Device for intravaginal delivery of active ingredients, method of preparation and use of device

Abstract

The present invention relates to the chemical, pharmaceutical and medical industries and to the preparation of novel pharmaceutical dosage forms and medical devices of pharmaceutical products suitable for transvaginal delivery and for the prevention and treatment of diseases of the female reproductive system. A composition for preparing a device for the intravaginal delivery of an active ingredient, and said device, which is an active-ingredient-free biopolymer matrix, comprising at least one structural polysaccharide selected from the group consisting of polysaccharides that are biodegradable in the vaginal cavity, at least one mucoadhesive component, and at least one pH adjusting agent, which is an organic acid. Compositions and devices may also comprise selective microbial substrates. Compositions for preparing a device for intravaginal delivery of an active ingredient and the device may comprise at least one therapeutically effective amount of an active ingredient. Vaginal delivery devices have a set of properties and features that increase therapeutic efficacy and ensure ease of use of the devices.

Description

Field of the Invention

[0001] The present invention relates to the chemical, pharmaceutical and medical industries and to the preparation of new pharmaceutical dosage forms and medical devices for pharmaceutical products suitable for vaginal delivery and for the prevention and treatment of diseases of the female reproductive system, including those associated with bacterial, fungal and viral infections caused by an imbalance of the microbiota, as well as menstrual cycle disorders, benign and malignant tumors of the reproductive organs, hyperplastic and dystrophic changes in the cervix, sexual dysfunction, reproductive dysfunction, menstrual dysfunction. The present invention also relates to methods for vaginal delivery of various active ingredients. More specifically, the present invention relates to the preparation of cryostructured pharmaceutical dosage forms for vaginal delivery of active ingredients. Prior art

[0002] Infectious diseases of the female reproductive system (including bacterial vaginosis, candidiasis, viral infections and vaginal disorders (dysbioses)) are one of the most common conditions that every woman faces at a certain point in time during her lifetime. Both systemic antimicrobial agents and local agents (including vaginal tablets, capsules, suppositories, ointments, gels and solutions) are used for treatment. In addition, local antibiotic therapy is preferred over oral administration because it reduces the risk of adverse events and side effects and increases the local concentration of antimicrobial agents. However, local dosage forms known from the prior art, such as suppositories, ointments, gels, solutions, etc., are characterized by the disadvantages associated with their inconvenience in use, mucosal irritation, itching, burning, etc., resulting in non-compliance with the treatment regimen, which limits its use and generally determines the selection that is conducive to systemic administration.

[0003] The characteristics of vaginal anatomy (open elongated cavity, similar to a tube of approximately 10-12 cm long and 3-4 cm in diameter) [Nara Gevorkovna Zatikyan Anatomy of the vagina https: / / vmc.clinic / news / 30 / 62 / anatomiya-vlagalischa / d,article / ], the histological structure of the mucosa (ensuring the continuous discharge of the contents of the vaginal cavity, the so-called "self-cleaning" effect), and the biological properties of vaginal secretions (high viscosity and low volume) [Anderson B.L., Cu-Uvin S., Raker CA et al. Subtle perturbations of genital microflora alter mucosal immunity among low-risk pregnant women / / Acta Obstet. Gynecol. Scand. 2011. Vol. 90, No. 5. Page 510.] significantly limit the effectiveness of drugs for vaginal administration based on traditional dosage forms (tablets, capsules, suppositories, ointments, gels and solutions).

[0004] The limitation of solid form is related to the suboptimal dissolution profile in the vagina and the surface distribution of the therapeutic agent. Due to the small volume of fluid in the vagina (up to 1.5 mL), the solid form cannot evenly provide the required concentration of the administered active substance or bacteria on the entire surface of the vaginal mucosa. There is an excess of material at the application site of the tablet or capsule, but it is not further distributed over the entire mucosa and only remains at the application site. Therefore, during treatment, the patient may experience vaginal dryness and tablet disintegration or capsule dissolution, or the lack of internal liquid required for the dissolution of the capsule and the active substance contained therein. Sometimes, capsules or tablets with active ingredients may fall from the vagina without disintegration, which adversely affects the effectiveness of treatment. Information about undissolved capsules can usually be found in consumer reviews on product websites or online distributors of corresponding drugs (for example, in FloraFemme intravaginal capsules [https: / / www.amazon.com / FloraFemme-Probiotic-Suppository-An tibiotics-Prevention / dp / B007HWMI6S], Lactogynal [https: / / 03online.com / news / ne_rastvorilas_kapsula_laktozhinal / 2018-1-1-373606https: / / irecommend.ru / content / bespoleznaya-trata-deneg-131], Lactonorm [https: / / 03online.com / news / ne_rastvoryaetsya_laktonorm / 2021-3-23-963866], Fluomizin vaginal tablets [https: / / health.mail.ru / consultation / 2674492 / https: / / www.babyblog.ru / com munity / living / post / 3182205] in the comments).

[0005] Semisolid dosage forms, such as suppositories, are superior in terms of uniform distribution of therapeutic agents (including probiotics and antimicrobials) throughout the vaginal mucosa; however, suppository masses or ointment bases that melt at body temperature typically leak from the vagina. The use of gels and solutions containing antimicrobials ensures a more uniform distribution throughout the vaginal mucosa; however, these forms are also prone to leakage, requiring horizontal positions to be maintained before and after application, which reduces compliance with treatment, and, therefore, reduces the effectiveness of therapy. In addition, the fat or matrix of semisolid dosage forms has limitations in terms of introducing a wide range of hydrophilic substances or bacteria, and the aqueous matrix has limitations in terms of the stability of the active substance introduced into its composition and requires the simultaneous introduction of preservatives, which adversely affects the physiology of the vagina.

[0006] Thus, the use of conventional solid and semisolid dosage forms for intravaginal administration of drug substances and probiotic microorganisms is associated with a number of problems that adversely affect the effectiveness of therapy, ease of use and patient compliance with long courses of therapy.Many patients do not complete initiated treatment.

[0007] Considering the physiological and morphological characteristics of the vagina and having the advantages of both solid dosage forms (stability during storage, versatility for various therapeutic agents, ease and convenience of administration, accuracy of quantitative administration) and semi-solid dosage forms (optimal and uniform distribution of therapeutic agents throughout the vaginal mucosa, comfort), it is relevant to develop dedicated dosage forms for intravaginal administration of active ingredients. Such dosage forms should create physiologically favorable conditions (e.g., pH, osmolality) in the vaginal environment after administration to reduce adverse reactions at the injection site, such as burning, itching, irritation and swelling. It is also preferred to maintain a healthy vaginal microbiome during and after antimicrobial therapy, for example, by using selective prebiotics that provide a nutrient-rich environment for vaginal lactobacilli and are not a growth substrate for opportunistic microflora.

[0008] One of the directions for creating such dosage forms is the development of frozen structured lyophilized vaginal dosage forms in the form of tablets and inserts. The closest solution to the group of the claimed invention is the following intravaginal dosage form.

