UA81099C2 - System for treating a mucosal surface comprising an immune response modifier - Google Patents

Abstract

A system for treating a condition associated with a mucosal surface, the system comprising an immune response modifier (IRM) compound chosen from imidazoquinoline amines, imidazopyndine amines, 6,7-fused cycloalkylimidazopyndine amines, imidazonaphihyndine amines, oxazoloquinoline amines, thiazoloquinoline amines, 1,2-bridged imidazoquinoune amines, and pharmaceutically acceptable salts thereof and an applicator device for applying the IRM compound to the mucosal surface. This system of IRM compounds and applicator may be used to treat conditions associated with mucosal surfaces such as cervical dysphasia and cervical intraepithelial neoplasia.

Description

Description of the invention

This application is a partial continuation of co-pending application Mo09/676,339 filed on September 29, 2000, which is a continuation of application Mo09/479,578 filed on January 7, 2000. (now US Pat

Mob, 245,776), which has priority according to the application MobO/115,253, submitted on January 8, 1999. This application also claims the priority of the previous application MoboO/213,420, submitted on June 22, 200Or.)Y. In addition, the disclosures of each of the aforementioned applications are incorporated herein by reference.

The present invention relates to systems and methods for the treatment of conditions associated with the surface of the mucous membrane 70, such as the vaginal part of the cervix. In particular, the systems and methods may include an immune response modifier (IRM) compound selected from imidazoquinolinamines, imidazopyridinamines, 6b,7-fused cycloalkylimidazopyridinamines, imidazonaphthyridinamines, oxazoloquinolinamines, thiazoloquinolinamines, 1,2-bridged imidazoquinolinamines, and pharmaceutically acceptable salts thereof. In one preferred embodiment, the invention encompasses systems and methods that are particularly useful for use on the cervix in the treatment of cervical conditions such as cervical dysplasia, including human papillomavirus (HPV)-associated dysplasia.

The present invention also relates to drug delivery devices and methods of use. Some aspects of the invention are directed to the delivery of a pharmacological agent to a selected site of localization with minimal delivery to the surrounding areas of the selected site of localization. In some arbitrary embodiments, the invention is particularly useful for local delivery of a pharmacological agent to the cervix.

Many compounds - imidazoquinolinamine, imidazopyridinamine, 6,7-fused cycloalkylimidazopyridinamine, 1,2-bridged imidazoquinolinamine, thiazolo- and oxazolo-quinolinamines and pyridineamines, imidazonaphthyridine and tetrahydroimidazonaphthyridine have shown strong immunostimulatory, antiviral and antitumor (including anticancer) activities, and have also shown useful as vaccine adjuvants to enhance the immune system's protective response to vaccines. These compounds are hereafter, sometimes collectively, referred to as "MIV" compounds (He) (immune response modifiers). The immune response modifier compound can be selected from the group consisting of imidazoquinolinamines, imidazopyridinamines, 6b,7-fused cycloalkylimidazopyridinamines, imidazonaphthyridinamines, oxazoloquinolinamines, thiazoloquinolinamines, 1,2-bridged imidazoquinolinamines, and their pharmaceutically acceptable salts. Methods of manufacturing such immune response modifiers and pharmaceutical compositions containing them are disclosed, for example, in US Patents MoMo 4,689,338; 5,389,640; 5,268,376; Gee! 4,929,624; 5,266,575; 5,352,784; 5,494,916; 5,482,936; 5,346,905; 5,395,937; 5,238,944; 5,525,612; 5,175,296; 5,693,811; 5,741,908; 5,939,090; 6,110,929; 4,988,815; 5,376,076; and PCT applications with publication numbers of the UUO 099/29693; MO 00/76505; UMO 00/76518 and M/O 00/76519). The full disclosure of each of these patents and patent applications is incorporated herein by reference. 3o The immunostimulatory, antiviral, and antitumor effects of these compounds have been discussed in detail, and some specific diseases have been identified as susceptible to treatment, including basal cell carcinoma, eczema, essential thrombocytopenia, hepatitis B, multiple sclerosis, neoplasia, psoriasis, rheumatoid arthritis, type herpes simplex virus, type II herpes simplex virus and warts. One of the immune response modifier compounds, known as imiquimod, is commercially available as a topical AIdag™ formulation for the treatment of C70 anogenital warts associated with human papillomavirus. c The mechanism of antiviral and antitumor action of these immune response modifiers is believed to be largely related to the enhancement of the immune response due to the induction of various important cytokines (for example, interferons, interleukins, tumor necrosis factor, etc.). Such compositions , have been shown to stimulate the rapid release of certain monocyte/macrophage-derived cytokines and are also capable of stimulating 75 B-cell secretion of antibodies that play an important role in the antiviral antitumor effects of these immune response modifiers. One of the predominant immunostimulatory responses to these compounds is induction of the production of interferon - (IPM)-o, which is believed to be very important for strong antiviral and antitumor activity. In addition, o upregulation of cytokines such as, for example, tumor necrosis factor, 1-1 and I/-6 also has potentially beneficial actions and is believed to contribute to the antiviral and antitumor properties of these compounds.(Se) 20 Although some positive results are known, the ability to provide a therapeutic effect through topical application of an immune response modifier to treat a specific condition at a specific location may be hampered by tissue irritation, washout of the composition, insufficient penetration, or undesirable systemic delivery of the topically applied composition. Accordingly, there is a need for new methods, compositions and systems to provide the greatest therapeutic effect from this class of compounds. 59 Local administration of a pharmacological agent to the tissue surface can provide localized

