RU2349321C2 - Systems and methods of mucosa surface treatment - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention claims treatment system for diseases affecting mucosa condition, and including immune response modifier (IRM) selected out of imidazoquinolinamines, imidazopyridinamines, cycloalcylimidazopyridinamines condensed in 6 and 7 positions, imidazonaphthyridinamines, oxazoloquinolinamines, thiazoloquinolinamines, imidazoquinolinamines with bridge link between 1 and 2 positions, pharmaceutically acceptable salts of indicated substances, and applicator for IRM effect compound application on mucosa surface. The claimed system including IRM effect compound and applicator can be applied in treatment of diseases affecting mucosa condition, such as cervical dysplasia and cervical intraepithelial neoplasia.

EFFECT: IRM delivery to mucosa.

20 cl, 8 ex, 4 tbl, 19 dwg

Description

This application is a partial continuation of the jointly filed application No. 09/676339 of September 29, 2000, which serves as a continuation of application No. 09/479578 of January 7, 2000 (currently US patent 6245776), claiming priority over application No. 60/115253 of January 8, 1999. This application also claims to have a benefit related to the priority of provisional application No. 60/213420 of June 22, 2000. It should be added that the contents of each of the above applications are hereby incorporated by reference.

The present invention relates to systems and methods for treating diseases affecting the condition of the mucous membranes, for example cervical-vaginal mucous membranes. In a specific embodiment, these systems and methods may include an immune response modifier (MIO) selected from imidazoquinolinamines, imidazopyridinamines, cycloalkylimidazopyridinamines condensed at positions 6 and 7, imidazonaphthyridinamines, oxazoloquinolinamines, and 2-position thiazoloquinoline-amines-imidazines acceptable salts of these substances. In one embodiment of the invention, systems and methods are provided that provide particular advantages in local application to the cervix during treatment of diseases such as cervical dysplasias, including dysplasia caused by human papillomavirus (HPV).

The present invention also relates to drug application devices and methods of use. Some aspects of the invention relate to drug delivery to a selected site with minimal involvement of the sites surrounding the selected site. In some embodiments of the invention, its particular advantages are shown for local application of the drug to the cervix.

Many compounds, such as imidazoquinolinamines, imidazopyridinamines, cycloalkylimidazopyridinamines condensed at positions 6 and 7, imidazoquinolinamines with a bridging position between positions 1 and 2, thiazolo and oxazoloquinolinamines, anti-pyridinamine, high imidazonaphthyridiamine, high imidazouraimidiuramioimiduino-imidioiminuetetraimidiuraminuetetiurimidiuraminuetetiurimino activity, and also found useful properties as adjuvants of vaccines that enhance the response of the protective immune system to aktsiny. These compounds, which are part of the subject invention, are sometimes referred to below under the general name MIO (immune response modifiers). MIO can be selected from the group consisting of imidazoquinolinamines, imidazopyridinamines, cycloalkylimidazopyridinamines condensed at positions 6 and 7, imidazonaphthyridinamines, oxazoloquinolinamines, thiazoloquinolinamines, imidazoquinolinamines with bridging salts of these two compounds and pharmaceutically acceptable compounds 1. Methods for the preparation of such MIOs and pharmaceutical compositions with their inclusion are described, for example, in US Pat. , 6110929, 4988815, 5376076 and PCT Publications WO 99/29693, WO 00/76505, WO 00/76518, WO 00/76519. A full description of each of these patents and patent applications is hereby incorporated by reference.

The immunostimulatory, antiviral and antitumor effects of these compounds have been the subject of extensive discussion; specific diseases were indicated in which these compounds are indicated, including basal cell carcinoma, eczema, essential thrombocythemia, hepatitis B, multiple sclerosis, neoplasia, psoriasis, rheumatoid arthritis, herpes simplex type I, herpes simplex type II, condylomas. One of the MIOs, known as imiquimod, has been marketed as a topical Aldara ™ for the treatment of anogenital warts associated with human papillomavirus.

It is believed that the mechanism of the antiviral and antitumor effects of these MIOs is largely associated with an increase in the immune response due to the induction of various active cytokines (e.g., interferon, interleukin, tumor necrosis factor, etc.). It was shown that such compounds stimulate the rapid release of certain cytokines from monocytes and macrophages and are also able to stimulate B cells to secrete antibodies that play an important role in the antiviral and antitumor effects of these MIOs. One of the predominant immunostimulatory responses to these compounds is the induction of synthesis of α-interferon (IFN), which is considered a very important component that determines the observed effective antiviral and antitumor effects. In addition, the upregulation of the release of cytokines, such as, for example, tumor necrosis factor (TNF), IL-1 and IL-6 also has a potentially positive effect, contributing to the antiviral and antitumor effects of these compounds.

Although some of the beneficial properties of MIOs are known, the ability to provide a therapeutic effect with the local application of a MIO in the treatment of a particular disease with a specific localization can be inhibited due to tissue irritation, rinsing of the composition, poor penetration of the drug, or undesired systemic effects of the locally applied compound. In this regard, there is a need for new methods, compositions and systems that provide the most powerful therapeutic effect of this class of compounds.

Local application of the drug to the surface of the tissue can lead to a localized therapeutic effect without concomitant systemic effects. However, local application is often difficult or impossible due to the anatomical features of the location of the tissue. In some cases, the application of the drug to the entire anatomical site, including or surrounding the target area, may be an alternative to direct local application. If, at the same time, the drug has irritating properties, this alternative entails, unfortunately, the possibility of irritation of the tissues surrounding the target area. In addition, even if the drug does not have an irritating effect, regional application requires, as a rule, the use of large volumes or concentrations of the substance to achieve a therapeutic result equivalent to that observed when applied directly to the target area.

The cervix is one example of a targeted area that is difficult to apply topically. In a standing position, the cervix is usually located in the uppermost part of the vaginal cavity. However, although the cervix is located in the upper part of the vaginal cavity, age, stage of the menstrual cycle, pregnancy, and other factors cause a change in the position of the cervix in different women and in the same woman in different periods of life.

Some diseases of the cervix can be successfully treated by local application of the drug. Cervical dysplasia is an example of a pathological condition that can be effectively treated by directly applying the drug to the surface of the cervix, where abnormal cells are usually located. Unfortunately, most of the currently available applicators for vaginal administration of drugs are not suitable for application to the surface of the cervix. Since cervical dysplasia can lead to cancer, only an adequate applicator is acceptable.

Most of the vaginal applicators currently available are designed to inject the drug into the vaginal cavity as a whole, and not to apply directly to the cervix. In general, the length and configuration of the applicators are not suitable for applying the drug to the very top of the vaginal cavity. The application of the drug to the middle or lower part of the vagina does not ensure the receipt of this drug to the tissue of the cervix in the upper part of the vagina. In addition, with the exception of certain body positions, under the influence of gravity there is an outflow of the drug from the cervix. The normal release and separation of fluids during menstruation and at other periods also leads to the outflow of the drug from the cervix. Thus, the use of any applicator that does not provide a systematic supply of the required amount of the drug to the very top of the vaginal cavity causes inadequate treatment.

Elimination of the functional deficiencies of modern vaginal applicators when administering the drug to the cervix, in which the drug is supplied in excess or in excessive concentration, may be unacceptable due to the risk of unwanted effects on surrounding tissues. At the same time, an excessive reduction in the volume or concentration of drugs in order to avoid irritation of surrounding tissues entails the risk of serious consequences of ineffective treatment.

Thus, there remains a need to create improved systems and methods for local application of drugs.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to a system for treating diseases that affect the condition of the mucous membranes. The system includes an immune response modifier (IMO) - a compound selected from the group consisting of imidazoquinolinamines, imidazopyridinamines, cycloalkylimidazopyridinamines condensed at positions 6 and 7, imidazoquinolinamines with a bridging linkage between positions 1 and 2 and pharmaceutically acceptable salts of these substances. The system also includes an applicator device for applying MIO to the surface of the mucous membrane.

Another aspect of the present invention relates to a system that includes an immune response modifier (MIO) - a compound selected from the group consisting of imidazoquinolinamines, imidazopyridinamines, cycloalkylimidazopyridinamines condensed at positions 6 and 7, imidazonaphthyridinamines, oxazoloquinolinamines, tinazinolines between positions 1 and 2 and pharmaceutically acceptable salts of these substances. The system also includes an applicator device for applying MIO to the surface of the mucous membrane.

For example, compounds with the properties of MIO can be 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine or 4-amino-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [ 4,5-s] quinolin-1-ethanol, or 2-propyl [1,3] thiazolo [4,5-s] quinolin-4-amine.

The system can be used to treat diseases that affect the condition of the mucous membrane of the cervix, in particular, with its vaginal part. Among examples of diseases that affect the condition of the mucous membrane, cervical dysplasia and cervical intraepithelial neoplasia can be cited.

In one embodiment of the invention, the applicator device consists of a hollow sleeve and a piston moving inside the sleeve.

Another aspect of the present invention relates to a method of treating a disease that affects the condition of the mucous membrane. The method involves the use of an immune response modifier (MIO) - a compound selected from the group consisting of imidazoquinolinamines, imidazopyridinamines, cycloalkylimidazopyridinamines condensed at positions 6 and 7, imidazonaphthyridinamines, oxazoloquinolinamines, pharmaceutically acceptable 2-dimethylamine compounds salts of these substances. The method also includes the use of an applicator device for applying MIO to the surface of the mucous membrane. In addition, this method involves applying MIO to the surface of the mucous membrane using an applicator device.

This method may consist in introducing the applicator device into the vagina, placing the distal tip of the applicator device near the vaginal part of the cervix and applying MIO on the vaginal part of the cervix.

At least some of the embodiments of this invention described herein relate to drug delivery systems and methods suitable for topically applying a drug to a target area. These systems and methods can be successfully used for intravaginal administration of the pharmaceutical composition. For example, some of the embodiments of the invention provide effective local application of the drug to the cervix for the treatment or prevention of diseases, including, for example, cervical dysplasia.

Additional aspects will be partially described in the description below and will become sufficiently clear from the description of the invention; training is possible with the practical application of the invention. It should be borne in mind that in several sections of the presentation of technical characteristics recommendations are given on a number of examples. The list of examples provided in each case is typical and cannot be considered exhaustive.

It should be borne in mind that both the above general description and the further detailed descriptions are only examples and explanations and do not carry a restrictive meaning.

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate some embodiments of the invention and, together with the description, serve to explain the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGA is a top view of the proposed medical system, including an applicator device and a container with MIO in one package.

FIGV is a top view of the proposed treatment system with several cartridges, pre-filled with MIO.

FIG.2 is a spatial image of the components of a disassembled device for intravaginal application of the drug.

FIGURE 3 is an image of the proximal end of the exemplary device for intravaginal application of the drug.

FIGURE 4 is a longitudinal section of an exemplary device for intravaginal application of the drug along the line 4-4; the pusher is moved to the proximal position.

FIG.5 is a longitudinal section of an exemplary device for intravaginal application of the drug; the pusher is extended to a distal position.