[0009] Vaginal dosage forms are provided in the article (B. Vitali et al. Association of Lactobacilluscrispatus with fructo-oligosaccharides and ascorbic acid in hydroxypropylmethylcellulose vaginal insert / Carbohydrate Polymers 136 (2016) 1161-1169), which describes a probiotic in the form of a vaginal insert, which is a hydroxypropylmethylcellulose (HPMC) matrix as a structural and mucoadhesive polymer containing skim milk powder, oligofructose, ascorbic acid and Lactobacillus crispatus (L. Crispatus) lactobacilli. The provided probiotic device is prepared by dissolving the ingredients in water, freezing and freeze drying. In dry form, the device is a porous cylinder with a diameter of 8.0-8.7 mm and a length of 22-24 mm. When placed in an aqueous solution, the vaginal insert absorbs water and increases in volume fivefold. The swollen device is able to gradually release the encapsulated lactobacilli. The disadvantage of this vaginal insert is that due to the use of HPMC as a structural polymer, the matrix absorbs water slowly (up to 3-4 hours), which can lead to a slower onset of therapeutic effect than the claimed device, especially under conditions of small volumes of fluid in the vagina, and does not fundamentally solve the problem of slow disintegration of the insert after vaginal insertion.

[0010] The article Chitosan / alginate complexes for vaginal delivery of chlorhexidine gluconate. Carbohydrate Polymers, 91(2), 651-658 by Abruzzo, A., Bigucci, F., Cerchiara, T., Saladini, B., Gallucci, M.C., Cruciani, F., et al. (2013) describes freeze-dried vaginal inserts of polyelectrolyte complexes based on chitosan and alginate as structural matrices, mannitol and chlorhexidine digluconate to enhance the structure of the freeze-dried product. The disadvantage of this solution is the use of polyelectrolyte complexes as structural components, which, from a functional point of view, significantly delay the release of the therapeutic agent (not more than 20-30% within 6 hours) compared to a neutral matrix due to electrostatic interactions of the matrix with the therapeutic agent ions. In addition, this solution is characterized by a more complex method for preparing the insert compared to the solutions described above and the claimed solution.

[0011] The closest solution to the group of claimed inventions is a pharmaceutical composition in the form of a lyophilized tablet and a vaginal delivery device based thereon (WO 2018 / 069888), containing gelatin as the main mucoadhesive component (alone or in combination with other mucoadhesive polymers), mannitol as a structural component, a pH regulator for creating an optimal value for the vaginal environment, and acyclovir as a therapeutic agent. The described form is characterized by a porous structure, rapid swelling and disintegration in water and aqueous solutions in less than two minutes. The tablets are prepared by dissolving gelatin and mannitol in an aqueous solution, dissolving or dispersing the therapeutic components in the resulting solution, filling into the form and subsequently lyophilizing. The hydration and disintegration of the tablets require less than 1 mL of liquid, which is the optimal amount for vaginal delivery and solves the problem of slow disintegration of vaginal tablets. This form has many advantages over known forms (tablets) intended for topical vaginal delivery of therapeutic agents; it provides a more predictable absorbed dose of the therapeutic agent during intravaginal administration, but due to the relatively small size, compared with semisolid dosage forms (gels, ointments, suppositories), it is less effective for topical delivery and uniform distribution of the therapeutic agent on the surface of the entire vaginal mucosa. In addition, compared with other forms, the application of dry tablets is less convenient and physiological, and the possibility of moistening the tablets to promote application is limited by their rapid disintegration after contact with aqueous solutions. An important disadvantage of intravaginal dosage forms containing gelatin is that the protein material, i.e., gelatin, can serve as an available substrate for pathogenic microbial communities (if present), while intravaginal lactobacilli do not consume gelatin. Therefore, applying such tablets to the vagina will promote the growth of undesirable microorganisms.

[0012] The technical problem solved by the claimed invention is to develop new matrix forms (devices without therapeutic agents) and dosage forms (devices containing a matrix with therapeutic agents) intended for vaginal administration in the prevention and treatment of diseases of the female reproductive system associated with bacterial, fungal and viral infections caused by an imbalance of the microbiota, and ensuring effective delivery, rapid disintegration in the vagina, maximum and uniform distribution of the therapeutic agent in the vaginal cavity, insignificant leakage from the vaginal cavity, sufficient exposure time to increase the effectiveness of the therapy, while ensuring the physiology of the device and convenient use, which increases compliance with the therapy. SUMMARY OF THE INVENTION

[0014] The technical result of the invented group is based on the use of biodegradable polysaccharides as structural components to prepare solid dosage forms (devices) for vaginal administration, which have the following set of properties and characteristics, which increase the effectiveness of the therapy while ensuring the ease of use of the device:

[0015] 1) In the initial state (before the device is inserted into the vagina and before contact with water or an aqueous solution), the device has a stable solid form, for example, similar to a tampon, which is easy to insert into the vagina;

[0016] 2) upon interaction with water or aqueous solutions, the device is effectively wetted to form a three-dimensional hydrogel structure while maintaining its original shape for up to 5 minutes, ensuring that the device can be hygienically inserted into the vaginal cavity manually or using a suitable applicator device;

[0017] 3) Under subsequent intravaginal mechanical action (compression due to the physiological elasticity of the vaginal wall), the hydrogel disintegrates to form a gel-like mass that ensures uniform distribution of the therapeutic agent in the vaginal cavity;

[0018] 4) the device is characterized by the necessary adhesion to the vaginal epithelial wall, providing sufficient exposure time for the therapeutic agent in the vaginal cavity;

[0019] 5) The device is characterized by structural strength in the initial state (before contact with water or aqueous solution) and provides nutritional support for lactobacilli of the vaginal microflora after device insertion;

[0020] 6) When wetting the device in water, ensure that the pH level is within pH 4.5 ± 0.6.

[0021] Table 1 provides in more detail the parameters of the claimed intravaginal delivery device for active ingredients.

[0022] Table 1.

[0023]

[0024]

[0025] The technical result is achieved by using an intravaginal delivery device (or medical device) for active ingredients, which is a novel pharmaceutical dosage form based on a biopolymer matrix. The device in one of the embodiments may not contain an active ingredient, i.e., may be an unfilled biopolymer matrix, which may also be used as a finished therapeutically active medical device. In another embodiment of the invention, the device is a biopolymer matrix containing one or more active ingredients, wherein the active ingredient can be introduced into the matrix at the initial stage of the preparation of the device: when the matrix components are mixed with the active ingredient before freezing and freeze drying, as well as at a subsequent stage of the preparation or when the finished product is used.

[0026] Compositions for preparing intravaginal delivery devices for active ingredients, and said devices, which are biopolymer matrices without active ingredients, comprising at least one structural polysaccharide selected from the group consisting of polysaccharides that are biodegradable in the vaginal cavity, at least one mucoadhesive component, and at least one pH adjuster that is an organic acid. The compositions and devices may also comprise a selective microbial substrate.