HF) therapeutic effect without concomitant systemic effects. However, local application is often difficult or impossible due to the anatomical location of the tissue. In some cases, application of the agent to the general anatomical area, including or surrounding the target tissue, may be an alternative to direct local application. But, if the agent has irritating properties, this alternative has no advantages because of the possibility of irritation of the tissues surrounding the target tissue. In addition, even if the agent has no irritant properties, regional application usually requires the use of a larger volume or concentration of the agent to achieve a therapeutically equivalent result to that achieved by direct application to the target tissue.

The cervix is one example of a target tissue that is difficult to apply a topical agent to. As for the permanent position, the cervix is usually located in the upper segment of the vaginal cavity. However, while the cervix is located in the upper segment of the vaginal cavity: age, estrous cycle, pregnancy or other factors cause variations in the anatomical location of the cervix in different women and in the same woman in different conditions.

Certain cervical conditions can mostly be treated with the local application of a pharmacological agent.

Cervical dysplasia is an example of a pathological condition that can be effectively treated by direct delivery of medication to the surface of the cervix, where atypical cells are usually found. Unfortunately, currently the most available applicators for vaginal delivery of the drug are inadequate for application to the cervical surface. And, since cervical dysplasia can lead to cervical cancer, an applicator that is /o smaller than optimal is not an acceptable option.

The most available now are vaginal applicators - for application in the vaginal cavity in general, and not for direct application on the cervix. In general, the length and configuration of the applicators are insufficient to ensure delivery of the agent to the upper segment of the vaginal cavity. Delivery to the middle or lower segment of the vagina does not guarantee that the agent will reach the cervical tissue in the upper segment of the vagina. Also, except in some body positions, gravity tends to cause agents to flow out of the neck. Normal secretion and flows of menstrual and non-menstrual fluids also drain the drug from the cervix. Thus, any applicator that is not capable of re-delivering an adequate amount of agent to the upper segment of the vaginal cavity is less risky than optimal treatment.

Overcoming the inaccuracies of existing vaginal applicators used for cervical delivery of an agent by delivering an excess volume or concentration of medication may be unacceptable due to the risk of unwanted effects on surrounding tissues. However, delivery of reduced volumes or concentrations to avoid irritation to surrounding tissue risks serious consequences of ineffective treatment.

Accordingly, there remains a need for improved delivery systems and methods of local application of the pharmacological agent. high school

One aspect of the invention includes a system for treating a condition associated with a mucosal surface.

The system includes an MIV (immune response modifier) compound selected from imidazoquinolinamines, i) imidazopyridinamines, b,/-fused cycloalkylimidazopyridinamines, 1,2-bridged imidazoquinolinamines and their pharmaceutically acceptable salts. The system also includes an applicator device for applying the immune response modifier composition to the mucosal surface. Gee! zo Another aspect of the invention includes a system containing an MIV (immune response modifier) compound selected from imidazoquinolinamines, imidazopyridinamines, 6b,7-fused cycloalkylimidazopyridinamines, Me) imidazonaphthyridinamines, oxazoloquinolinamines, thiazoloquinolinamines, 1,2-bridged imidazoquinolinamines, and their pharmaceutically acceptable salts. . The system also includes an applicator device for application of the MIV (immune response modifier) composition to the mucosal surface. --

For example, the modifier of the immune response can be 1-(2-methylpropyl)-1H-imidazo|4,5-c|-quinolin-4-amine, co or 4-amino-a, a-dimethyl-2-ethoxymethyl-1H-imidazoi| 4,5-c|quinoline-1-ethanol or 2-propyl/1,3|hiazolo|4,5-c|quinoline-4-amine.

