the absence or presence of sweating on the surface of the suppository, and the average weight of the suppository (normal - 2.66-2.94 g / suppository), the melting point of suppositories (norm - not more than + 37 ° C) and the time of complete deformation of suppositories (norm - not more than 15 minutes). The data are presented below in table 1 and in figure 1 (panel A - suppositories according to example 2, panel B - suppositories according to example 1, panel C - suppositories according to example 3).

Table 1. The results of a study of the appearance and physico-chemical properties of suppositories

The composition according to example 1 The composition according to example 2 The composition according to example 3 Appearance of suppositories Suppositories are white with a slightly yellowish tinge, odorless, hygroscopic, torpedo-shaped. Slight softening of the surface layer of suppositories and sweating of the surface of suppositories is observed. The time of complete deformation, minutes 8-9 8-9 9-10 Melting point, ° С 37 36 37 Average weight g 2,804 2,676 2,723

Thus, the compositions of the vaginal suppositories according to the invention, obtained according to examples 1-3, met the requirements presented, according to OFS.1.4.1.0013.15 "Suppositories" of the State Pharmacopoeia of the XIII edition to the dosage form "vaginal suppositories" in terms of appearance and the rest quality indicators of suppositories, including the weight of suppositories, as well as the melting point and time of complete deformation of the suppositories.

Example 5

We investigated in accordance with clause 3.3 OFS.1.2.4.0002.15 "Microbiological purity" of the State Pharmacopoeia of the Russian Federation of the XIII edition the microbiological purity of the suppositories obtained according to example 1, performing serial dilutions (1:10, 1:50, 1: 100, 1: 500 and 1: 1000) of the suppository according to example 1 in a buffer solution containing 5% polysorbate 80, introducing 1.0 ml of each dilution of the test drug into 6 Petri dishes, and 0.2 ml of Bacillus cereus suspension, strain ATCC 10702 was added to 2 Petri dishes (hereinafter also indicated as B. cereus), in 2 Petri dishes - 0.2 ml of suspension of Candida albicans, strain ATCC 10231, and another 2 Petri dishes - 0.2 ml of suspension of Aspergillus brasiliensis, strain ATCC 9642 (hereinafter also referred to as Asp. Brasiliensis). Cups with Bacillus cereus were poured with 10-15 ml of molten and chilled soya-casein agar, cups with cultures of Candida albicans and Aspergillus brasiliensis - the same amount of Saburo agar. At the same time, in tubes filled with 10 ml of liquid nutrient medium - Mossel broth or soya-casein broth, depending on the needs of the corresponding microorganism - individually added 1.0 ml of Pseudomonas aeruginosa suspension, strain ATCC 9027 (hereinafter also referred to as Ps. Aeruginosa ), and Staphylococcus aureus, strain ATCC 6538-P (hereinafter also referred to as St. aureus). Instead of dilutions of the preparation, the same amount of solvent was added to the control plates and tubes. Crops were incubated under standard conditions for 48 hours for bacteria (Bacillus cereus, Pseudomonas aeruginosa and Staphylococcus aureus) and for 5 days for fungi (Aspergillus brasiliensis and Candida albicans). (All of these microorganisms, collectively, are hereinafter referred to as "test microorganisms" or simply "microorganisms".)

After the end of the incubation time, the crops were examined, noting the appearance of typical growth of test microorganisms in control plates and test tubes that did not contain the drug, and the test subjects (with various dilutions of the drug). The presence of test microorganisms in the test cups and test tubes, similar to the control ones, is indicated by the sign “+”, lack of growth by the sign “-”, insignificant growth by the sign “-”. If on media with the drug a decrease in the number of colonies on plates or lack of growth of test microorganisms was observed, a conclusion was drawn about the presence of an antimicrobial effect on the drug.

For quantitative determination of aerobic test microorganisms, a plate agar method (modified depth method) was used. Samples were taken from the studied series of suppositories from 5 different blisters (each with 5 suppositories). A sample (10 g) was placed in a sterile flask containing 100 ml of buffer solution and sterile glass beads with a diameter of 5-6 mm. The mixture was heated in a water bath to a temperature of no higher than 40 ° C and shaken vigorously until a homogeneous emulsion was obtained, then 1 ml was taken from this emulsion, introduced into a sterile Petri dish, 7-10 ml of molten and cooled nutrient medium was added and quickly mixed with rotational movements . After agar solidification, the plates were inverted and incubated.

Colonies of test microorganisms were counted, firstly, after 48-72 hours of incubation and, secondly, after 5 days of incubation. The number of microorganisms in 1 g or 1 ml of medium was calculated by the formula:

,

,

where N is the number of microorganisms in 1 g or 1 ml of medium,

C is the number of colonies in all Petri dishes,

n is the number of Petri dishes,

d is the dilution coefficient of the sample,

10 - conversion factor when sowing on a Petri dish in a volume of 0.1 ml.

The result, measured in CFU (colony forming units), was rounded to 2 significant digits. The results for the compositions of examples 1, 2 and 3 are presented in tables 2, 3 and 4, respectively.

Table 2. The result of determining the antimicrobial action of dilutions of the composition of suppositories in example 1.

Dilution of the drug Test microorganisms B. cereus ATCC 10702 St. aureus ATCC 6538-P Ps. aeruginosa ATCC 9027 C. albicans ATCC 10231 Asp. brasiliensis ATCC 9642 1:10 - - - - - 1:50 - ± - - - 1:80 ± ± ± ± ± 1: 100 ± ± ± ± ± Microorganism growth control + + + + +

Table 3. The result of determining the antimicrobial action of dilutions of the composition of the suppositories in example 2.