[0027] Compositions and devices for preparing intravaginal delivery devices for active ingredients may include at least one therapeutically effective amount of active ingredient. The active ingredient may be selected from the group consisting of antibacterial agents (including macrophages), and / or preservatives, and / or antifungal agents, and / or antiretroviral agents, as well as hormones, cytostatic agents, vaccines intended for intravaginal administration. In addition, probiotic microorganisms, including lactobacilli, consortia of probiotic microorganisms for intravaginal administration may be used as active ingredients, wherein selective substrates for the microorganisms may be additionally included in the composition and device.

[0028] Possible options for the formulation of the initial composition for preparing the claimed device and the composition of the resulting device are provided in Table 2.

[0029] Table 2.

[0030]

[0031]

[0032] The structural polysaccharide is selected from the group consisting of polysaccharides biodegradable in the vaginal cavity, preferably polysaccharides in which glucose molecules are mainly linked to each other by α-(1→4) and α-(1→6) glycosidic bonds, such as starch, amylopectin, dextrin, polydextrose.

[0033] The mucoadhesive component may be selected from the group consisting of hydroxypropylcellulose, carboxymethylcellulose, hyaluronic acid, guar gum or xanthan gum.

[0034] As the organic acid, acids suitable for intravaginal administration can be used, including ascorbic acid, pyruvic acid, malic acid, lactic acid, succinic acid, and the like.

[0035] The selective substrate is preferably selected from the group consisting of: oligosaccharides biodegradable in the vaginal cavity, preferably for intravaginal lactobacilli, whose chains contain about 2-20 monosaccharide units, for example, lactulose, raffinose, maltodextrin, fructooligosaccharides, isomaltooligosaccharides, inulin, glycogen.

[0036] The intravaginal delivery device for active ingredients is designed as a bulky, oval, solid dry body, which in one embodiment can be similar to the shape of a feminine tampon. The device is made of a biodegradable polysaccharide and is characterized by the parameters provided in Table 1, including the ability to absorb liquid (aqueous solution) in an amount required to fill the internal volume of the interconnected (connected) macropores, forming a hydrogel that retains its initial shape for a certain period of time (up to 5 minutes), and the device is characterized by a strength sufficient to insert the device into the vaginal cavity.

[0037] The group of claimed inventions also includes:

[0038] A method of preparing a therapeutic agent for vaginal administration comprising preparing aqueous solutions of the initial composition ingredients, mixing them, freezing the resulting mixture at a temperature selected from the range of -15°C to -30°C for 3-18 hours, followed by freeze drying.

[0039] The method for intravaginal delivery of active ingredients for treating and / or preventing diseases of the female reproductive system comprises inserting the obtained device into the vagina, wherein the device is pre-maintained (up to 5 minutes) soaked with water or an aqueous solution before being inserted into the vagina until a hydrogel is formed. Diseases of the female reproductive system include bacterial vaginosis; suppurative inflammatory diseases (vulvitis, vaginitis, endometritis, adnexitis, pelvic peritonitis), sexually transmitted infections (gonorrhea, trichomoniasis, chlamydia, ureaplasmosis, candidiasis, genital herpes, papillomavirus infection, cytomegalovirus infection, HIV infection), benign and malignant tumors of the reproductive organs, myoma, hyperplastic and dystrophic changes of the cervix (erosion and pseudoerosion), sexual dysfunction (pain during sexual intercourse), reproductive dysfunction (abortion, premature birth, infertility), menstrual dysfunction (oligomenorrhea or menorrhagia, amenorrhea, excessive menstrual bleeding, dysmenorrhea, anovulation), etc.

[0040] The composition and concentration of the ingredients of the polymer composition based on which the claimed device (medical device) is prepared are found experimentally and determined by the following factors.

[0041] A class of polysaccharides in which glucose molecules are linked to each other by α-(1→4) and α-(1→6) glycosidic bonds is selected, on the one hand, due to their biocompatibility and lack of irritation to the mucosa, and biodegradability by vaginal lactobacilli. The use of natural starch (e.g., corn, potato, tapioca starch, sago, etc.) or biodegradable modified starch is envisioned as a structural polysaccharide. For example, glycogen (the closest structural analog of plant starch) is the main nutritional substrate for vaginal lactobacilli flora. Unlike the pathogenic microorganisms of the vagina, lactobacilli are able to ferment starch, and therefore they are selective prebiotics for lactobacilli. Due to the non-biodegradability of the matrix, the use of other classes of biocompatible polysaccharides as structural components (e.g., some cellulose-based polymers) does not result in effective release of the encapsulated therapeutic agent.

[0042] The claimed concentration range of the structural polysaccharide in such a composition is in the range of 40 to 100 mg / mL. At values ​​of this component below 40 mg / mL, undesirable cleavage of the sample often occurs during freeze drying, and at concentrations above 100 mg / mL, the viscosity of the initial polymer composition is greatly increased, which causes technical difficulties when manipulating it, especially in terms of the uniform distribution of insoluble components (e.g., lactobacilli, antibacterial agents and antifungal agents) included in the polymer matrix. The specified limits are also optimal for the properties of the resulting matrix. At low concentrations of the structural polysaccharide, a hydrogel with low strength is formed; at high levels of this component, the strength of the hydrogel is too high for effective degradation in the vagina.

[0043] To ensure long-term retention of the hydrogel particles in the vaginal cavity, the dosage form composition includes at least one mucoadhesive polymer. The introduction of the mucoadhesive component into the composition of the device improves adhesion to the vaginal epithelium, which was demonstrated during model experiments on acrylamide gel. Substances of polysaccharide nature, including hydroxypropyl cellulose, carboxymethyl cellulose, hyaluronic acid, gelatin, agarose, sodium alginate, guar gum and xanthan gum, were used as mucoadhesive components in the experiments. The best adhesive properties in the composition with structural polysaccharides and selective substrates were exhibited by hydroxypropyl cellulose, carboxymethyl cellulose, hyaluronic acid and guar gum, the first two polymers are not bioabsorbable polysaccharides and will be gradually eliminated from the female body with natural secretions, and hyaluronic acid and guar gum are biodegradable by enzymes located in the vaginal cavity.

[0044] For various additives, the optimal amount of this component is 10-40 mg / 1 mL of water or aqueous solution in the initial composition or 150-300 mg / 1 g of the final product, selected experimentally in a dry, freeze-structured form. The use of smaller amounts of this component results in weak mucoadhesive properties of the proposed device. The use of larger amounts of the mucoadhesive component (exceeding the specified upper limit of the range provided) makes it difficult to introduce it into the composition due to process limitations of the viscosity of the prepared polymer solution before freeze-structuring.

[0045] In order to achieve the physiological acidity of the intravaginal environment, organic acids, in particular ascorbic acid, pyruvic acid, malic acid, succinic acid, lactic acid, etc., are used in the matrix in the amount necessary to ensure that the pH after wetting the dry dosage form with water is within pH 4.5 ± 0.6. These specific acids are selected due to their solid phase state in the claimed device when the device is used, their non-volatility during lyophilization, their low hygroscopicity and their rapid solubility in an aqueous environment. The concentration range of these acids is determined experimentally by the acidity of the composition before lyophilization, which must be within the above values.