The system can be used to treat a condition associated with the mucosal surface of the cervix, optionally, the vaginal segment of the cervix. Examples of conditions related to the mucosal surface «

They include cervical dysplasia and cervical intraepithelial neoplasia. with c In an illustrative embodiment of the invention, the applicator can include an empty tube and a sliding piston within the tube. ;" Another aspect of the invention includes a method of treating a condition associated with a mucosal surface. The method includes an immune response modifier (IRM) selected from imidazoquinolinamines, imidazopyridinamines, 6b,7-condensed cycloalkylimidazopyridinamines, imidazonaphthyridinamines, oxazoloquinolinamines,

Go! thiazoloquinolinamines, 1,2-bridged imidazoquinolinamines and their pharmaceutically acceptable salts. The method also includes an applicator device for application to the surface of the mucous membrane of the compound MIV (modifier - immune response). In addition, the method further includes applying the immune response modifier compound to the surface of the mucous membrane using an applicator device.

The method may include inserting the applicator device into the vagina, positioning the distal end of the applicator device adjacent to the vaginal segment of the cervix, and applying the MIV compound to

Ge of the vaginal segment of the neck.

At least some of the embodiments disclosed herein provide systems and methods of drug administration suitable for local administration of an agent to a target tissue. The systems and methods may be useful for intravaginal delivery of a pharmacological composition. For example, some embodiments provide effective topical application of a pharmacological agent to the cervix for the treatment or prevention of conditions including, for example, cervical dysplasia. Additional aspects will be further set forth in part in the description, and in part will be apparent from the description, or may be learned application of the invention. It will be understood that at some points in the description, general principles are provided by way of example. In each case, the examples given are exemplary only and are not intended to be limiting.

It should be understood that both the foregoing general description and the following detailed description are illustrative and illustrative only, and not restrictive.

The accompanying drawings, which are included and form part of this description, illustrate some variants of implementation of the 65 Invention and, together with the description, are intended to explain the principles of the invention.

Fig. 1A is a top view of a treatment system including an applicator device and a container containing a compound

MIV (immune response modifier) packaged together;

Fig. 1B is a top view of the treatment system with cartridges: pre-filled with the MIV compound (immune response modifier),

Fig. 2 - a perspective view of the components of the intravaginal delivery device in the disassembled state;

Fig. 3 - a proximal flank view of a sample of an intravaginal means of delivery;

Fig. 4 is a longitudinal section of a sample of an intravaginal delivery device, taken through line 4-4, with the push-out element located proximally;

Fig. 5 is a longitudinal section of a sample of an intravaginal delivery device with an ejection element advanced 7/o distally;

Figure 6 is a close-up view of the proximal end of the intravaginal delivery device shown in Figure 5;

Fig. 7 is a close-up view of the distal end of the intravaginal delivery device shown in Fig. 5;

Fig. 8 is an exploded perspective view of components of an optional alternative implementation of an intravaginal delivery device according to the invention;

Fig. 9 is a longitudinal section of the intravaginal delivery device in Fig. 8 with the push-out element located proximally;

Figure 10 is a longitudinal section of the intravaginal delivery device of Figure 8 with the ejection element advanced distally;

Fig. 11 is a close-up view of the distal end of the intravaginal delivery device shown in Fig. 10;

Fig. 12 is a close-up view of the proximal end of the drug delivery means shown in Fig. 10;

Fig. 13 is a perspective view of an alternative proximal end for an intravaginal means of delivery;

Fig. 14 is a perspective view of another alternative proximal end for an intravaginal means of delivery;

Fig. 15 is a longitudinal section of a sample of an intravaginal delivery device pre-filled with a composition; high school

Fig. 16 - a diagram comparing the passage of imiquimod through hairless skin of a mouse from three pharmaceutical compositions containing 595 imiquimod; at

Fig. 17 - a diagram comparing the passage of imiquimod through the hairless skin of a mouse from four pharmaceutical compositions containing different concentrations of imiquimod and isostearic acid;

Fig. 18 - a diagram comparing the average concentration of imiquimod in the serum of rats after one He!

From an intravaginal dose of composition A or composition B; and

Figures 19A and 198 show bar graphs of the pharmacokinetic comparison of imiquimod in rats after intravaginal administration of composition A or composition B.

Now a description of some illustrative variants of the invention will be made, examples of which are illustrated in the accompanying drawings. Wherever possible, the same numerals will be used throughout the drawings to refer to the same or similar parts. co

The present invention may be partially directed to medication applicators and methods of delivery of a pharmacological agent to a selected localization site. In some arbitrary implementations, dispensers for intravaginal delivery of a pharmacological agent may be particularly suitable. In arbitrary implementation options, the described dispensers can provide local application of a pharmacological agent to "

An intravaginal site of localization, such as the cervix, for the treatment of conditions including, for example, cervical dysplasia. In general, dispensers can be used to deliver a pharmacological agent at a frequency and . the amount necessary to obtain the desired treatment result. a In the description, general principles are provided by giving examples. In each specific case, the given examples serve only as samples. This is not to say, however, that the examples are limiting.