FIG.6 is a closeup image of the proximal part of the device for intravaginal application of the drug shown in FIG.5.

FIG.7 is a closeup image of the distal part of the device for intravaginal application of the drug shown in FIG.5.

FIG. 8 is a spatial view of the components of a possible disassembled alternative embodiment of a device for intravaginal drug administration in accordance with the invention.

FIG.9 is a longitudinal section of a device for intravaginal application of the drug shown in FIG.8; the pusher is moved to the proximal position.

FIG.10 is a longitudinal section of a device for intravaginal application of the drug shown in FIG.8; the pusher is extended to a distal position.

11 is a closeup image of the distal part of the device for intravaginal application of the drug shown in FIG.10.

FIG. 12 is a close-up view of the proximal portion of the drug application device shown in FIG. 10.

FIG.13 is a spatial image of an alternative variant of the proximal part of the device for intravaginal application of the drug.

FIGURE 14 is a spatial image of another alternative variant of the proximal part of the device for intravaginal application of the drug.

15 is a longitudinal section of a typical device for intravaginal application of a drug pre-filled with such a tool.

FIG.16 is a graph comparing the drug transfer of imiquimod through the skin of hairless mice from three pharmaceutical formulations, each of which contains 5% imiquimod.

FIG. 17 is a graph comparing drug transfer of imiquimod through the skin of hairless mice from four pharmaceutical formulations containing different concentrations of imiquimod and isostearic acid.

FIG. 18 is a graph comparing average concentrations of imiquimod in rat serum after a single intravaginal application of a dose of composition A or composition B.

FIGS. 19A and 19B are histograms comparing the pharmacokinetic behavior of imiquimod in rats after vaginal application of composition A or composition B.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

This section provides detailed references to some examples of embodiments of the present invention illustrated in the accompanying drawings. Where possible, the same item numbers will be indicated throughout the drawings to indicate identical or similar parts.

The present invention may partially relate to drug applicators and methods for delivering a drug to a selected location. In some embodiments, such devices may be especially useful for intravaginal administration of a drug. In embodiments of the invention, the devices shown can provide topical intravaginal application of a drug, for example, to the cervix for the treatment of diseases such as cervical dysplasia. In general, such devices can be used to apply the drug with a certain regularity and in the quantities required to obtain the expected treatment result.

In this specification, recommendations can be made using a number of examples. In each case, the cited series of examples serves only as an example; this does not mean that an exhaustive list of examples is given.

As used in this specification, the term “drug” includes any substance or combination of substances that can be used to diagnose, treat, restore health, improve symptoms, prevent or otherwise take measures to monitor the patient’s health. The term “disease” refers to any infectious, non-infectious, pathological, physiological, biochemical or other condition of a patient’s body that may be treated in accordance with the present invention.

In the text of the present description, unless otherwise specified separately, the terms "proximal" and "distal" are relative. The term "proximal" refers to a location near the user (for example, at the user's hand, which he manipulates the device), and the term "distal" describes the location at the maximum distance from the user. Thus, in a typical embodiment of the invention, the proximal part of the applicator will be near the hand or in the hand of the user, and the distal part will be near the area of the tissue where the drug will be applied.

As used in the text, the term “disease affecting the state of the mucous membrane” refers to an infectious, non-infectious, neoplastic or other condition of the patient’s body that affects the condition of the mucous membrane or a site that is sufficiently close to the surface of the mucous membrane, a condition that can be treated with therapeutic or a prophylactic agent applied locally to the surface of the mucous membrane.

Unless otherwise expressly agreed, the term “treat” and derivatives such as “treatment”, etc., are used as generic to indicate the application of a drug to a patient’s body area according to any indications and is not intended to distinguish between preventive, therapeutic, diagnostic, palliative or other procedures. The term "therapeutically effective amount" means an amount of a drug applied that provides the desired therapeutic effect, for example, inducing the release of cytokines, the manifestation of antiviral or antitumor activity. The term “therapeutically effective amount” includes the concept of a unit dose of a drug used during treatment for the time required to achieve the desired therapeutic effect.

Some applications of the devices and methods provided by the present invention can be successfully used to supply a drug to the cervix through the vagina in order to treat (prevent, diagnose, improve the body, etc.) diseases of the cervix. In some embodiments, the devices provided by the present invention can be particularly effective in applying an immune response modifier (MIO) to the cervix to treat the corresponding cervical disease. Examples of immune response modifiers suitable for use in the present invention include those that have been described, for example, in US Pat. Nos. 4,689,338, 5,389,640, 5,268,376, 4929624, 5266575, 5352784, 5494916, 5482936, 5346905, 5395937, 5238944 , 5525612, 5175296, 5693811, 5741908, 5939090, 6110929, 4988815, 5376076 and in PCT publications WO 99/29693, WO 00/76505, WO 00/76518, WO 00/76519. A full description of each of these patents and applications is incorporated herein by reference. Some MIO options suitable for use within the scope of the present invention include 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine (imiquimod), as well as compounds and compositions similar to those described in joint application US No. 09/479578 and in PCT publication WO 00/06577. A full description of each of these patents and applications is incorporated herein by reference.

In general, the term “user” of the devices described here (also called applicators) refers to healthcare professionals using drugs to treat patients, and patients as such, using the drugs themselves.

In some embodiments, devices can provide accurate delivery of a desired amount of drug to a selected site with a reduced likelihood of inadvertent application to surrounding tissues. Typically, a given amount is a therapeutically effective amount in a single dose. Accurate application of the drug to the selected area can significantly reduce the amount necessary to obtain a therapeutic result, while minimizing the risk of irritation of tissues adjacent to the selected application area.

In the case of intravaginal application, the use of the device can reduce the intensity of side effects of the drug. So, if a drug needs to be delivered only to the cervix, for example, with cervical disease, getting this drug on areas not related to the upper part of the vaginal cavity can unnecessarily affect the lower parts of the vaginal cavity and other surrounding tissues. Moreover, the drug not only affects non-target areas, but also has the potential of tissue irritation by the drug itself or other components of the pharmaceutical composition.

Intravaginal devices may inter alia provide for the precise administration of such an amount of a drug (or a composition containing it) that is less than the amounts commonly used to administer other intravaginal drugs. In some embodiments of the invention, intravaginal devices may provide an approximate amount of from 0.01 to 10 ml, in other embodiments, from about 0.5 to 4 ml and usually about 1.0 ml.

These devices may be pre-filled with therapeutically effective amounts of certain drugs; it is possible to fill the applicators with the user at the time of application. In the latter case, the configuration of the applicator may be such that a drug can be introduced into it from any source (for example, an aluminum tube, a plastic tube, etc.) that can be connected to the applicator for filling. Some applicator options can typically accommodate maximum drug volumes. Alternatively, applicators may be marked with marks for filling with such quantities of a drug that are less than the maximum applicator capacity.

In one embodiment of the present invention, it is possible to use a pre-filled device, which eliminates the possibility of error in choosing the volume of the drug. In yet another embodiment, the applicators may be pre-filled with a composition containing a certain amount of an immune response modifier (MIO) for a single application. The applicator, both filled and unfilled, can be placed in a package, for example, of foil, which allows you to maintain sterility and prevent moisture from entering.

The applicator can be made by known methods, including injection molding processes, allowing to obtain plastic applicators from polymeric materials, for example, high density polyethylene, low density polyethylene, low density polyethylene with a linear structure, polypropylene.

FIG. 1A illustrates a medical system 400 including an applicator device 10 and a reservoir for formulation 401 and placed in a package 402. The design of the apparatus 10 can ensure that it is filled with the composition coming from reservoir 401 through a channel connecting them for drug delivery .

FIG. 1B shows a system 400 in which the composition is contained in pre-filled cartridges 401A-401D; the cartridges can be loaded into the applicator device 10 one at a time.

FIG.2 and FIG.4 represent a possible embodiment of the invention for intravaginal application device 10. As can be seen, the distal part 1 and the proximal part 2 can enter the device 10; the longitudinal axis XX passes through the entire device. FIGURE 2 is a spatial exploded view of the device 10, consisting of an elongated sleeve 3 with a dispensing part 4, a guide rod 5 and a cavity 6 passing through all the parts. The guide rod 5 may be provided with a handle 7, which is, for example, two opposing protrusions 8a and 8b, intended to fix the device 10 in use. In some embodiments, the elongated sleeve 3 may be from about 6 cm to about 24 cm long; usually the length is about 10-18 cm.

The pusher 11 can move along the cavity 6 of the elongated sleeve 3; the pusher may consist of a tip 12 and a drive portion 13. The tip 12 may include a groove 14 for accommodating the user's thumb or other working finger to distally advance the push rod 11 in the cavity 6. The piston 15 may be mounted on the drive portion 13 of the push rod 11 and may be provided with a distal tip 16 opposite the end portion 17. The removable cover 18 can be mounted on the distal portion 4 of the device 10 using known methods, such as threading or friction engagement.

FIG. 3 shows a view from the side of the distal part of the device 10, and FIG. 4 shows a longitudinal section of the device 10 along the line 4-4 indicated in FIG. 3. In FIG. 4, the piston 15 is mounted on the drive portion 13 of the pusher 11 and is in the first position, providing a space 20 for storing or supplying a certain amount of the drug.

In some possible embodiments, space 20 occupies a drug volume of about 5-0.1 ml (typically, a volume of about 2-0.5 ml; in some embodiments, the volume is about 1.0 ml). In one embodiment of the invention, the drive portion 13 of the pusher 11 can be placed in the hole 19 of the piston 15, if possible. If in this embodiment, the pusher 11 is moved to the proximal position, then the drive portion 13 of the pusher 11 can completely exit the hole 19, and the piston 15 cannot be moved to the proximal position using the pusher 11. This option can help prevent aspiration of the drug after it is extruded from space 20, as well as aspiration of the tissue into the dispensing part 4 of the sleeve 3 when the pusher 11 is moved to the proximal position.

In addition, in some embodiments, the cavity 6 may be provided with a stopper 40 (for example, tide 41), which may enter the cavity 6, thereby preventing the piston 15 from moving to the proximal position. Regardless of whether the device 10 is pre-filled with the drug or is filled by the user at the time of use, the position of the stopper 40 can fix the maximum amount of space 20 containing a certain amount of the drug. This stopper can be an effective limiter to prevent the set dose of the drug from being exceeded if the device 10 is filled by the user before use.

It is shown that the cover 18 is mounted on the dispensing part 4. The cover 18 can be held by friction engagement on the outer surface 35 of the dispensing part 4. As another option or addition, the cover 18 can be provided with a leg 18a, which is in friction engagement with the distal part 1 of the cavity 6 Alternatively, the distal portion 1 of the cavity 6 may have an internal thread (not shown) where a leg 18a having an external thread will be screwed. The lid 18 can also be made with an eyelet 18b, which facilitates the grip of the lid 18 when removed from the sleeve 3.

The cover 18 can, as an option, be delivered in a design that facilitates its removal (the presence of knurling, protrusions, etc.). Alternatively, a mark can be made, for example, in the form of an arrow on the cover 18 to indicate the direction of movement when unscrewing during removal, which facilitates the use of the specified device.