[0046] In addition to the structure-forming agent biodegradable by lactobacilli, the presence of the selective substrate in the composition of the oligosaccharide-based device ensures the rapid growth of lactobacilli after the introduction of the probiotic culture or the prebiotic carrier of the lactobacilli pool during antibiotic therapy. It is known that the molecular weight of the ф polysaccharide affects the fermentation rate of lactobacilli. In addition, shorter polysaccharides and oligosaccharides are superior to longer polymer chains. On the other hand, the introduction of a significant amount of disaccharides into the biopolymer matrix has been shown to be suboptimal in terms of forming a gel structure with good mechanical properties. Therefore, as a result of the research conducted, it was experimentally determined that the optimal chain length of the oligosaccharide is about 2-20 monosaccharide units per chain, which produces a stronger structure in a dry form, ensuring the convenience of its preparation. Compared with the matrix without oligosaccharides, the introduction of oligosaccharides of this chain length ensures the rapid growth of lactobacilli. Therefore, unlike the introduced disaccharides (e.g., maltose and lactulose), the device maintains its solid gel structure with specified mechanical properties. In the claimed technical solution, the oligosaccharide selected from the group of lactulose, raffinose, maltodextrin, oligofructose, oligoisomaltoligosaccharide and inulin is used as the selective substrate of intravaginal lactobacillus. It is also possible to introduce glycogen in addition. The optimum amount of substrate in the initial composition is 10-40mg / 1mL water or aqueous solution, and the optimum amount in the finished dry frozen structured form is 100 to 250mg / 1g device, which ensures the optimal growth of lactobacillus culture (for example, Lactobacillus crispatus) without damaging the mechanical properties of the device. Experiments show that under the substrate content less than 20mg / mL, the proliferation rate of the corresponding lactobacillus decreases, and under the substrate concentration higher than 40mg / mL, after the freeze-dried sample is moistened, it is observed that the hydrogel strength decreases, which may be due to the interaction between the chain of the structural polymer and the substrate and the high osmotic pressure produced by the substrate dissolved in the hydrogel.

[0047] In the claimed technical solution, various lactobacilli preferably obtained from vaginal strains can be used as therapeutic agents at 1×10 6 -1×10 9 CFU / cm 3 In various probiotic preparations for intravaginal administration, a single dose of probiotics is usually 10 8 Up to 10 9 CFU. Therefore, strengths within these ranges can be considered optimal for achieving clinically significant effects. In selecting the range of the amount of drug substance in the initial composition and device, consideration was given to the usual strengths used in drug products for intravaginal administration. Therefore, depending on the size and volume of the device, the dose of drug substance administered will not exceed the dose of these substances used in standard gynecological practice.

[0048] It is desirable to prepare the device as an oval body, which may be similar to a feminine tampon, for example. This form has proven itself well in feminine hygiene devices due to ease of insertion and positioning within the organ, good retention and comfort for the woman. Thus, the present invention allows the preparation of devices of any shape and size without significant changes in the technology.

[0049] In order to ensure the long-term stability of the therapeutic agent in the polymer matrix, the presence of water is undesirable during the entire storage period. Freeze-drying is used to remove water, which results in the formation of a solid, rigid, porous structure. The structure of the biopolymer matrix is ​​formed by a structural biopolymer, which is not completely dissolved when the freeze-dried matrix is ​​moistened in water subsequently, but forms a hydrogel with an internal structure and a stable external shape. Therefore, when the solution is frozen and then freeze-dried, the biopolymer solution undergoes frozen structuring. The solution of the structural biopolymer (for example, starch) based on glucose connected by α-glycosidic bonds forms a gel (cryogel (cryogel)) due to freezing treatment, and therefore, can be used as a structure forming agent. Meanwhile, for example, hydroxypropyl methylcellulose solution does not form a gel due to freezing treatment. After freeze-drying the matrix and re-wetting, the hydroxypropyl methylcellulose solution is completely dissolved in water, which does not allow the use of a device containing such a structure forming agent for insertion into the vagina without a syringe. The insertion of such a device in a dry form is extremely difficult, uncomfortable, and can also be traumatic to the vaginal wall.

[0050] Due to the high porosity and sponge-like structure of the biopolymer matrix, when the device is wetted with water, it absorbs water rapidly, and it therefore becomes a reservoir of liquid in which the introduced therapeutic agent is dissolved or dispersed, ensuring the release of the therapeutic agent. This property advantageously distinguishes the use of the claimed device from other solid dosage forms such as tablets or capsules, which are slowly dissolved in a limited amount of vaginal fluid after being inserted into the vagina, without ensuring the uniform distribution of active ingredients on the entire inner surface of the organ. Therefore, due to the use of the qualitative and quantitative compositions of the biopolymer matrix components, due to the pre-wetting of the claimed device before it is inserted into the vagina, the hydrogel is formed, and it maintains the shape of the initial solid device and has a smooth surface, which ensures that it is comfortably inserted into the vaginal cavity. Therefore, the mechanical properties of the resulting hydrogel (fracture stress limit during compression and crushing, see Table 1) are sufficient to facilitate hygienic insertion into the vagina, for example, using a vaginal applicator. After insertion into the vaginal cavity, the hydrogel is deformed due to the shear stress from the physiologically elastic vaginal wall, gradually transforming into the consistency of a conventional (soft) gel, evenly covering the surface of the mucosa without leaking from the vaginal cavity. Lower breaking stress values ​​lead to the destruction of the hydrogel formed after the device is wetted in the hand or applicator, which makes it difficult or impossible to insert into the vagina. Higher levels do not provide rapid deformation of the hydrogel in the vagina and transformation to the consistency of a soft gel, which slows down the release of the therapeutic agent and does not ensure effective distribution of the device across the mucosa.

[0051] The listed properties of the intravaginal delivery devices (medical devices) for active ingredients - biopolymer matrices without active ingredients and biopolymer matrices with active ingredients - are implemented by the use of qualitative and quantitative compositions of the biopolymer matrix components and the parameters of the method of preparing the devices (characterizing the freezing protocol of the initial composition for subsequent freeze drying).

[0052] The resulting properties of the device (listed in Table 1) provide for more convenient and effective use compared to the dosage form adopted as the prototype. Unlike the prototype, the device is applied as a swollen hydrogel containing a large volume of liquid, which ensures a more uniform distribution after the hydrogel disintegrates in the vaginal cavity compared to the prototype and is comparable to ointments and suppositories, and unlike the latter, the hydrogel does not have flowability and can remain in the vaginal cavity for a long time.

[0053] The claimed device (biopolymer matrix and medical device or device based thereon) has many advantages compared to known medical devices and tools for insertion into the vagina for the prevention and / or treatment of diseases of the female reproductive system.

[0054] 1) Compared with solid dosage forms (tablets, capsules):

[0055] a. Dissolving the therapeutic agent (hydrophilic) or pre-rapid resuscitation of freeze-dried microorganisms (e.g., probiotics, when introduced) by wetting the device in water immediately before administration, which increases its bioavailability to the vaginal mucosa;

[0056] b. The hydrogel is distributed more quickly and evenly throughout the mucosa, which increases the active area and exposure time of the applied therapeutic agent on the mucosa;

[0057] c. Comfort during insertion and placement of the device in the vaginal cavity.