Dilution of the drug Test microorganisms B. cereus ATCC 10702 St. aureus ATCC 6538-P Ps. aeruginosa ATCC 9027 C. albicans ATCC 10231 Asp. brasiliensis ATCC 9642 1:10 - - - - - 1:50 - - ± - - 1:80 ± ± ± ± ± 1: 100 ± ± ± ± ± Microorganism growth control + + + + +

Table 4. The result of determining the antimicrobial action of dilutions of the composition of the suppositories in example 3.

Dilution of the drug Test microorganisms B. cereus ATCC 10702 St. aureus ATCC 6538-P Ps. aeruginosa ATCC 9027 C. albicans ATCC 10231 Asp. brasiliensis ATCC 9642 1:10 - - - - - 1:50 - ± - - - 1:80 ± ± ± ± ± 1: 100 ± ± ± ± ± Microorganism growth control + + + + +

Thus, the vaginal suppositories obtained with sodium tetraborate in accordance with the present invention comply with the requirements of the General Pharmacopoeia Monograph 1.4.1.0013.15 Suppositories, expanding the arsenal of topical preparations suitable for the treatment of infectious and inflammatory diseases of the vulva and vagina, including, without limitation, vaginal candidiasis, have microbiological stability and ensure their uniform distribution of the active substance over the mucosa and high bioavailability of the active substance during their medical use suppositories.

Claims (20)

1. A vaginal suppository for the treatment of infectious and inflammatory diseases of the vulva and vagina, containing sodium tetraborate dispersed in a solid fat base, said suppository as a solid fat containing a mixture of medium chain fatty acids triglycerides, diglycerides and monoglycerides with a hydroxyl number of 40 to 50 mg KOH / g, and the specified suppository also contains an emulsifier and an additive to prevent a decrease in the melting temperature and time of complete deformation of the suppository, m as an emulsifier, this suppository contains polyoxyethylene (20) sorbitan monooleate, and distilled monoglycerides as an additive to prevent a decrease in the melting temperature and time of complete deformation of the suppository. 2. The vaginal suppository according to paragraph 1, characterized in that the infectious and inflammatory diseases of the vulva and vagina are diseases of the vulva and vagina caused by Candida fungi. 3. The vaginal suppository according to paragraph 2, characterized in that the infectious and inflammatory diseases of the vulva and vagina caused by Candida fungi are diseases of the vulva and vagina caused by one or more of Candida albicans, Candida glabrata, Candida tropicans, Candida pseudotropicans, Candida krusei Candida parakrusei, Candida parapsilosis and Candida guillermondi. 4. The vaginal suppository according to any one of paragraphs 2-3, characterized in that the infectious and inflammatory diseases of the vulva and vagina caused by Candida fungi are vaginal or vulvovaginal candidiasis. 5. The vaginal suppository according to paragraph 1, characterized in that it contains the active component in an amount of from 0.25 to 0.55 g per 1 g of the mass of the suppository. 6. The vaginal suppository according to paragraph 1, characterized in that it contains distilled monoglycerides in an amount of from 0.005 to 0.025 g per 1 g of the mass of the suppository. 7. The vaginal suppository according to paragraph 1, characterized in that it contains a mixture of medium chain fatty acids triglycerides, diglycerides and monoglycerides with a hydroxyl number of 40 to 50 mg KOH / g in an amount of 0.40 g to 0.70 g per 1 g of the mass of the suppository. 8. The vaginal suppository according to paragraph 1, characterized in that the mixture of medium chain fatty acids triglycerides, diglycerides and monoglycerides with a hydroxyl number of 40 to 50 mg KOH / g is Witepsol W. 9. The vaginal suppository according to paragraph 7, characterized in that Witepsol W is Witepsol W35. 10. The vaginal suppository according to paragraph 1, characterized in that it contains polyoxyethylene (20) sorbitan monooleate in an amount of from 0.01 to 0.06 g per 1 g of the mass of the suppository. 11. A method of manufacturing a vaginal suppository according to any one of paragraphs 1 to 10, characterized in that: a) dissolve a weighed portion of sodium tetraborate in glycerin, preheated to a temperature of + 50-60 ° C, followed by stirring the resulting mixture until a clear solution is obtained, followed by filtration of the resulting solution; b) jointly melt samples of the base - solid fat at room temperature - and monoglycerides distilled at a temperature of + 75-80 ° C and with constant stirring, followed by filtration of the obtained melt; c) add to the melt obtained in step (b) a portion of polyoxyethylene (20) sorbitan monooleate, followed by stirring, thereby obtaining a mixture; g) cool the mixture obtained in step (c) to a temperature of + 55-60 ° C; d) combine the specified cooled mixture with the solution obtained in step (a), followed by stirring them at a temperature of + 55-60 ° C until a homogeneous suppository mass is obtained; f) cool the suppository mass obtained in step (e) to a temperature of + 42-45 ° C with constant stirring; g) the suppository mass cooled in step (e) is poured into molds, followed by cooling of the indicated suppository mass until it solidifies, to obtain vaginal suppositories. 12. The method according to paragraph 11, characterized in that the basis of the solid fat at room temperature is a mixture of medium chain fatty acids triglycerides, diglycerides and monoglycerides with a hydroxyl number of 40 to 50 mg KOH / g. 13. The method according to any one of paragraphs 11 to 12, characterized in that at the end of step (g), optionally, they are marked on the resulting vaginal suppositories and sequentially pack said vaginal suppositories in primary and secondary packaging.

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