In FIG. 5, the plunger 11 is moved to a distal position, which facilitates the release of the drug from the space 20. In the illustrated embodiment, when the plunger 11 is moved to the distal position, the distal tip 16 of the piston 15 moves beyond the distal part 4 of the elongated sleeve 3. In addition, the distal the tip 16 may have a convex or domed shape to ensure complete removal of the drug from the space 20.

FIG.6 is a closeup image of one of the options; the proximal part 2 of the applicator device 10 is shown. The illustration shows that the platform 14 of the pusher 11 forms a protrusion 25 at the junction with the tip 12 of the pusher 11. When the pusher 11 is moved distally along the cavity 6, the protrusion 25 may take a fixed position when in contact with the guide rod 5 of the elongated sleeve 3, which will indicate that the drug is completely squeezed out of the space 20 of the device 10.

FIG.7 is a closeup image of a possible variant of the invention. The distal part 1 of the applicator device 10 is shown. It is seen that a converging cone 30 can be included in the distal part of the space 20 of the cavity 6. The outer surface 31 of the piston 15 can also end with a converging cone 32, which can reach the distal tip 16. The presence of paired cones 30 and 32 may facilitate the complete removal of the drug contained in the space 20 when moving to the distal position of the plunger 11. The piston 15 may also be provided with an o-ring 33 made, for example p, a circular flange 34 which may fit snugly against the walls of cavity 6 by providing the opportunity to remove a substantial portion, if not all, of the drug from the lumen 6 as piston 15 move in the distal position. Thus, the cavity 6 may have at least two different diameters — the diameter of the cavity L _D and the outlet diameter D _D. Typically, the cavity diameter L _D may be approximately 5 to 15 mm, and the outlet diameter 2 to 10 mm. In the sample applicator device 10 with a maximum space capacity of 20 equal to about 1 ml, the length of the elongated sleeve 3 may be about 12-20 cm, L _D may be 10 mm, and D _D approximately 6 mm.

The outer surface 35 of the distal portion 1 of the elongated sleeve 3 may also end in a converging cone 36, which will facilitate the insertion of the distal portion 1 of the device 10 into the vagina. After the drug leaves space 20, the converging cone 36 may also help ensure that the entire amount of the drug administered remains at the delivery site. So, with the introduction of the drug to the cervix, the vaginal wall surrounding the distal part 1 can move tightly along the distal tip 1, erasing the remaining amount of the drug from the tip; this, this applicator is structurally different from applicators with a cylindrical tip without rounding or with rounding.

In use, the user can place the thumb and middle fingers on the protrusions 8a and 8b or hold the handle 7 to fix the device 10 in the selected position, and place the index finger on the platform 14 to move the pusher 11 to the distal position so that the distal tip 16 of the piston 15 extrudes a drug from space 20 into the intravaginal space, for example on the surface of the mucous membrane of the cervix.

FIG. 8 is an exploded view of the components of an embodiment of a device for intravaginal administration of a drug 100. As can be seen from the diagram, the proximal part 101 and the distal part 102 can enter the device 100; the longitudinal axis XX passes through the entire device. FIG. 8 shows an elongated sleeve 103 with a dispensing portion 104, a guide rod 105 and a cavity 106 passing through all the parts. The cover 108 is held on the distal portion 102 of the device 100 by a friction or threaded connection, as indicated for the removable cover 18 of the device 10.

The guide rod 105 of the elongated sleeve 103 may be provided with a handle 107 with a tip 118, due to which the device 100 is more convenient to hold when administering the drug. In the embodiment of FIG. 8, the edge 118 can completely cover the circumference of the guide rod 105. It should be remembered that the edge 118 does not have to be solid; in some embodiments, it is simply not there.

The pusher 111 can move in the cavity 106; it may include a tip 113, a drive portion 114, and a rod 115 located between them. The tip 113 may be provided with a pad 116 for placing the thumb or other working finger of the user's hand, if necessary, to move the plunger 111 to a distal position during use. The pad 116 may have a concave surface 117 to better fix the user's fingers. The piston 120 may be fixedly mounted to the drive portion 114 of the pusher 111, or the drive portion 114 may be removably inserted into the bore 122a of the end portion 122. A distal tip 121 may be included with the piston 120. In some embodiments, the distal tip 121 may end with a protrusion or a domed tide to further ensure complete elimination of the drug.

FIG. 9 is a longitudinal section of a device 100 with a space 130 into which a predetermined amount of a drug enters and in which the plunger 111 is retracted to the proximal position in the cavity 106 of the elongated sleeve 103.

FIG. 10 shows that when the plunger 111 advances to a distal position, the distal tip 121 of the piston 120 may extend beyond the distal portion 102 of the elongated sleeve 103.

11 is a close-up view of the distal portion 102 of the device 100, showing that the space 130 may end with a converging cone 131 in the distal portion 102 of the cavity 106. In this embodiment, the converging cone 131 of the space 130 may have a shape corresponding to the shape of the cone 132 in the distal portion the piston 120. The presence of paired surfaces of the cones 131 and 132 will facilitate the complete removal of the drug from the space 130.

The piston 120 may also be provided with a sealing ring 133, made, for example, in the form of a circular collar 134, which can fit snugly against the walls of the cavity 106, making it possible to remove the entire amount of the drug as the piston 120 moves to the distal position. The outer surface 135 of the distal portion 102 of the elongated sleeve 103 may be in the shape of a cone 136 for the reasons discussed above.

As with the device 10, in some embodiments, the cavity 106 may be provided with a stopper 140 (for example, a tide 141) that can enter the cavity 106, thereby preventing the piston 120 from moving to the proximal position. Regardless of whether the device 100 is pre-filled with medicine or is filled by the user at the time of use, the position of the stopper 140 can fix the maximum amount of space 130 containing a predetermined amount of drug to be delivered to the device.

FIG. 12 is a close-up view of a variant of the proximal portion 101 of the applicator device 100 shown in FIG. 10, which shows that when the plunger 111 is completely moved to the distal position, the pad 116 of the tip 113 can enter the guide rod 105 of the elongated sleeve 103. This the feature allows to reduce the likelihood that some or all of the drug released from the space 130, as a result of aspiration will fall back into the space 130 under the influence of random movement atelier 111 to the proximal position after drug release.

In some embodiments of the invention, the guide rod 105 of the elongated sleeve 103 and the tip 113 of the pusher 111 can be designed so that the user receives an audible and / or tactile signal when the drug is released. In such an embodiment, the guide rod 105 in the cavity 106 may be provided with a protrusion 145, for example, a tide 146, in the area adjacent to the platform 116 when the pusher 111 is completely moved to the distal position. The pad 116 may be of such a size that when it is moved to a distal position at tide 146, a click is heard, and also when the tide passes, the user feels a light push with his hand, which is a signal to completely remove the drug. Tide 146 can also “lock” the pusher 111 in the distal portion, blocking the reverse movement of the pusher 111 to the proximal position.

It should also be borne in mind that in addition to the diameter of the cavity L _D and the outlet diameter D _{D, the} cavity 106 is also characterized by a diameter P _{0 of} the guide rod 105. The cavity 106 may be provided with a conical part 150 located between the diameters P ₀ and L _D. In one example of the invention, a device 100 with a maximum drug storage space of about 1 ml, an elongated sleeve 103 is almost 15-17 cm long, L _D may be 11-15 mm, and D _D 7-12 mm.

In yet another embodiment, the portion of the elongated sleeve 103 extending from the distal to the proximal portion, shown as cylindrical (see, for example, FIG. 9), can be made in the form of a cone converging from the proximal to the distal portion. Such a design can improve the filling of the applicator device with the drug from the proximal portion of the elongated sleeve, rather than from the distal. It follows that in the absence of this cone, an attempt to move the piston to the distal position after loading the drug into the device may be unsuccessful due to air entrapment between the piston seal and the cavity wall. When using a cone-shaped cavity, there may be a gap between the piston and the wall where air will exit when the piston moves to the distal position. The cone may occupy the entire elongated sleeve, or the circular cone may be located near the area where the piston must accommodate a given amount of the drug in the distal portion of the elongated sleeve.

FIG. 13 illustrates an embodiment of a guide rod of an elongated sleeve of devices for intravaginal administration of a drug 10,100 as proposed in the composition of the present invention. In this case, the guide rod 201 of the elongated sleeve 200 may be configured with an orientation indicator 203 of the device 200 along the longitudinal axis XX. 13, the opposite sides 204 and 205 are linear, so that the guide rod acquires an oval configuration in cross section. In this embodiment, the protrusion 206 may extend along the perimeter of the guide rod 201. However, it is possible that the protrusion will be completely absent or be placed in parts along the perimeter.

FIG. 14 shows another embodiment of the guide rod of the elongated sleeve 300 of the device for intravaginal administration of the drug. In this embodiment, the guide rod 301 of the elongated sleeve 300 may also be configured with an orientation indicator 303 of the device 300 along the longitudinal axis XX. The guide rod 301 may be provided with corner pieces 304a-304d. The walls 305a-305d of the guide rod 301 between the corner parts 304a-304d form a converging cone from the diameter P _{0 of the} guide rod to the main diameter L _D. In the drawing, the proximal part of each of the walls 305a-305d may have a cavity 306a-306d formed by a concave surface directed distally to the surface of the walls 305a-305d. In addition, a pusher pad 350 (not shown) may have a concave surface 351 in the distal portion and four corner portions 352a-352d; the shape of the latter ensures their tight entry into the corner parts 304a-304d of the walls 305a-305d. The protrusion or collars (not shown in this embodiment) may or may not surround the proximal portion of the guide rod 301, as has already been said with respect to devices 10 and 110.

A device for intravaginal administration of drugs can provide an accurate supply of a certain volume, which is less than the volumes commonly used for other vaginal drugs. Many vaginal applicators are designed for the introduction of approximately 5 ml of the drug, and there is not local application, but entry into the vaginal cavity as a whole.

In various embodiments of the invention, for example in the embodiment shown in FIG. 15, the applicator 10 may be pre-filled with the product P in order to avoid the possibility of improper administration of the drug into the applicator. However, if the applicator device must be filled at the time of its use, such design features of the device as stoppers can allow you to set the maximum volume, avoiding the possibility of exceeding the specified dosage.

Any of the above applicators may have a length sufficient to place the distal part at the cervix or at a minimum distance from it; the applicator passes through the vagina, and the proximal part of the applicator is located outside. The length of the applicator can be varied to ensure the delivery of MIO to the very top of the vaginal cavity; the proximal part of the applicator is located outside. The length of the applicator, for example, can take into account the anatomical features of the body of women, so that treatment of women with a longer vaginal cavity will not be difficult.

In practice, the device for intravaginal administration of drugs can be held by the proximal part with the thumb and middle finger, and the index finger can be pressed onto the platform of the pusher (i.e., move the pusher to the distal position) to deliver the drug.