[0058] 2) Compared with semisolid and liquid dosage forms (gels, suppositories, ointments, solutions):

[0059] a. It can be used for a wide range of therapeutic agents, including live microorganisms;

[0060] b. It is not fluid and does not leak from the vagina;

[0061] c. It ensures the accuracy of the dosing of the administered therapeutic agent;

[0062] d. It ensures stability during long-term storage without the use of preservatives.

[0063] Thus, the use of the proposed device combines the advantages of solid and liquid vaginal dosage forms, eliminating their inherent disadvantages.

[0064] Other therapeutic agents besides those listed above, for example, vitamins, tissue regeneration stimulators, medicinal plant extracts, or preparations based thereon, etc., may be added to the initial composition and device.

[0065] In some cases, in each of the above-described embodiments of the present invention, the claimed device may further comprise one or more additional substances included in the matrix, which may be lubricants, fillers, preservatives, adhesives, stabilizers, emulsifiers, solubilizers, dyes, fillers, and osmotic pressure regulators. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] The invention is illustrated by photographs, wherein Figure 1 From left to right, photographs of the dried samples obtained in the examples are presented: 2, 3, 6 and 9; Figure 2 Shown from left to right are photographs of swollen samples obtained in Examples after being kept in water for 100 seconds: 2, 3, 6 and 9.

[0068] Embodiments of the invention

[0069] The following is a detailed description of the claimed invention. The description of the present invention is illustrative and demonstrates the feasibility of achieving the claimed technical results. The technical solution can be subjected to various changes and modifications that can be understood by those skilled in the art when reading this specification. Such changes do not limit the scope of the claims. For example, the composition of the ingredients, their ratios, their combinations, weight and dimensional characteristics, the selection of active ingredients, and the technical solutions for preparing the device (which depends on the composition of the selected ingredients) can vary. In addition, the claimed device can be used to fix a wide range of active components.

[0070] The intravaginal delivery device for active ingredients according to the present invention is a solid lyophilized vaginal dosage form comprising ingredients within the range listed in Table 2.

[0071] The method for obtaining the claimed device (medical device) comprises the following operations (stages):

[0072] 1) An aqueous solution is prepared from a mixture of a matrix-forming polysaccharide, a selective substrate for microorganisms and a mucoadhesive component.

[0073] 2) One of the above organic acids is introduced into the resulting solution to obtain a solution with a desired pH value.

[0074] 3) If necessary, the active ingredient (therapeutic agent) or several such ingredients are introduced into the solution. When probiotic microorganisms are in the device composition, dried cells of these microorganisms (e.g., lactobacilli) are dispersed in the resulting solution, or a solution or suspension of a drug substance is introduced.

[0075] 4) The prepared polymer composition is transferred to an injection mold of desired volume and geometry, then frozen at a temperature selected from the range of -15°C to -30°C for 3-18 hours and then freeze-dried.

[0076] The temperature and time regime for the freezing treatment of the polymer composition obtained at stage 3 is determined experimentally. The upper limit of this range is due to the fact that at temperatures above -15°C the polymer composition of the claimed formulation generally does not freeze due to the effects of supercooling, and that the use of temperatures below -30°C is not practical for economic reasons due to increased energy costs.

[0077] The proposed frozen structured biopolymer matrix of the medical device is a three-dimensional macroporous material, which is prepared by freezing and subsequent freeze-drying of an aqueous solution of a selected polymer of the composition of a specified formulation. The dry macroporous polymer material formed according to this scheme retains its shape well, does not exhibit fluidity, and has a high stability, which is usually a characteristic of dry materials. As initial polymers for its formation, the present invention involves the use of various polysaccharides, including starch and its derivatives, glycogen, while dextrins, maltodextrins, oligofructose, inulin and other related biopolymers are used as selective substrates for intravaginal lactobacilli.

[0078] Freeze drying of the frozen initial polymer composition produces a solid, highly porous material with a sponge-like morphology having an average pore cross section of 5-100 μm and a density of 0.1-0.3 g / cm 3 The specific density of the present invention can absorb water very quickly (in a few seconds to a few minutes), and the amount of the water is the amount required for filling the internal volume of the interconnected (connected) macropores to form a hydrogel with an initial shape and a specified mechanical property. In a dry form, the polysaccharide matrix ensures the stability of the therapeutic agent in the composition of the claimed medical device, has good antimicrobial protection properties and ensures the long-term retention of the therapeutic agent vitality. Hydroxypropyl cellulose, carboxymethyl cellulose, hyaluronic acid, guar gum or xanthan gum are included in the matrix so that the target medical device has a high mucosal adhesion to the epithelium, which ensures long-term presence in the vaginal cavity. Therefore, the biopolymer of the frozen structured matrix is ​​selected in a manner that makes its polysaccharide matrix serve as a substrate for microbial community bacteria and fully degraded in women.

[0079] Before use, the claimed therapeutic agent is usually moistened in water or an aqueous solution to saturate it with liquid, after which a finger or applicator can be used to insert the device into the vaginal cavity. When placed in an aqueous solution before insertion into the vagina, the device absorbs liquid and swells, and in the swollen state it is a hydrogel (hydrated polymer system), and its smooth surface is different from the dry form, ensuring comfortable insertion and staying in the vaginal cavity. In the vagina, on the one hand, mechanical deformation, destruction and grinding of the hydrogel occur, and on the other hand, the structural polysaccharide of the matrix is ​​biodegraded by vaginal microorganisms. The method of application can be selected by the user according to his own preference. In some cases (e.g., a large amount of secretions), it is possible to apply the therapeutic agent without pre-wetting or moistening, but in this case, it is desirable to use an applicator to minimize the trauma to the vaginal mucosa during application. Therefore, due to excessive secretion of vaginal secretions, the rapid saturation of the device by liquid occurs.

[0080] Therefore, the resulting device can serve as a finished medical device, which can be inserted into the vagina using a non-applicator method or an applicator method (through a dedicated tube). In the latter case, the medical device can be a device placed in a corresponding applicator, which in one embodiment can be made of two elements: an external perforated holding tube (tube) and an internal ejector rod (piston). The tube is perforated to promote water to enter the device when the applicator with the device inside it is immersed in water or an aqueous solution. The device can be wetted in any convenient way before it is inserted into such a medical device, including being placed in a container with water or saline solution, filling the applicator with the device inserted inside with water or solution, or another method suitable and acceptable to the user. The applicator can be made of any acceptable material (polymer or cardboard) and has a design similar to a syringe. The outer tube usually has a smooth surface for the application of the device, and can have a rounded end with a wing to keep the device in the applicator before it is inserted, or can be perforated. The properties of the perforation in terms of size, shape, position and number of holes are selected to ensure that the liquid can freely enter the device during wetting.

[0081] Examples 1-26 provided in Table 3 demonstrate but are not exhaustive of the feasibility of the present invention in carrying out the claimed objectives.

[0082] Table 4 provides the parameters of the method for preparing the device according to the example and the characteristics of the resulting device.