In this context, the term "pharmacological agent" includes any agent or combination of agents that can be used to diagnose, treat, improve, prevent, or otherwise affect a patient's condition. The term "condition" refers to any infectious, non-infectious, pathological, physiological, biochemical or other condition of a patient that can be treated in accordance with the invention. Throughout the description, unless otherwise indicated, the terms "proximal" and "distal" are the term "proximal" refers to the nearest location of the user (eg, the hand of the user using the dispenser) and the term "distal" refers to the location remote from

Ge) of the user. Thus, in a typical embodiment of the invention, the proximal end of the delivery means will be closest to the user's hand, and the distal end of the device will be located closest to the tissue site in which the agent will be applied. 5B In this context, "mucosa-related condition" means an inflammatory, infectious, neoplastic or other condition involving the surface of the mucosa, or located in sufficient proximity to the surface (F, of the mucosa) to be affected by a therapeutic or prophylactic agent , applied locally to the surface of the mucous membrane.

Unless otherwise indicated, the term "treat" and derivatives such as therapy, treatment, etc., are used herein to indicate the administration of a pharmacological agent for any reason to a patient, and are not intended to distinguish between prophylactic, therapeutic, diagnostic , palliative or other procedure. The term "therapeutically effective amount" means the amount of an agent administered to provide a desired therapeutic effect, such as cytokine induction, antiviral or antitumor activity. "Therapeutically effective amount" includes a unit dose of an agent used during a course of therapy to achieve the desired therapeutic effect.

Some arbitrary embodiments of the devices and methods of the invention may be useful for delivering an agent to the cervix through the vagina for the treatment (ie, prevention, diagnosis, amelioration, etc.) of a cervical condition. In some arbitrary embodiments, the dispensers of the invention may be particularly useful for delivery (MIV) to the neck for a cervical condition. Приклади МІВ (модифікаторів імунної відповіді), що можуть використовуватися у винаході, включають модифікатори, розкриті, наприклад, в |(патентах США МоМо 4,689,338; 5,389,640; 5,268,376; 4,929,624; 5,266,575; 5,352,784; 5494,916; 5,482,936; 5,346,905; 5,395,937; 5,238,944 ; 5,525,612; 5,175,296; 5,693,811; 5,741,908, 5,939,090; 6,110,929; 4,988,815; 5,376,076 and applications

PCT with publication numbers UMO 99/29693; UMO 00/76505; MO 00/76518 and MO 00/76519). The full disclosure of each of these patents and applications is incorporated herein by reference. Some optional immune response modifiers that may be used in the invention include 1-(2-methylpropyl)-1H-imidazo|4,5-c)quinolin-4-amine (imiquimod) and compounds and compositions such as disclosed in US application Mo09/479,578, which examination is not completed, and applications

PCT with publication number MUO 00/06577|Y. The full disclosure of each of these patents and applications is incorporated herein by reference.

In general, the "user" of the described dispensers (also referred to herein as applicators) includes 7/5 health care workers, those who apply the agent to a patient, or patients themselves who apply them to themselves.

In some arbitrary implementations, dispensers can provide accurate delivery of a prescribed amount of a pharmacological agent to a selected localization site with a reduced probability of accidental delivery to surrounding tissues. Typically, the prescribed amount is a therapeutically effective single dose amount

Precise application of the agent to the selected site of localization can preferably reduce the amount of agent necessary to achieve a therapeutic result, while reducing the possibility of irritation of adjacent tissues.

In the case of intravaginal applications, the dispenser can reduce unwanted side effects caused by the agent. For example, when in the case of cervical pathology it is desirable to deliver the agent only to the cervix, the delivery of the agent to localization sites other than the upper segment of the vaginal cavity can unnecessarily expose the lower segment of the vagina and other surrounding tissues to action. This not only exposes healthy tissues to the action of the agent, but also potentially irritates the tissues, which can be caused both by the agent itself and by other components of i) the pharmaceutical composition.