In some options, the pusher in preparation for use can be pre-installed in a certain position in the cavity of the elongated sleeve. If the applicator device must be filled before use, an inner thread may be applied to the distal portion of the elongated sleeve to connect to the medically-secured element of the container of the medication (for example, an aluminum tube) so that there is a sealed threaded connection when moving the drug from the container into the space of the applicator device.

Applicators can be placed in packages providing storage under aseptic conditions and protection against moisture. The bag can be made of any material suitable for the protection of medicines, for example, non-laminated and laminated foil (for example, metal plus a layer of plastic). In some embodiments, the package may protect against moisture loss from the formulation or from oxidation of the drug.

The applicator may be included in any system or be a component used in the implementation of the method, requiring the use of additional parts or components. In one of the options in these systems and methods includes an immune response modifier (MIO), intended for the treatment or prevention of diseases that affect the condition of the mucous membranes. So, for example, MIO can be included in the composition for applying to the surface of the mucous membrane of the cervix with the aim of treating various diseases, including cervical dysplasia, for example, intraepithelial neoplasia.

In some embodiments, certain formulations may be used to apply MIO to the surface of the mucous membranes. In a number of variants, the compositions can enhance the therapeutic effectiveness of MIO by facilitating penetration through the mucous membrane or by increasing the duration of contact of the MIO with the surface of the mucous membranes. The pharmaceutical composition may contain a system of preservatives, making it possible to pack it in containers for reusable use.

Compounds - modifiers of the immune response (MIO)

As indicated above, many compounds from the group of modifiers of the immune response (MIO), which include imidazoquinolinamines, imidazopyridinamines, cycloalkylimidazopyridinamines condensed at positions 6 and 7, imidazoquinolinamines with a bridging linkage between positions 1 and 2, thiazolo- and oxazolinedinones and tetrahydroimidazonaphthyridinamines and the subject of the present invention showed significant immunomodulatory activity. Some of the variants of the immune response modifier compounds are 1H-imidazo [4,5-c] quinolin-4-amines depicted in the following Formulas I-V:

Here, R _{11 is} selected from the group consisting of alkyl with one to ten carbon atoms, hydroxyalkyl with one to six carbon atoms, acyloxyalkyl in which the acyloxy moiety is an alkanoyloxy radical with one to four carbon atoms or a benzoyloxy radical and the alkyl fragment contains from one to six carbon atoms, benzyl, phenylethyl and phenyl, and the benzyl, phenylethyl or phenyl substituent may optionally be substituted in the benzene ring by one or two moieties independently selected from the group consisting of alkyl with one to four carbon atoms, an alkoxyl radical with one to four carbon atoms and halogen, provided that if the said benzene ring has two of these moieties as substituents, then these fragments together should contain no more than six carbon atoms.

R _{21 is} selected from the group consisting of hydrogen, alkyl with one to eight carbon atoms, benzyl, phenylethyl and phenyl, wherein the benzyl, phenylethyl or phenyl substituent can be substituted on the benzene ring with one or two moieties independently selected from the group consisting of alkyl with one to four carbon atoms, an alkoxyl radical with one to four carbon atoms and halogen, with the proviso that if said benzene ring has two said fragments as substituents, then these fragments cops should contain no more than six carbon atoms, and

R _{1 is} selected in each case independently from the group consisting of an alkoxyl radical with one to four carbon atoms, halogen and alkyl with one to four carbon atoms; n is an integer from 0 to 2. Here there is a condition that if n = 2, then these groups R ₁ together must contain no more than six carbon atoms.

Here, R _{12 is} selected from the group consisting of straight or branched alkenyl containing from two to ten carbon atoms, and substituted straight chain or branched alkenyl containing from two to ten carbon atoms, wherein the substituent is selected from the group consisting of alkyl with a straight or branched chain containing from one to four carbon atoms, and cycloalkyl with the number of carbon atoms from three to six; cycloalkyl contains from three to six carbon atoms with substituents representing straight or branched chain alkyl groups containing from one to four carbon atoms, and

R _{22 is} selected from the group consisting of hydrogen, straight or branched chain alkyl containing from one to eight carbon atoms, benzyl, phenylethyl and phenyl, wherein the benzyl, phenylethyl or phenyl radical may be substituted in the benzene ring with one or two fragments, if necessary independently selected from the group consisting of straight or branched chain alkyl with one to four carbon atoms, a straight or branched chain alkoxyl group containing from one to four carbon atoms, and g logena, with the proviso that the substitution of the benzene ring by two such moieties total content of carbon atoms in them does not exceed six and

R _{2 is} selected in each case independently from the group consisting of a straight or branched chain alkoxyl radical containing from one to four carbon atoms, halogen and a straight or branched chain alkyl containing from one to four carbon atoms; n is an integer from 0 to 2. Here there is a condition that if n = 2, then these R ₂ groups together must contain no more than six carbon atoms.

R _{23 is} selected from the group consisting of hydrogen, straight or branched chain alkyl containing from one to eight carbon atoms, benzyl, phenylethyl and phenyl, wherein the benzyl, phenylethyl or phenyl radical may be substituted in the benzene ring by one or two fragments, independently selected from the group consisting of straight or branched chain alkyl with one to four carbon atoms, a straight or branched chain alkoxyl group containing from one to four carbon atoms, and halogen, under the condition and that when a benzene ring is replaced by two such fragments, the total carbon content in them will not exceed six, and

R _{3 is} selected in each case independently from the group consisting of a straight or branched chain alkoxyl radical containing from one to four carbon atoms, halogen and a straight or branched chain alkyl containing from one to four carbon atoms; n is an integer from 0 to 2. Here there is a condition that if n = 2, then these R ₃ groups together must contain no more than six carbon atoms.

Here R ₁₄ is -CHR _x R _y , where R _y is hydrogen or a carbon-carbon bond, provided that if R _y is hydrogen, then R _x is an alkoxyl radical with one to four carbon atoms, hydroxyalkoxy a radical with one to four carbon atoms, 1-alkynyl with two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl, in which the alkoxyl moiety contains from one to four carbon atoms and the alkyl moiety contains from one to four carbon atoms, 2- , 3- or 4-pyridyl under the additional condition that if R _y is a carbon-carbon bond, then R _y and R _x together form a tetrahydrofuranyl group with possible substitution with one group or a large number of groups selected from the group consisting of hydroxyl and hydroxyalkyl with one to four carbon atoms.

R _{24 is} selected from the group consisting of hydrogen, alkyl containing from one to four carbon atoms, phenyl and substituted phenyl, wherein the substituent is selected from the group consisting of alkyl with one to four carbon atoms, alkoxy group containing from one to four carbon atoms, and halogen, and

R _{4 is} selected from the group consisting of hydrogen, a straight or branched chain alkoxyl radical containing from one to four carbon atoms, halogen and a straight or branched chain alkyl containing from one to four carbon atoms.

Here, R _{15 is} selected from the group consisting of hydrogen; a straight or branched chain alkyl radical containing from one to ten carbon atoms, and a straight or branched chain alkyl radical containing from one to ten carbon atoms, wherein the substituent is selected from the group consisting of a cycloalkyl radical containing from three to six carbon atoms, and a cycloalkyl radical containing from three to six carbon atoms and substituted by a straight or branched chain alkyl radical containing from one to four carbon atoms; a straight or branched chain alkenyl radical containing two to ten carbon atoms and a substituted straight or branched chain alkenyl radical containing two to ten carbon atoms, the substituent selected from the group consisting of three to six cycloalkyl radicals carbon atoms, and a cycloalkyl radical containing from three to six carbon atoms and substituted by a straight or branched chain alkyl radical containing from one to four carbon atoms; a hydroxyalkyl radical with one to six carbon atoms; an alkoxyalkyl radical in which the alkoxyl moiety contains from one to four carbon atoms and the alkyl moiety contains from one to six carbon atoms; an acyloxyalkyl radical in which the acyloxy moiety is an alkanoyloxy radical containing from two to four carbon atoms, or a benzoyloxy radical, and the alkyl fragment contains from one to six carbon atoms; benzyl radical; phenylethyl radical; phenyl radical, while this benzyl, phenylethyl or phenyl substituent can be substituted in the benzene ring with one fragment or two fragments independently selected from the group consisting of an alkyl radical containing from one to four carbon atoms, an alkoxyl radical containing from one to four carbon atoms, and halogen, provided that if the specified benzene ring is replaced by two of these fragments, the total number of carbon atoms in them should be no more than six.

R ₂₅ is

Here, R _S and R _T are independently selected from the group consisting of hydrogen, an alkyl radical with a carbon atom of one to four, a phenyl radical and a substituted phenyl radical, where the substituent is selected from the group consisting of an alkyl radical with a carbon atom of one to four, alkoxyl radicals containing from one to four carbon atoms and halogen.

X is selected from the group consisting of an alkoxyl radical containing one to four carbon atoms, an alkoxyalkyl radical in which the alkoxyl fragment contains one to four carbon atoms, and the alkyl fragment contains one to four carbon atoms, a hydroxyalkyl radical containing one up to four carbon atoms, a haloalkyl radical containing from one to four carbon atoms, an alkylamide radical in which the alkyl group contains from one to four carbon atoms, amino o a radical substituted by an amine radical in which the substituent is an alkyl or hydroxyalkyl radical containing from one to four carbon atoms, an azide radical, chlorine, a gyroxyl radical, a 1-morpholine radical, a 1-pyrrolidine radical, an alkylthiol radical containing from one to four carbon atoms as well

R _{5 is} selected from the group consisting of hydrogen, a straight or branched chain alkoxyl radical containing from one to four carbon atoms, a halogen and a straight or branched chain alkyl radical containing from one to four carbon atoms.

The use of a pharmaceutically acceptable salt of any of the above compounds is possible.

Preferred MIOs, which are cycloalkylimidazopyridinamines condensed at positions 6 and 7, are described by Formula VI below:

Here m = 1, 2 or 3.

R ₁₆ selected from the group consisting of hydrogen; a cyclic alkyl radical containing three, four or five carbon atoms; straight or branched chain alkyl radicals containing from one to ten carbon atoms; a substituted or branched chain alkyl radical containing from one to ten carbon atoms, wherein the substituent is selected from the group consisting of a cycloalkyl radical containing from three to six carbon atoms and a cycloalkyl radical containing from three to six carbon atoms and substituted by an alkyl a straight or branched chain radical containing from one to four carbon atoms; a fluoro- or chloralkyl radical containing from two to ten carbon atoms and one atom and a larger number of fluorine or chlorine atoms; a straight-chain or branched-chain alkenyl radical containing one to ten carbon atoms and a straight-chain or branched-chain alkenyl radical containing two to ten carbon atoms, the substituent selected from the group consisting of three to six cycloalkyl radicals carbon atoms, and a cycloalkyl radical containing from three to six carbon atoms and substituted by a straight or branched chain alkyl radical containing from one to four carbon atoms; a hydroxyalkyl radical containing from one to six carbon atoms; an alkoxyalkyl radical in which the alkoxyl moiety contains from one to four carbon atoms and the alkyl moiety contains from one to six carbon atoms; an acyloxyalkyl radical in which the acyloxy moiety is an alkanoyloxy radical containing from two to four carbon atoms, or a benzoyloxy radical, and the alkyl moiety contains from one to six carbon atoms, provided that any said alkyl, substituted alkyl, alkenyl, substituted alkenyl the hydroxyalkyl, alkoxyalkyl or acyloxyalkyl radical does not contain a carbon atom completely substituted by carbon atoms and directly bonded to the nitrogen atom; benzyl radical; phenylethyl radical; phenyl radical; said benzyl, phenylethyl or phenyl substituent may be substituted on the benzene ring with one moiety or two moieties independently selected from the group consisting of an alkyl radical containing one to four carbon atoms, an alkoxyl radical containing one to four carbon atoms, and a halogen provided that when replacing the indicated benzene ring with two of the mentioned fragments, these fragments should contain a total of not more than six carbon atoms.