[0083] The devices according to Examples 1-24 were prepared by preparing an aqueous solution of the components used: structural polysaccharide, selective substrate, mucoadhesive component, subsequently mixing them and introducing the pH modifier into the resulting mixture. The devices according to Examples 1-21 were prepared using the active ingredient and the active ingredient was introduced into the mixture before the start of freeze structuring; in Examples 25 and 26, the active ingredient was introduced after freeze structuring. Thus, the resulting device was immersed in an aqueous solution of the active ingredient and kept at room temperature for 3 minutes until the device was saturated with the designated therapeutic agent.

[0084] In particular, when probiotic microorganisms are used as active ingredients (Examples 1-9 and 16-18), the dried microbial cells are dispersed in a mixture of an aqueous solution of a structural polysaccharide, a selective substrate and a mucoadhesive component. The prepared suspension is metered into an injection mold, frozen and freeze-dried. The dry form of the resulting device is a cylindrical rod with rounded ends (see Figure 1 ), has a porous, sponge-like texture and contains Lactobacillus cells encapsulated in a polysaccharide matrix.

[0085] The properties of intravaginal delivery devices for active ingredients prepared according to Examples 1 to 26 were investigated; the results of the investigations are presented in Table 4.

[0086] Swelling capacity and hydration time

[0087] The hydration time and swelling properties of the device were studied by placing a sample of the device weighing 0.5 g in 10 mL of excess water. Then, one of the samples was removed and weighed every 30 seconds. Swelling was determined as the weight ratio of the wet sample to the dry sample after reaching the weight limit of the wet sample. The swelling properties of all samples from Examples 1-21 varied in the range of 4-8. The maximum mass of the hydrated sample was reached in the range of 30 seconds to 5 minutes after being placed in an aqueous environment.

[0088] Release of drug substance from the device

[0089] To study the release of the drug, a dry sample weighing 0.5 g was placed in a vial with 200 mL of NaCl solution (0.9 wt%) and incubated at 37° C. on a shaker (speed 40 rpm). At certain intervals, the sample was taken from the vial and the concentration of the drug substance in the solution was measured by HPLC. In all experiments, a fairly rapid release of the drug substance from the polymer matrix of the device was observed: for the devices from Examples 10, 11, 14, 15, more than 80% of the contained chlorhexidine digluconate, miramistin, clindamycin and tenofovir were released within 5 minutes; for the devices from Examples 12 and 13, more than 80% of the contained metronidazole and fluconazole were released within 60 minutes.

[0090] Release of Lactobacillus from the device

[0091] To study the release of lactobacilli, a dry sample weighing 0.5 g was placed in a Petri dish with 20 mL of a buffer solution simulating vaginal fluid pH 4.2 (composition per 1 L: 3.51 g NaCl, 1.40 g KOH, 0.222 g Ca(OH)2, 0.018 g bovine serum albumin, 2 g lactic acid, 1 g CH3COOH, 0.16 g glycerol, 0.4 g urea and 5 g glucose) and incubated on a shaker at 37°C. At certain intervals, the sample was removed from the Petri dish and the concentration of the microorganisms in the culture medium was measured turbidimetrically by the absorption of the solution at 600 nm. For the products from Examples 1-8, the increase in the turbidity of the solution occurred almost linearly until a plateau corresponding to the complete release of the microorganisms from the biopolymer matrix was reached, and the time to reach the plateau ranged from 4 to 8 hours.

[0092] Survival rate of bacteria encapsulated in the device

[0093] The count of viable bacteria was determined immediately after encapsulation and preparation of the device and during storage for 90 days at +2-8°C and 25°C. For this purpose, a sample of the device weighing 0.5 g was dissolved in 20 mL of saline under vigorous stirring. A series of dilutions were prepared from the resulting suspension, which were then inoculated onto a Lactobacillus agar medium. The colonies were then counted.

[0094] The survival rate of bacteria during the preparation process was determined as the ratio of the number of live bacteria to the number of introduced bacteria during the preparation process. For Examples 1-8 and 16-18, the survival rate was 30-70%.

[0095] The survival rate of the lactobacilli during storage was determined as the ratio of the number of live microorganisms during a certain period of time to the number of live microorganisms immediately after the preparation of the device. For the devices from Examples 1-8, the count of live bacteria was 92-105% when stored at +2-8°C for 90 days, and 84-98% when stored at +25°C.

[0096] Antimicrobial activity of devices containing Lactobacillus

[0097] After storing the samples for 90 days, the antimicrobial activity against Candida albicans (C.albicans), Escherichia coli (E.coli), and Gardnerella vaginalis (G.vaginalis) was studied. A sample weighing 0.5 g was dissolved in 10 mL of MRS medium supplemented with 0.05% cysteine. The resulting culture was incubated anaerobically at 37°C for 24 hours. In order to obtain a cell-free supernatant (CFS), the cell culture was centrifuged at 5500 rpm for 10 min and the supernatant was collected, after which the supernatant was passed through The solution was filtered through a GP filter (0.22 μm Merck Millipore Cork, Ireland).

[0098] CFS was 2.5×10 5The concentration of CFU / mL is added to the suspension of microorganism Candida albicans, Escherichia coli, vaginal Gardnerella and incubated for 24 and 48 hours. Microbial count is determined with turbidimetry at 600nm. Determine inhibition % relative to the control sample that does not add CFS. The inhibition % to Escherichia coli, vaginal Gardnerella is>90%, and the inhibition % to Candida albicans is>80%. The suspension of the obtained microorganism is inoculated on suitable culture medium and incubated for 48 hours, and thereafter before and after adding CFS to colony count. All devices from embodiment 1-8 show that colony number has reduced by more than 3 orders of magnitude, which not only shows the antibacterial activity of CFS obtained after cultivating the sample of the prepared device, but also shows its bactericidal activity.

[0099] Antimicrobial activity of devices containing drug substances

[0100] The antimicrobial activity of the product against Candida albicans, Escherichia coli, and Gardnerella vaginalis was studied. For this purpose, the standard test procedure for determining the resistance of microorganisms to antibiotics was adjusted. For this purpose, a cylindrical sample of the device containing the antimicrobial agent was cut into discs with a diameter of 15 mm and a thickness of about 2 mm using a scalpel. A device according to Example 13 (to which no antimicrobial agent component was added) was also prepared, served as a placebo, and was also cut into discs.

[0101] 1×10 6 Suspensions of microorganisms Candida albicans, Escherichia coli, and Gardnerella vaginalis at a concentration of CFU / mL are inoculated onto appropriate culture media in petri dishes. Cut discs of the device containing the antimicrobial component are placed in the center of each culture dish. Placebo samples not containing the antimicrobial component are also placed in several culture dishes. In addition, the culture dishes are incubated for 48 hours, after which the antimicrobial effect of the device is evaluated by the diameter of the growth zone around the disc. The culture grows uniformly over the entire area of ​​the petri dish; the presence of the middle placebo disc of the culture dish does not result in any significant changes in the growth pattern. In the case of the device with the antimicrobial component, an area in which the growth of microorganisms is inhibited is formed around the disc. The diameter of this area serves as a measure of the size of the antimicrobial activity. The antimicrobial activity against Gardnerella vaginalis increases in the series of fluconazole < metronidazole < chlorhexidine < miramis stop < clindamycin. The antimicrobial activity against Escherichia coli increases in the series of fluconazole < clindamycin < chlorhexidine < miramis stop < metronidazole. The antimicrobial activity against Candida albicans increases in the series of metronidazole < clindamycin < chlorhexidine < miramistil < fluconazole.