This is also -CHR _x R _y , where

R _y is hydrogen or a carbon-carbon bond, provided that when R _y is hydrogen, R _x represents an alkoxyl radical containing one to four carbon atoms, a hydroxyalkoxy radical containing one to four carbon atoms, 1-alkynyl a radical containing from two to ten carbon atoms, a tetrahydropyranyl radical, an alkoxyalkyl radical in which the alkoxyl fragment contains from one to four carbon atoms and the alkyl fragment contains from one to four carbon atoms, 2-, 3- or 4-pyridyl th radical with the further proviso that when R _y - is a carbon-carbon bond, then R _y and R _x together form a tetrahydrofuranyl group optionally substituted with one substituent or more substituents independently selected from the group consisting of hydroxyl radical and a hydroxyalkyl radical containing one to four carbon atoms.

R _{26 is} selected from the group consisting of hydrogen, a straight or branched chain alkyl radical containing from one to eight carbon atoms, a straight or branched chain hydroxyalkyl radical containing from one to six carbon atoms, a morpholinoalkyl radical, a benzyl radical, a phenylethyl radical and a phenyl radical, wherein the benzyl, phenylethyl or phenyl substituent may be substituted on the benzene ring with a moiety selected from the group consisting of a methyl and methoxy radical and halogen-containing group and

-C (R _s ) (R _T ) (X),

where R _S and R _T are independently selected from the group consisting of hydrogen, an alkyl radical containing from one to four carbon atoms, a phenyl radical and a substituted phenyl radical, where the substituent is selected from the group consisting of an alkyl radical containing from one to four atoms carbon, an alkoxyl radical containing from one to four carbon atoms, and halogen.

X is selected from the group consisting of an alkoxyl radical containing one to four carbon atoms, an alkoxyalkyl radical in which the alkoxyl fragment contains one to four carbon atoms, and the alkyl fragment contains one to four carbon atoms, a haloalkyl radical containing one up to four carbon atoms, an alkylamide radical in which the alkyl group contains one to four carbon atoms, an amine radical, a substituted amine radical, in which the substituent represents oboj alkyl or hydroxyalkyl radical containing from one to four carbon atoms, azido radical, alkylthio radical containing from one to four carbon atoms and morfolinalkilnogo radical in which the alkyl moiety contains one to four carbon atoms, and

R _{6 is} selected from the group consisting of hydrogen, fluorine and chlorine atoms, a straight or branched chain alkyl radical containing one to four carbon atoms, and a straight or branched chain fluorine or chloralkyl radical containing one to four carbon atoms and at least one fluorine or chlorine atom.

The use of pharmaceutically acceptable salts of the above compounds is possible.

Preferred IMOs that are imidazopyridinamines are described by Formula VII below:

Here, R _{17 is} selected from the group consisting of hydrogen, the radical —CH ₂ R _w , in which R _{w is} selected from the group consisting of a straight, branched or cyclic alkyl radical containing from one to ten carbon atoms, a straight chain alkenyl radical or a branched chain containing from two to ten carbon atoms, a straight or branched chain hydroxyalkyl radical containing from one to six carbon atoms, an alkoxyalkyl radical in which the alkoxyl moiety contains from one to four carbon atoms a, and the alkyl fragment contains from one to six carbon atoms, a phenylethyl radical, and also the group —CH = CR _z R _z , in which each radical R _{Z is} independently selected as straight, branched or cyclic alkyl containing from one to six carbon atoms.

R _{27 is} selected from the group consisting of hydrogen, a straight or branched chain alkyl radical containing from one to eight carbon atoms, a straight or branched chain hydroxyalkyl radical containing from one to six carbon atoms, an alkoxyalkyl radical in which the alkoxy fragment contains from one to four carbon atoms, and the alkyl fragment contains from one to six carbon atoms; benzyl, phenylethyl and phenyl radicals, wherein the benzyl, phenylethyl and phenyl substituents may be substituted on the benzene ring with a moiety selected from the group consisting of a methyl radical, methoxy radical and halogen; morpholinoalkyl radical in which the alkyl fragment contains from one to four carbon atoms.

R ₆₇ and R _{77 are} independently selected from the group consisting of hydrogen and an alkyl radical in which the content of carbon atoms is from one to five, provided that R ₆₇ and R ₇₇ total contain no more than six carbon atoms, and under the additional condition that if R ₇₇ is hydrogen, then R _{67 is} not hydrogen, and R _{27 is} not hydrogen or a morpholinalkyl radical, provided that R ₆₇ is hydrogen, then R ₇₇ and R ₂₇ are not hydrogen.

The use of pharmaceutically acceptable salts of the above compounds is possible.

Preferred IMOs representing imidazoquinolinamines are described by Formula VIII below:

Here Z is selected from the group consisting of radicals:

- (CH ₂ ) _p -, where p = 1-4;

- (CH ₂ ) _a -C (R _D R _E ) (CH ₂ ) _b -, where a and b are integers, and a + b can take values from 0 to 3, R _D is hydrogen or an alkyl radical containing from one to four carbon atoms, a R _E selected from the group consisting of an alkyl radical containing from one to four carbon atoms, hydroxyl, - OR _F , where R _F is an alkyl radical containing from one to four carbon atoms, and - NR _{G R'G} , where R _G and _{R'G are} independently selected from the group consisting of hydrogen and an alkyl radical containing from one to four carbon atoms, and

- (CH ₂ ) _a - (Y) - (CH ₂ ) _b -, where a and b are integers, and a + b can take values from 0 to 3, Y is O, S or - NR _j -, where R _j is hydrogen or an alkyl radical containing from one to four carbon atoms;

q can be 0 or 1, and R _{8 is} selected from the group consisting of an alkyl radical with one to four carbon atoms, an alkoxyl radical with one to four carbon atoms and halogen.

The use of pharmaceutically acceptable salts of the above compounds is possible.

The corresponding chains of MIO, which are thiazolo- and oxazoloquinolinamines and pyridinamines, are described by Formula IX:

Here, R _{19 is} selected from the group consisting of oxygen, sulfur, and selenium;

R ₂₉ selected from the group comprising hydrogen and the following radicals:

alkyl;

- alkyl-OH;

- halogen alkyl;

alkenyl;

- alkyl-X-alkyl;

-alkyl-X-alkenyl;

- alkenyl-X-alkyl;

- alkenyl-X-alkenyl;

- alkyl-N (R ₆₉ ) ₂ ;

- alkyl-N ₃ ;

- alkyl-O-C (O) -N (R ₅₉ ) ₂ ;

heterocyclyl;

- alkyl-X-heterocyclyl;

- alkenyl-X-heterocyclyl;

- aryl;

- alkyl-X-aryl;

- alkenyl-X-aryl;

heteroaryl;

- alkyl-X-heteroaryl; and

- alkenyl-X-heteroaryl.

R ₃₉ and R ₄₉ are independently selected from the group consisting of hydrogen, halogen and the following radicals:

X-alkyl;

halogen;

alkyl halide;

- N (R ₅₉ ) ₂ ,

if R ₃₉ and R ₄₉ are taken together, they form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring.

X is selected from the group consisting of —O—, —S—, —NR ₅₉ -, —C (O) -, —C (O) O—, —OC (O) - and a bond.

Each R ₅₉ radical is independently selected from the group consisting of hydrogen and a C _1-8 alkyl radical.

The corresponding chains of MIO, which are imidazonaphthyridines and tetrahydroimidazonaphthyridines, are described by Formulas X and XI below:

Here, A represents = N-CR = CR-CR =; = CR-N = CR-CR =; = CR-CR = N-CR = or = CR-CR = CR-N =;

R ₁₁₀ selected from the group comprising hydrogen and the following radicals:

C _1-20 alkyl or C _2-20 alkenyl, unsubstituted or substituted by one substituent or a large number of substituents selected from the group consisting of the following radicals:

aryl;

heteroaryl;

heterocyclyl;

-O-C _1-20 alkyl;

-O- (C _1-20 alkyl) _0-1 aryl;

-O- (C _1-20 alkyl) _0-1- heteroaryl;

-O- (C _1-20 alkyl) _0-1- heterocyclyl;

-C _1-20 alkoxycarbonyl;

-S (O) _0-2 -C _1-20 alkyl;

-S (O) _0-2 - (C _1-20 alkyl) _0-1 aryl;

-S (O) _0-2 - (C _1-20 alkyl) _0-1- heteroaryl;

-S (O) _0-2 - (C _1-20 alkyl) _0-1 -heterocyclyl;

-N (RO) ₂ ;

-N ₃ ;

oxo;

halogen;

-NO ₂ ;

-IT;

-SH and

—C _1-20 alkyl-NR ₃₁₀ —O — X — R ₄₁₀ or —C _2-20 alkyl — NR ₃₁₀ —O — X — R ₄₁₀ , where Q is —CO— or —SO ₂ -, X is a bond , -O- or -NR ₃₁₀ ; R ₄₁₀ is aryl; heteroaryl; heterocyclyl, or - C _1-20 alkyl or C _2-20 alkenyl, unsubstituted or substituted by one substituent or a large number of substituents selected from the group consisting of the following radicals:

aryl;

heteroaryl;

heterocyclyl;

-O-C _1-20 alkyl;

-O- (C _1-20 alkyl) _0-1 aryl;

-O- (C _1-20 alkyl) _0-1- heteroaryl;

-O- (C _1-20 alkyl) _0-1- heterocyclyl;

-C _1-20 alkoxycarbonyl;

-S- (O) _0-2 -C _1-20 alkyl;

-S- (O) _0-2 - (C _1-20 alkyl) _0-1 aryl;

-S- (O) _0-2 - (C _1-20 alkyl) _0-1- heteroaryl;

-S- (O) _0-2 - (C _1-20 alkyl) _0-1- heterocyclyl;

-N (R ₃₁₀ ) ₂ ;

-NR ₃₁₀ -CO-O-C _1-20 alkyl;

-N ₃ ;

oxo;

halogen;

-NO ₂ ;

-They

-SH

or R ₄₁₀ with the following structure:

Here Y is -N- or -CR-.