[0102] Determination of device porosity using optical microscopy

[0103] To investigate the internal structure and porosity of the devices, dried samples of the devices were cut with a razor and examined under an optical microscope. All investigated devices of all provided examples had a porous structure with open, interpenetrating pores. 90% of the pore sizes calculated from the distance between the closest structural elements of the device were in the range of 5 to 100 μm and were practically indistinguishable between different devices.

[0104] Modeling the ability of materials to adhere to epithelial walls

[0105] In order to study the adhesion ability of the material to the vaginal epithelial wall, the inclined plate method is used. For this reason, a thin layer (5mm) of a solution containing 10% (weight) acrylamide, 0.1% methylenebisacrylamide and 0.1% potassium persulfate and tetramethylethylenediamine is poured into a flat mold and polymerized at room temperature. The sample of the device is cut into a thin plate of about 5mm thickness and placed in a saline solution for hydration. After the acrylamide gel is formed, the gel is moistened with saline and various samples are placed on it, and the plate is placed in an incubator at 37°C. After balancing for 20 minutes, the plate is tilted at an angle of 30 to 90 degrees and the flow or rolling rate of the sample is observed. Commercially available suppositories, 1% starch solution and samples of the device obtained from Example 9 with and without the addition of hyaluronic acid are used as control samples. As a measure of adhesion ability, determine the angle at which the sample is observed to slide or flow 10cm along the surface in 1 minute. For the molten suppository the angle was 45 degrees, for the 1% starch solution the angle was 30 degrees, for the device from Example 9 obtained without the addition of hyaluronic acid the angle was 45 degrees and for the device from Example 9 obtained with the addition of hyaluronic acid the angle was 60 degrees.

[0106] Alternatively, the sheet of acrylamide gel was removed from the mold, moistened with saline, and the same weight of the sample of the suppository, 1% starch gel, the sample from Example 9 with or without the addition of hyaluronic acid was placed in the middle, the sheet was rolled into a tube and placed in an incubator at 37°C in a vertical position, simulating the placement of the sample in the vagina. The time taken for the contents of the tube to leak out of the tube was observed. The 1% starch solution leaked within 30 minutes; the suppository sample leaked within 1 hour. Whether or not hyaluronic acid was present, the sample from Example 9 did not leak or fall out within 4 hours.

[0107] Comparison of the release of Lactobacillus from different dosage forms

[0108] In order to compare the release of lactobacilli from different dosage forms, commercially available vaginal tablets, commercially available vaginal gelatin capsules and samples from Example 4 containing the same amount of lactobacilli were studied. The vaginal tablets, capsules and samples were placed in a vial and 3 mL of saline was added. The samples from Example 4 were prehydrated in saline, simulated the method of application, and crushed with gentle pressure. In addition, they were placed on an oscillator at 20 rpm and 37°C. After 1 hour, 0.5 mL of the solution was taken and the concentration of released lactobacilli was determined by inoculation onto lactic acid agar with an accuracy of 1 order of magnitude. In the case of tablets, swelling and partial disintegration of the tablets were observed within 1 hour. The count of bacteria detected was 10 6 CFU. In the case of capsules, within 1 hour, deformation and stickiness of the capsules and their adhesion to the wall were observed, with virtually no visible signs of disintegration and release of bulky contents. The count of detected bacteria was 10 4 CFU. The sample from Example 4 was a gel slurry. The count of bacteria detected was 10 7 CFU.

[0109] Mechanical strength (fracture stress limit during compression crushing)

[0110] To investigate the limits of the fracture stress during compression crushing, a dry cylindrical sample of the device is placed on a horizontal surface. A glass Petri dish is placed on top, a weight of 0.1 to 1.0 kg is placed on it, and the system is kept at room temperature for 1 hour. The limit of the onset of failure is determined by the appearance of clearly visible cracks.

[0111] Thus, compared to the prebiotic-based vaginal gel preparations, vaginal tablets and suppositories and hard capsules with freeze-dried lactobacilli, medicaments for the treatment of infectious diseases of the female reproductive system and medicaments for restoring the microflora as part of a two-component therapy for bacterial vaginosis known from the prior art:

[0112] 1) Providing the possibility of therapy with vaginal strains of microorganisms (including personalized microbial strains) that are most compatible with the environment of administration;

[0113] 2) provide high viability of microorganisms during preparation and storage at room temperature;

[0114] 3) the biopolymer matrix includes components that serve as selective nutrient substrates for lactobacilli of the vaginal flora but are unsuitable for the development of pathogenic flora;

[0115] 4) provide rapid hydration of the device after wetting and effective (amount over time) release of the drug substance and live microorganisms of the therapeutic agent after intravaginal administration;

[0116] 5) provide rapid achievement of physiological vaginal pH following administration of the device;

[0117] 6) The frozen structured polysaccharide matrix of the device softens upon hydration and deforms into a soft gel between the vaginal walls, which reduces discomfort after insertion;

[0118] 7) The device has the shape of a tampon that is familiar to patients and is easy to insert. After insertion, even if the patient takes a vertical position immediately after insertion, the contents do not leak out, which is confirmed by a model experiment.

[0119] The claimed device provides a more uniform drug distribution throughout the vaginal mucosa compared to the prototype and also contains a selective substrate compared to the neutral filler - mannitol to create optimal conditions for vaginal lactobacilli and prevent the reduction of their population during treatment.

[0120]

[0121]

[0122]

[0123]

[0124]

Claims

1. A composition for preparing an intravaginal delivery device for an active ingredient, comprising at least one structural polysaccharide selected from the group consisting of polysaccharides that are biodegradable in the vaginal cavity, at least one mucoadhesive component, and at least one pH adjuster, wherein the pH adjuster is an organic acid, in the following amounts per 1 mL of water or aqueous solution: Structural polysaccharides - 40-100mg, Mucoadhesive component - 10-40 mg, Organic acid - 10-30 mg.

2. The composition according to claim 1, characterized in that The structural polysaccharide is selected from the group of polysaccharides whose glucose molecules are linked together by glycosidic bonds α-(1→4) and α-(1→6).

3. The composition according to claim 1, characterized in that The structural polysaccharide is selected from the group consisting of starch, amylopectin, dextrin and polydextrose.

4. The composition according to claim 1, characterized in that The mucoadhesive component is selected from the group consisting of hydroxypropyl cellulose, carboxymethyl cellulose, hyaluronic acid, guar gum, and xanthan gum.

5. The composition according to claim 1, characterized in that The organic acid is one suitable for intravaginal administration, including ascorbic acid, pyruvic acid, malic acid, lactic acid or succinic acid.