R ₂₁₀ selected from the group comprising hydrogen and the following radicals:

-C _1-10 alkyl;

-C _2-10 alkenyl;

aryl;

-C _1-10 alkyl-O-C _1-10 alkyl;

-C _1-10 alkyl-O-C _2-10 alkenyl; and

—C _1-10 alkyl or C _2-10 alkenyl substituted with one substituent or a large number of substituents selected from the group consisting of the following radicals:

-IT;

halogen;

-N (R ₃₁₀ ) ₂ ;

-CO-N (R ₃₁₀ ) ₂ ;

-CO-C _1-10 alkyl;

-N ₃ ;

aryl;

heteroaryl;

heterocyclyl;

-CO-aryl and

-CO-heteroaryl.

Each of R ₃₁₀ radicals is independently selected from the group consisting of hydrogen and a C _1-10 alkyl radical.

Each of the radicals R is independently selected from the group consisting of hydrogen and radicals C _1-10 alkyl, C _1-10 alkoxy, halogen and trifluoromethyl radical.

The use of pharmaceutically acceptable salts of the above compounds is possible.

Here

B is NR-C (R) ₂ —C (R) ₂ —C (R) ₂ -; -C (R) ₂ -NR-C (R) ₂ -C (R) ₂ ; -C (R) ₂ -C (R) ₂ -NR-C (R) ₂ or -C (R) ₂ -C (R) ₂ -C (R) ₂ -NR-.

R ₁₁₁ selected from the group consisting of hydrogen and radicals

—C _1-20 alkyl or —C _2-20 alkenyl unsubstituted or containing one substituent or more substituents selected from the group consisting of the following radicals:

aryl;

heteroaryl;

heterocyclyl;

-O-C _1-20 alkyl;

-O- (C _1-20 alkyl) _0-1 aryl;

-O- (C _1-20 alkyl) _0-1- heteroaryl;

-O- (C _1-20 alkyl) _0-1- heterocyclyl;

-C _1-20 alkylalkoxycarbonyl;

-S (O) _0-2 -C _1-20 alkyl;

-S (O) _0-2 - (C _1-20 alkyl) _0-1 aryl;

-S (O) _0-2 - (C _1-20 alkyl) _0-1- heteroaryl;

-S (O) _0-2 - (C _1-20 alkyl) _0-1 -heterocyclyl;

-N (R ₃₁₁ ) ₂ ;

-N ₃ ;

oxo;

halogen;

-NO ₂ ;

-IT;

-SH and

—C _1-20 alkyl-NR ₃₁₁ —O — X — R ₄₁₁ or —C _2-20 alkyl — NR ₃₁₁ —O — X — R ₄₁₁ , where Q is —CO— or —SO ₂ -, X is a bond , -O- or -NR ₃₁₁ ; R ₄₁₁ is aryl; heteroaryl; heterocyclyl; or - C _1-20 alkyl or C _2-20 alkenyl, unsubstituted or having one substituent or more substituents selected from the group consisting of the following radicals:

aryl;

heteroaryl;

heterocyclyl;

-O-C _1-20 alkyl;

-O- (C _1-20 alkyl) _0-1 aryl;

-O- (C _1-20 alkyl) _0-1- heteroaryl;

-O- (C _1-20 alkyl) _0-1- heterocyclyl;

-C _1-20 alkoxycarbonyl;

-S- (O) _0-2 -C _1-20 alkyl;

-S- (O) _0-2 - (C _1-20 alkyl) _0-1 aryl;

-S- (O) _0-2 - (C _1-20 alkyl) _0-1- heteroaryl;

-S- (O) _0-2 - (C _1-20 alkyl) _0-1- heterocyclyl;

-N (R ₃₁₁ ) ₂ ;

-NR ₃₁₁ -CO-O-C _1-20 alkyl;

-N ₃ ;

oxo;

halogen;

-NO ₂ ;

-IT;

-SH

or R ₄₁₁ with the following structure:

Here Y is -N- or -CR-.

R _{211 is} selected from the group consisting of hydrogen and radicals

-C _1-10 alkyl;

-C _2-10 alkenyl;

aryl;

-C _1-10 alkyl-O-C _1-10 -alkyl;

-C _1-10 alkyl-O-C _2-10 alkenyl; and

—C _1-10 alkyl or C _2-10 alkenyl with one substituent or a large number of substituents selected from the group consisting of the following radicals:

-IT;

halogen;

-N (R ₃₁₁ ) ₂ ;

-CO-N (R ₃₁₁ ) ₂ ;

-CO-C _1-10 alkyl;

-N ₃ ;

aryl;

heteroaryl;

heterocyclyl;

-CO-aryl and

-CO-heteroaryl.

Each of the radicals R _{311 is} independently selected from the group consisting of hydrogen and a C _1-10 alkyl radical.

Each of the radicals R is independently selected from the group consisting of hydrogen and radicals C _1-10 alkyl, C _1-10 alkoxy, halogen and trifluoromethyl radical.

The use of pharmaceutically acceptable salts of the above compounds is possible.

The compounds mentioned above are described in the patents and applications referred to in the discussion of the background; all are incorporated herein by reference.

The substituents R _{11 to} R ₁₁₁ mentioned in this document are generally referred to as “1-substituents”. Of the 1 substituents, preference is given to alkyl radicals containing from one to six carbon atoms and hydroxyalkyl radicals containing from one to six carbon atoms. As variants of 1-substituents, a 2-methylpropyl or 2-hydroxy-2-methylpropyl radical can be used.

The substituents R _{21 to} R ₂₁₁ referred to herein are generally referred to as “2-substituents”. Variants of the 2-substituents are hydrogen, an alkyl radical containing from one to six carbon atoms, an alkoxyalkyl radical in which the alkoxy fragment contains from one to four carbon atoms, and the alkyl fragment also contains from one to four carbon atoms, and a hydroxyalkyl radical, containing one to four carbon atoms. As other variants of the 2 substituents, hydrogen and the following radicals can be used: methyl, butyl, propyl, hydroxymethyl, ethoxymethyl, methoxyethyl.

In cases where the index n can take the values 0, 1, 2, preference is given to the values 0 or 1.

Pharmaceutical formulations containing MIO

The amount of a compound having the properties of MIO and therapeutically effective in a particular situation will depend on circumstances such as the activity of a particular compound, method of application, characteristics of the composition and disease for which treatment is prescribed. Therefore, it is practically impractical to name specific amounts of a substance for use; at the same time, those skilled in the art will be able to determine the necessary therapeutically active amounts of the compounds based on the recommendations given herein, the information available on this subject, and routine tests.

The pharmaceutical compositions described below may find application in local application of MIO. Many of the formulations indicated here are especially effective for local application to the surface of mucous membranes. In some embodiments of the invention, the content of the composition can affect the pharmacokinetics of MIO so that reduced concentrations of MIO produce the same pharmacodynamic effect as compositions with a higher content of MIO.

In General, the pharmaceutical composition, which is an example embodiment of the present invention, includes MIO, fatty acid, a preservative system and, if necessary, a viscosity enhancer (for example, carbomer product). MIOs can be obtained by the methods previously described in the patents listed in the Background section, and in US patents 4988815, 5367076, 5175296, 5395937, 5741908, incorporated herein by reference. Unless otherwise specifically stated, all content values are given in mass percent relative to the total weight of the composition.

The amount of MIO present in the pharmaceutical composition of the present invention should be such as to be effective in treating a particular disease, preventing relapse, or developing immunity to the disease. The preferred amount of MIO is from about 0.1 to about 9 wt.% With respect to the total weight of the composition. Alternatively, the content of MIO will not exceed about 5 wt.%; the most preferred content is in the approximate range of from 0.1 to 3 wt.% when applying the drug to the surface of the mucous membrane.

Typically, the pharmaceutical composition of the present invention is formulated as an oil-in-water emulsion. The oil component of the drug includes MIO and fatty acid. Fatty acid is present in the composition in an amount sufficient to dissolve the MIO. The approximate fatty acid content is 2-45%, the typical content is 10-30%, the preferred content is 15-18% with respect to the total weight of the preparation. Fatty acids such as isostearic acid can be used to prepare formulations. On the other hand, MIO can be dissolved in linear carboxylic acids containing from six to eight carbon atoms.

The medicament of the present invention may also include an emulsifier, for example a nonionic surfactant. Suitable surfactants may, for example, include polysorbate 60, sorbitan monostearate, polyglyceryl-4-oleate, polyoxyethylene (4) lauryl ether, etc. In some formulations, surfactants such as poloxamers (e.g., Pluronic F68 manufactured by BASF, Ludwigshafen, Germany) and sorbitan trioleate (e.g. Span 85 manufactured by Sigma Chemical Co., St. Louis, Missouri, USA) are used, which are used separately or in combination. A nonionic surfactant is usually present in an amount of from about 0.5% to about 10% with respect to the total weight of the preparation. In preferred embodiments, the total emulsifier content does not exceed about 5% of the total weight of the drug; more preferably, this content is about 3.5% of the total weight of the drug.

The drug of the present invention may also contain a viscosity enhancer, for example, carbomer; preferably, the viscosity enhancer is characterized by adhesion to the mucous membranes. Carbomer may be present in a concentration of approximately 0.1-8%. The preferred content may be about 0.5-4%, more preferred about 0.5-3%, most preferred about 1.0% of the total weight of the drug. Suitable carbomers include polyacrylic acids such as Carbopol 934P, Carbopol 971P, Carbopol 940 and Carbopol 974P, manufactured by B. F. Goodrich. Carbopol 974P is preferred.

In some embodiments, a chelating agent may be included. Such a compound forms chelates with metal ions. In the case of the presence of metal ions, a violation of the gel formation process can occur due to suppression of ionization, which facilitates gelation in the preparation containing carbomer. Alternatively, it is possible to use the disodium salt of EDTA (ethylenediaminetetraacetic acid) in a concentration of about 0.0001-0.5%. Typically, the concentration of this substance is approximately 0.0005-0.1% of the total weight of the drug.

You can enter into the composition of any preservative from the group which includes methylparaben, sorbic acid, propylene glycol, etc. In one embodiment, methyl paraben and sorbic acid are present in exemplary concentrations from 0.05 to 0.3% at a preferred concentration of 0.15% of the total weight of the preparation. Propylene glycol is administered in amounts up to almost 30%; preferred content of about 5%. It was found that this combination of preservatives can successfully pass the test for the effectiveness of preserving action (Preservation Effectiveness Test-PET, 1997 European Pharmacopeia, Test 5.1.3 Efficacy Antimicrobial Preservation - Topical Preparations - A. Criteria - European Pharmacopoeia 1997, Test 5.1. 3 - The effectiveness of antimicrobial preservatives, Preparations for local application, Criteria). This property allows the use of the composition in a reusable device without adversely affecting the stability of the composition. Methylparaben and sorbic acid can be dissolved in propylene glycol before entering into the composition of the drug.

The remaining components of the drug may include water, which ensures the removal of the drug from the surface of the mucous membrane under the action of normal physiological cleaning processes.