6. A composition, characterized in that It also comprises a selective microbial substrate taken in an amount of 10-40 mg / 1 mL of water or aqueous solution, wherein the selective microbial substrate is selected from the group consisting of oligosaccharides biodegradable in the vaginal cavity.

7. The composition according to claim 6, characterized in that The selective substrate is selected from the group of substrates intended for intravaginal lactobacilli.

8. The composition according to claim 6, characterized in that The selective substrate is selected from the group of oligosaccharides whose chain contains 2 to 20 monosaccharide units.

9. The composition according to claim 6, characterized in that The selective substrate is selected from the group consisting of lactulose, raffinose, maltodextrin, fructooligosaccharides, isomaltooligosaccharides, inulin and glycogen.

10. The composition according to claim 1, characterized in that It also contains at least one active ingredient in a therapeutically effective amount.

11. The composition according to claim 10, characterized in that The active ingredient is selected from the group consisting of antibacterial agents including macrophages, and / or antiseptics, and / or antifungals, and / or antiretroviral agents, as well as hormones, cytostatic agents, vaccines intended for intravaginal administration.

12. The composition according to claim 11, characterized in that The antibacterial agent, and / or preservative, and / or antifungal agent, and / or antiretroviral agent, or hormone or cell growth inhibitor or vaccine is taken in the following amount per 1 mL of water or aqueous solution of the composition: Antibacterial agent - 5-50mg, Preservatives - 0.1-10 mg, Antifungal - 5-50 mg, Antiretroviral agents - 10-50 mg, Hormones - 0.02-2mg, Cytostatics - 5-50 mg, Vaccine - 2-1000 μg.

13. The composition according to claim 6, characterized in that It also comprises at least one therapeutically effective amount of an active ingredient selected from the group consisting of probiotic microorganisms, including lactobacilli, and communities of probiotic microorganisms for intravaginal administration.

14. The composition according to claim 13, characterized in that Probiotic microorganisms were measured at 1×10 6 -1×10 9 CFU / 1mL water or aqueous solution.

15. An intravaginal delivery device for active ingredients prepared from the composition according to claim 1, which is a solid volumetric body with a macroporous structure, comprising after freezing and freeze-drying at least one structural polysaccharide selected from the group consisting of polysaccharides biodegradable in the vaginal cavity, at least one mucoadhesive component, at least one pH regulator, the pH regulator being an organic acid, in the following amounts per 1 g of the device: structural polysaccharide - 400-700 mg, mucoadhesive component - 150-300 mg, organic acid - 50-100 mg, The total content of all ingredients does not exceed 1 gram.

16. The device according to claim 15, characterized in that The moisture content does not exceed 9%.

17. The device according to claim 15, characterized in that The macroporous structure is characterized by an average pore size of 5-100 μm and a 3 The specific density.

18. The device according to claim 15, characterized in that It is designed to absorb water or aqueous solution in an amount necessary to fill the internal volume of the macropores for no more than 5 minutes, forming a hydrogel that retains its original shape, and the hydrogel is characterized in that the ultimate stress limit during compression crushing is sufficient to non-destructively introduce the hydrogel into the vaginal cavity.

19. The device according to claim 18, characterized in that The hydrogel has an ultimate stress limit of 0.2-1.0 N during compression crushing.

20. The device according to claim 15, characterized in that It is designed to absorb at least 3 mL of water or aqueous solution per gram of the device or not less than 70% of the weight of the device saturated with water.

21. The device according to claim 15, characterized in that The structural polysaccharide is selected from the group of polysaccharides whose glucose molecules are linked together by glycosidic bonds α-(1→4) and α-(1→6).

22. The device according to claim 15, characterized in that The structural polysaccharide is selected from the group consisting of starch, amylopectin, dextrin and polydextrose.

23. The device according to claim 15, characterized in that The mucoadhesive component is selected from the group consisting of hydroxypropyl cellulose, carboxymethyl cellulose, hyaluronic acid, guar gum, and xanthan gum.

24. The device according to claim 15, characterized in that The organic acid is one suitable for intravaginal administration, including ascorbic acid, pyruvic acid, malic acid, lactic acid or succinic acid.

25. The device according to claim 15, characterized in that It also comprises a selective microbial substrate in an amount of 100-250 mg / 1 g of the device.

26. The device according to claim 25, characterized in that The selective substrate is selected from the group of substrates intended for intravaginal lactobacilli.

27. The device according to claim 25, characterized in that The selective substrate is selected from the group of oligosaccharides whose chain contains 2 to 20 monosaccharide units.

28. The device according to claim 25, characterized in that The selective substrate is selected from the group consisting of lactulose, raffinose, maltodextrin, fructooligosaccharides, isomaltooligosaccharides, inulin and glycogen.

29. The device according to claim 25, characterized in that It also comprises at least one therapeutically effective amount of an active ingredient selected from the group consisting of probiotic microorganisms, including lactobacilli, and communities of probiotic microorganisms for intravaginal administration.

30. The device according to claim 29, characterized in that Probiotic microorganisms were measured at 1×10 6 -1×10 9 CFU / 1mL water or aqueous solution.

31. The device according to claim 15, characterized in that It also contains a therapeutically effective amount of said active ingredient, which is selected from the group consisting of antibacterial agents including macrophages, and / or antiseptics, and / or antifungal agents, and / or antiretroviral agents, as well as hormones, cytostatic agents, vaccines intended for intravaginal administration.

32. The device according to claim 31, characterized in that The antibacterial agent, and / or preservative, and / or antifungal agent, and / or antiretroviral agent, or hormone or cytostatic agent or vaccine is taken in the following amount per 1 g of the device: Antibacterial agent - 30-250mg, Preservatives - 0.5-70 mg, Antifungal - 30-250mg, Antiretroviral agents - 50-250 mg, Hormones - 0.1-15mg, Cytostatics - 3-250mg, Vaccine - 0.01-10mg The total content of all ingredients does not exceed 1 gram.

33. The device according to claim 15, characterized in that It is made in the form of an oval volume body shaped close to a tampon 20 to 100 mm long with a diameter of 5 to 20 mm.

34. A method of preparing a device according to claim 15, comprising preparing an aqueous solution of the components of the composition according to claim 1, mixing them, freezing the resulting mixture at a temperature selected from the range of -15°C to -30°C for 3-18 hours, and subsequently freeze-drying.

35. A method for intravaginal delivery of an active ingredient for treating and / or preventing diseases of organs of the female reproductive system, comprising intravaginal administration of the device according to claim 15.

36. The method according to claim 35, characterized in that Prior to intravaginal administration, the device is pre-moistened in water or an aqueous solution.

37. The method according to claim 35, characterized in that The device is allowed to sit in the water or aqueous solution for up to 5 minutes.

38. The method according to claim 35, characterized in that The device is applied with an applicator.

39. The method according to claim 35, characterized in that The device is used for the treatment and / or prevention of bacterial vaginosis; purulent inflammatory diseases, sexually transmitted infections, benign and malignant tumors in the reproductive organs, fibroids, hyperplastic and dystrophic changes in the cervix, sexual dysfunction, reproductive dysfunction, menstrual dysfunction.

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