In addition to giving the drug the possibility of adhesion to the mucous membranes, the carbomer increases the viscosity of the drug, forming a stabilizing gel. The pH at which gelation occurs is influenced by many factors, such as the amount of oil phase, the content of active substance and the amount of carbomer. In some formulations, the presence of metal ions and surfactants leads to an increase in pH at which a carbomer gel is formed. So, in the absence of a chelating agent or in the presence of elevated surfactant contents, the pH of gelation can increase. Therefore, it may be necessary to introduce an organic or inorganic base or other substance to facilitate gelation. The corresponding chain of inorganic bases may include, for example, KOH, NaOH, etc. The pH of the drug of the present invention is usually about 3.0-7.0, a preferred value is about 4.0-6.0.

Application of the drug to the mucous membranes

According to the invention, the compositions in question can be applied topically, in particular to non-keratinized epithelial surfaces, such as mucosal surfaces. The mucous membranes include the mucous membranes of the cheeks, gums, nose, trachea, bronchi, gastrointestinal tract, rectal cavity, urethra, ureters, vaginal cavity, uterine cavity, etc. Depending on the concentration of MIO, the composition of the drug and the nature of the mucous membrane, the therapeutic effect of MIO can only extend to the surface layers of the mucous membrane or to deep tissues.

In one embodiment, the MIO described herein can be applied locally to the vaginal or supravaginal cervical region for the treatment of dysplasia, for example, cervical intraepithelial neoplasia. In some embodiments, the compositions described above may have a particular advantage when applying MIO to the mucous membrane of the cervix for a time sufficient to obtain the desired therapeutic effect without undesirable systemic absorption of MIO.

Cervical Intraepithelial Neoplasia (CIN)

Each year, approximately 16,000 new cases of invasive cervical cancer are diagnosed in the United States, despite having a broad screening program for women aimed at detecting predictable cellular changes. In addition, in the United States alone, about 3,000 deaths caused by cervical cancer are recorded, which is usually associated with untimely detection of primary cancerous lesions.

A microscopic examination of Pap smears during screening was accepted for use in the 1950s as a way to detect abnormal cells in the cervix caused by inflammation and dysplasia, including cervical cancer. This screening method is widespread in industrialized countries; he had a strong influence on cervical cancer mortality rates. The presence of abnormal cells during the Papanicolaou study makes it necessary to carefully monitor the development of the disease with the prospect of therapeutic treatment or surgical destruction or excision of cells in a state of cancer or precancer. Excision is expensive, painful and involves the possibility of unsuccessful results, ranging from 2 to 23%; in advanced cases, the percentage of unsuccessful results increases. Recently, data have been recorded on the failure rate for laser treatments of approximately 10%.

It was previously suggested that the etiological factor causing cervical cancer is the herpes virus. However, the focus of attention gradually shifted towards the human papillomavirus (HPV), when it was shown that the cytopathogenic effect of HPV in experimental systems very realistically reproduced the effect that was observed in humans. The use of advanced experimental methods in the recent past has made it possible to characterize the full range of HPV subtypes; as a result, it was concluded that high-risk HPV subtypes (e.g., HPV 16, 18 and less commonly HPV 31, 33, 35, 45) are very likely to be exceptional factors (i.e., oncogenic substances) that trigger cervical dysplasia and further cancer. The mechanism for converting a healthy cell into dysplastic under the influence of HPV is associated with the presence of high-risk oncogenic proteins (E6 and E7) encoded by HPV; these proteins bind p53 and Rb gene products that suppress cancer cells, which disrupt the cell cycle control mechanism in which p53 and Rb play an important role. In addition, the use of these molecular methods made it possible to come to the epidemiologically important conclusions that HPV isolated from almost 93% of cervical tumors; this observation was an additional support for the generally accepted conclusion that infection with this virus is the most important factor initiating cervical cancer.

HPV infection often occurs in sexually active women, but the virus does not necessarily lead to dysplasia or cancer in most of these cases. Infected women carriers of resistant viral DNA are at five times greater risk of persistent dysplasia than women who have cleared the virus. The importance of a cell-mediated immune (COI) response to an infection of the PMI is illustrated by evidence that the antibody-mediated immune response is ineffective in combating established infections; this was shown by the fact that patients with invasive cervical cancer often had high levels of antibodies to the viral proteins E6 and E7. This type of response probably reflects the widespread exposure to antigen due to tumor growth. In contrast to the humoral immune response, which is thought to have no negative effects, the cell-mediated immune response (TP-1 type response) appears to effectively control tumor development. Regression of intraepithelial lesions is associated with the occurrence of cell infiltrate containing CD4 ⁺ T cells, CD8 ⁺ T cells, natural killer cells (NK) and macrophages. The formation of such an inflammatory infiltrate is usually associated with tumor regression, in contrast to those cases when a woman’s body is not able to give an inflammatory response, as a result of which the disease progresses. In addition, in patients with a defect in cellular immunity, the incidence of cervical cancer is increased, while in individuals with defects in antibody production an identical level of susceptibility is not observed.

In one use case of the invention, the authors propose a local application of MIO application for non-invasive treatment of cervical diseases, including cervical intraepithelial neoplasia (CIN).

Intravaginal applicators for applying MIO

To obtain a positive therapeutic or prophylactic effect in case of cervical diseases, preference is given to intravaginal application of the MIO described here. MIO can be introduced into the composition of the dosage composition or be in the device to ensure contact of the MIO with the surface of the mucous membrane of the cervix for a time sufficient to obtain the desired therapeutic effect. For applying MIO, any device (i.e., any applicator) of those described in this application and / or shown in the diagrams can be used.

In addition to the use of the already described applicators, MIOs can be incorporated into suppositories administered intravaginally using appropriate suppository applicators.

Such applicators include well-known cardboard tubes for administering drugs to the vaginal cavity. The compositions described herein can also be applied using a drum applicator, for example, such as is described here and (or) shown in the diagrams. An example of a suitable drum applicator can be found in US Pat. No. 5,282,789, incorporated herein by reference.

In one of the possible options MIO can be applied directly to the mucous membrane of the cervix. So, MIO can be applied locally to the mucous membrane of the cervix with the use of a direct applicator, as described previously, or an applicator with a cervical cap. One example of a suitable cervical cap can be found in US Pat. No. 4,858,624, which is incorporated herein by reference. Appropriate MIO formulations for direct application to the cervix are described above and in the following examples. In general, MIO, which is part of one of the compositions A-J in the following examples, can be placed in the cavity of the cervical lid for subsequent direct application to the cervix. These compositions can also be applied using other types of applicators, including those shown in the drawings and described in the text. As an application of the invention, it is possible to use MIO together with a viscosity regulator, for example, carbomer, to increase the residence time of MIO on the cervix.

The following examples are presented to further describe the compositions containing MIO, and methods of use according to the invention. At the same time, these examples do not limit the variety of compositions and methods.

EXAMPLES

EXAMPLE 1. ASSESSMENT OF SAFETY, PHARMACOKINETICS (FC) AND PHARMACODYNAMICS (PD) 1- (2-METHYLPROPYL) -1H-IMIDAZO [4,5-C] HINOLIN-4-AMINE (IMIVIMODA), APPLIED ON MY SHEAN

Ways

The results of a randomized double-blind study using a placebo aimed at elucidating the effect of a single increasing dose of imiquimod are described. 50, 100, 150, 200, and 250 mg of imiquimod were injected into a preparation made in the form of a cream; the drug was on the cervix for 8 hours. The composition of imiquimod cream (composition A) is shown in Table 1. Each group that took a certain dose included 8 patients (6 received the drug and 2 placebo); however, two patients were selected as the leading respondents, and the remaining 6 patients received treatment after an acceptable response from the leading respondents. The safety level was assessed by the number of adverse events (AEs), laboratory analysis data and colposcopy results (photographs were taken before the dose was applied and 24 hours after the dose was administered, and if necessary 48 hours after the dose was applied). The level of systemic exposure (FC) was determined by the content of imiquimod and metabolites within 48 hours after application of the dose; PD data was obtained on the basis of serum cytokine assays (tumor necrosis factor-α (TNF-α), interferon-α (IFN-α), interleukin-1 receptor agonist (IL-1RA), interleukin-6 (IL-6 ), neopterin (NPT), 2 ', 5'-oligoadenylate synthetase (2', 5'-AS)) during the application of the dose and at certain points within 48 hours after the application of the dose. Statistical criteria for evaluating AE, demographic data, laboratory tests, vital signs, and ECG were used, such as Fisher’s exact test, Wilcoxon’s rank sum criterion, and Kruskall-Wallis test. Changes in cytokine contents between groups were compared by the Wilcoxon rank sum criterion, and deviations from the baseline were evaluated by the Spearman rank correlation method.

results

The study involved 39 healthy women aged 18 to 50 years who underwent surgical sterilization. The body weight of the participants differed from the ideal value within 25%. All women received normal baseline colposcopic data; histological examinations of the cervix uteri revealed healthy cells and cells with borderline dyskariosis. Each of the 39 participants had cases of AE with a slight increase in body temperature as the most common symptom (92%). There were no differences between the groups in relation to persons who experienced one case of AE or several such cases, or in relation to the type of AE, possibly or probably attributed to the effect of the drug. Two serious AEs associated with extraneous factors were noted - ankle fracture and subsequent surgical treatment. In some laboratory parameters and heart rate, statistically significant changes were found that were not considered clinically important. There were no changes in cardiograms and in the results of physical activity. Pelvic examinations and colposcopy revealed some reactions in 2 out of 6 patients who received 250 mg of the drug: small vesicles or minor ulcerations. Such reactions took place within 48 hours. No measurable serum imiquimod levels (> 5 ng / ml) were detected. Significant deviations from the baseline were observed for IFN and IL-6 in the 250 mg group, as well as for NPT, 2 ', 5'-AS and IL-1RA in the groups receiving 150, 200 and 250 mg of the drug.

The study showed that single doses of imiquimod in the amount of up to 250 mg when applied to the cervix for 8 hours to healthy volunteers are safe and have a minimal systemic effect. Application of a dose of 150 mg to the cervix leads to an increase in the systemic concentration of certain cytokines.

TABLE 1 Components and indicators Composition A (wt.%) Imiquimod 5,0 Isostearic acid 25.0 Benzyl alcohol 2.0 Cetyl alcohol 2.2 Stearyl alcohol 3,1 White petrolatum 3.0 Polysorbate 60 3.4 Sorbitan monostearate 0.6 Glycerol 2.0 Methylparaben 0.2 Propylparaben 0.02 Water 52.98 Xanthan gum 0.5 pH 5.1 Viscosity, cP 0.33 × 10 ⁵

EXAMPLE 2. PREPARATION OF PHARMACEUTICAL COMPOSITION B

This section describes a new composition for vaginal application, which has stability, high viscosity and storage stability. The composition meets the criteria of the European Pharmacopoeia regarding the preservative efficacy test (PET). The contents of the ingredients (wt.%) In this composition (composition B) are shown in table. 2 below.

Imiquimod was dissolved in isostearic acid containing Span 85. Pluronic F68, EDTA, Carbopol 974P, propylene glycol, sorbic acid and methyl paraben were dissolved in water. After emulsification to form an oil-in-water emulsion, sodium hydroxide was added to adjust the pH to about 5.2. The pH range for this composition can range from 4.8 to 6.0.

TABLE 2 Components and indicators Composition B (wt.%) Imiquimod 5 Isostearic acid 28 Pluronic f68 2.98 Purified water 43.78 Carbopol 974P 1.7 Na ₂ EDTU 0.05 Propylene glycol fifteen Sorbic acid 0.15 Methylparaben 0.15 Span 85 2.02 5 n. Naon 1.17 pH 5.1 Viscosity, cP 6.4 × 10 ⁵

EXAMPLE 3. TRANSFER OF AN IMQUIMOD THROUGH THE SKIN OF A HAIRLESS MOUSE WHEN USING TWO COMPOSITIONS - A AND B - WITH THE CONTAINMENT OF THE BASIC SUBSTANCE 5 MAC.%

FIG.16 is a graph of the results of a study of the penetration of imiquimod from compositions A and B (examples 1 and 2) on the example of the skin of hairless mice according to the procedure described in US patent 5238944, the full contents of which are incorporated herein by reference.

A brief description of the method is as follows. The skin of hairless mice was obtained from females aged 5 to 7 weeks (Charles River). The skin was stored on ice until the start of the experiment. The skin of mice was reinforced in a diffusion cell of the type described in US Pat. No. 5,238,944. The skin was positioned with the epidermal side up between the upper and lower parts of the diffusion cell, held together by a hinge lock.

Part of the cell under the skin layer was filled to the brim with absorbing liquid (0.1 N HCl) so that the skin was in contact with the liquid. The absorbing liquid was mixed with a magnetic stick and a magnetic stirrer.

Approximately 100 ± 5 mg of the test composition was applied to the epidermal (upper) side of the skin in an even layer, affecting only that area that would be in contact with the absorbing fluid when the skin was fixed in the diffusion cell. The composition was applied to the skin before the introduction of the absorbing liquid into the lower part of the cell.

The cell was placed in a thermostat with a temperature of 31 ° C. To maintain a constant temperature, a heat exchanger connected with a water bath and a circulation fan were installed in the thermostat. The absorbing liquid was stirred with a magnetic stirrer throughout the experiment in order to ensure uniformity of the sample and reduce the thickness of the diffusion barrier layer on the dermal side of the skin. At certain points in time (1, 2, 4, 6, 8, 12, and 24 hours), the entire volume of the absorbing liquid was completely removed and a new portion of the liquid was introduced. The removed absorbing liquid was analyzed for the imiquimod content by the unmodified HPLC method with the following parameters.

The detector is ultraviolet (258 nm). Mobile phase: acetonitrile-water mixture (25: 75) containing 1% triethylamine and 0.2% 1-octanesulfonate; The pH was adjusted to 2.0 by the addition of H ₃ PO ₄ . Stationary phase: C8 Zorbax RX-C8, 5 μm. Flow rate: 2 ml / min. Duration of separation: about 10 minutes.

The total amount of diffused substance was plotted on a time dependence graph to obtain the stationary velocity value.

EXAMPLE 4. Transfer of imiquimod through the skin of a hairless mouse when using formulations - C-F - with the contents of the main substance (imiquimod) 1 and 3 wt.% And variable concentration of isosyresis

Table 3 below presents data on the concentration of imiquimod, the concentration of isostearic acid, viscosity, pH, and the steady-state transfer rate (μg / h) of C-F formulations through the skin of hairless mice.

The same results are given in FIG.17. The experiment procedure for studying the penetration of the analyte through the skin was the same as in example 3.

TABLE 3 Structure The concentration of MIO, wt.% The concentration of ISK, wt.% Viscosity × 10 ^-5 cP Stationary transfer rate, μg / h FROM one 5,6 5.8 18.1 D one 28 8.8 26.1 E 3 16.8 eleven 39.9 F 3 28 10 71.5

EXAMPLE 5. PHARMACOKINETIC COMPARISON OF THE BEHAVIOR OF IMIVIMOD IN THE RAT ORGANISM AFTER ONE-TIME INTRAVAGINAL APPLICATION OF COMPOSITION A AND COMPOSITION B

We compared the time profiles of the concentrations of imiquimod in rat serum after ovariectomy with a single intravaginal application of composition A or composition B. Doses of two compositions with a base substance content of 5 wt% were selected so that they were 35 mg / kg. After applying the dose, the animals were donned collars in order to prevent licking of the drug. After about 6 hours, the vagina was washed and the collars removed. Blood samples were taken before application of the dose and after 0.5, 1, 2, 3, 4 and 24 hours after application. Due to the higher viscosity of composition B, its intravaginal application was much easier; this composition was retained better than composition A.

Serum was analyzed for imiquimod by HPLC. The change in the average concentration of imiquimod over time is shown in FIG. 18. The time to reach the maximum concentration of imiquimod in serum (T _max ) was the same for both formulations (1 h). However, the maximum concentration of imiquimod (C _max ) was about 1.6 times higher for composition B than for composition A, and the area under the corresponding concentration-time curve (AUC) was 3.5 times higher (FIG. 19A and FIG. 19B). Based on these data, it can be concluded that the rate and degree of absorption of imiquimod were higher when using composition B compared to composition A.

EXAMPLE 6. PREPARATION OF PHARMACEUTICAL COMPOSITION G

The content of the composition (wt.%) G is presented in table.4.

The oil phase was prepared as follows. Imiquimod (20.0 g) was slowly introduced with stirring into isostearic acid (3000 g). The mixture was stirred and heated to 55 ° C to facilitate dissolution of the basic substance. Upon completion of dissolution, heating was completed. Sorbitan trioleate (200 g) was added and mixed thoroughly. With stirring, carbomer 974 was slowly added. Mixing was continued until the carbomer was uniformly distributed in the oil phase. Next, the oil phase was kept for cooling to a temperature below 30 ° C.

The aqueous phase was prepared as follows. Sorbic acid (30.0 g) and methyl paraben (40.0 g) were added with stirring to propylene glycol (1000 g). This mixture was carefully heated with stirring (<45 ° C) until a solution was obtained. The heat source was removed. Polaxamer 188 (500 g) was added to the solution. The mixture was stirred until the Polaxamer component was completely wetted. The resulting suspension was added to a solution of Na ₂ EDTA (10.0 g) in purified water (13950 g). This mixture was stirred until a clear solution was obtained.

A sodium hydroxide solution was prepared by dissolving sodium hydroxide granules (50 g) in purified water (1000 g).

The oil phase was added to the aqueous phase, after which a sodium hydroxide solution was introduced. The resulting mixture was stirred for at least 30 minutes to obtain a soft and shiny cream. The pH value was determined and, if necessary, adjusted to 5.6-5.8 by the addition of sodium hydroxide solution.

EXAMPLE 7. PREPARATION OF H-J PHARMACEUTICAL COMPOSITIONS

Pharmaceutical formulations H-J were prepared according to the method described in example 6. The content of the compositions (wt.%) Are presented in table 4.

TABLE 4 Components G, wt.% N, wt.% I, wt.% J, wt.% Isostearic Acid (874) 15.00 15.00 3 p.m. 18.00 Imiquimod 0.10 0.50 1,50 3.00 Sorbitan trioleate 1.00 1.00 1.00 1.00 Propylene glycol 5.00 5.00 5.00 5.00 Sorbic acid 0.15 0.15 0.15 0.15 Methylparaben 0.20 0.20 0.20 0.20 Purified water 75.00 74.60 73.60 69.10 Na ₂ EDTU 0.05 0.05 0.05 0.05 Polaxamer 188 2,50 2,50 2,50 2,50 Carbomer 974 1.00 1.00 1.00 1.00 Sodium hydroxide to the necessary content to the necessary content to the necessary content to the necessary content Amount, wt.% one hundred one hundred one hundred one hundred

From the discussion above, it follows that imidazoquinolinamines, imidazopyridinamines, cycloalkylimidazopyridinamines condensed at positions 6 and 7, and imidazoquinolinines with a bridge between positions 1 and 2 described in this application may be useful in the treatment of diseases that affect the condition of the mucous membranes in including cervical dysplasia. In addition, the described pharmaceutical compositions can be especially convenient for local application of MIO on the surface of the mucous membrane.

From the above detailed descriptions and examples, the conclusion follows clearly that changes and variations can be made to the composition of compounds, compositions, devices, systems and methods that are the subject of consideration. Other embodiments of the invention will be apparent to those skilled in the art. The authors intended to show that the descriptions and examples given in this document should be considered only as illustrations of the application.

Claims (20)

1. A system for the treatment of diseases affecting the condition of the mucous surface of the cervix or the vaginal part of the cervix, aimed at improving immunostimulating, antiviral and antitumor properties, containing
an immune response modifier (MIO) selected from imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines and their pharmaceutically acceptable salts; isostearic acid; a preservative comprising propylene glycol and a cervical applicator device for applying to the mucosal surface of the MIO, characterized in that the cervical applicator device is pre-filled with a therapeutically effective amount of an immunomodulatory compound. 2. The system according to claim 1, characterized in that the applicator device consists of a hollow sleeve containing a distal transfer part and a proximal part, and a piston moving inside the sleeve. 3. The system according to claim 1, characterized in that the applicator device is formed from high density polyethylene, low density polyethylene, linear low density polyethylene or polypropylene. 4. The system according to claim 1, characterized in that the cavity of the hollow sleeve has at least two diameters. 5. The system according to claim 1, characterized in that the cavity of the hollow sleeve has a length of from 6 cm to 24 cm 6. The system according to claim 1, characterized in that the cavity of the hollow sleeve has a diameter of from 5 mm to 15 mm 7. The system according to claim 1, characterized in that the distal transfer portion of the hollow sleeve has a diameter of from 2 mm to 12 mm 8. The system according to claim 1, characterized in that the applicator device delivers from 0.01 ml to 10 ml of the substance. 9. The system according to claim 1, characterized in that the MIO is contained in a container separated from the specified device. 10. The system according to claim 1, characterized in that it is additionally equipped with divisions on the applicator device to assist the user in determining the number of MIO in the applicator device. 11. The system according to claim 1, characterized in that the disease associated with the surface of the mucous membrane is cervical dysplasia. 12. The system of claim 10, wherein the disease affecting the condition of the mucous membrane is cervical intraepithelial neoplasia. 13. The system according to claim 2, characterized in that it further comprises a part designed to drive the piston to the distal part. 14. The system according to item 13, wherein the device has such a configuration that the movement of the specified part to the proximal part is limited when the piston is near the distal part. 15. The system according to item 13, wherein the piston is associated with the specified part with the possibility of separation. 16. The system according to item 13, wherein the specified part moves along the hollow sleeve. 17. The system according to claim 2, characterized in that it further comprises a stopper restricting the movement of the piston back to the proximal part. 18. The system according to claim 2, characterized in that the piston includes a portion protruding from the distal part when the piston is at the greatest distance from the proximal part. 19. The system according to claim 2, characterized in that the outer distal part is made in the form of a cone. 20. The system of clause 15, wherein the length of the specified part is less than the distance from the proximal part to the piston when the piston is located at the greatest distance from the proximal part.

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