Intravaginal dispensers can arbitrarily provide accurate delivery of the volume of the agent (or its composition), which is smaller than the volumes usually used for the introduction of other intravaginal He! with means In some optional embodiments, intravaginal dispensers can deliver approximately 0.1-10ml, in other optional embodiments approximately 0.5 to 4ml, and typically approximately 1.Oml. at

Dispensers may be prefilled with a therapeutically effective amount of a particular agent or filled by the user immediately prior to administration. In the latter embodiment, the dispensers may be configured to accept the agent from its source (eg, aluminum tube, plastic tube, etc.) which may be attached to the dispenser for filling the latter. Some optional dispensers can usually be provided with a fixed maximum volume of agent. Alternatively, or in addition, the dispensers may have an ascending marking for filling quantities smaller than the maximum volume of the dispenser. "

In an arbitrary embodiment of the invention, the pre-filled dispenser can be provided with the possibility of eliminating the filling of the delivery means with the wrong amount of agent. In one arbitrary embodiment of the invention, the dispensers can be pre-filled with the composition, including the amount of the compound; Single-use IMR (Immune Response Modifier) The dispenser, pre-filled or empty, can be packaged in an outer wrapper, such as foil, which maintains sterility and can isolate from moisture.

The dispenser can be formed by known methods, including a casting process that forms a plastic applicator from polymeric materials such as high density polyethylene, low density polyethylene, linear low density polyethylene, or polypropylene. - Figure 1A shows a treatment system 400 that includes an applicator device 10 and a composition container 401 packaged together in a package 402. The device 10 can be configured to be filled with the composition contained in the container 401 by placing them in fluid communication of one with another 18 shows a treatment system 400 where the composition is contained in pre-filled cartridges

Ge) 401a-4014, capable of being loaded into the distribution device 10 one at a time.

Figures 2 and 4 show an arbitrary version of the intravaginal delivery device 10 according to the invention. As can be seen, the device 10 may include a distal end 1, a proximal end 2 and a longitudinal axis bvo X-X passing through them. Figure 2 is an exploded perspective view of the components of the device 10, including an elongated tube 3 having a delivery end 4, a working end 5 and a lumen b passing through

F) him. The working end 5 may include a manual adjustment 7 of the type of opposing protrusions va and 865 for fixing the device 10 during use. In some embodiments, the elongated tube C may have a length of about 10 cm to about 24 cm, typically about 10 cm to about 18 cm. The ejectable member 11 may slide within the lumen b of the elongated tube C and may include an ejectable end 12 and a trigger end 13. The ejectable end 12 may include a platform 14 for placing a user's thumb or index finger to advance the distal ejectable member 11 in within the lumen 6. The piston 15 may be capable of being mounted on the trigger end 13 of the ejectable part 11 and may have a distal tip 16 with an opposite end 17. The cap 18 may be 65 removable and mounted on the distal end 4 of the device 10 by known means, such as, for example, a thread or a ground fit.

Fig. 3 is a view of the distal end of the device 10, and Fig. 4 is a longitudinal section of the device 10 taken along line 4-4 of Fig. 3. Figure 4 shows a piston 15 mounted on the trigger end 13 of the ejectable part 11 and located in the initial position, which provides a chamber 20 for holding or receiving a defined amount of pharmacological agent.

In some arbitrary embodiments, the chamber 20 provides a volume of pharmacological agent from about bml to 0.1 ml, usually from about 2 ml to 0.5 ml, and, arbitrarily, about 1.0 ml. In an optional embodiment of the invention, the trigger end 13 with the ejectable part 11 can be detachable, inserted into the hole 19 of the piston 15. Thus, in this arbitrary embodiment of the invention, if the ejectable part 11 is moved proximally, the trigger end 13 of the ejectable part 11 can be freely ejected from the opening 19 and the piston 15 will not move proximally with the ejectable member 11. This optional aspect can prevent aspiration of the agent after the agent is released from the chamber 20 and can also prevent aspiration of tissue into the delivery end 4 of the tube 3 if the ejectable part 11 is moved proximally

In addition, in some arbitrary implementations, the lumen b may include a stopper 40, such as a 7/5 projection. A1, which can be released into the lumen 6 to prevent proximal movement of the piston 15. Whether the device 10 is pre-filled with the agent or filled by the user during use, the position of the stopper 40 can provide a fixed maximum volume of the chamber 20 to contain a predetermined amount of the agent.

This stopper can protect the user from exceeding a specific dose of the agent if the device 70 is filled by the user before use.

The cap 18 is shown mounted on the delivery end 4. The cap 18 may be frictionally fitted to the outer surface 35 of the delivery end 4. Alternatively, or in addition, the cap 18 may include a rod 18a which is frictionally fitted to the distal end 1 of the lumen b. The distal end 1 of the lumen 6 may alternatively have an internal thread (not shown) which may be connected by means of an external thread (not shown) which may be present on the outer surface of the rod 18a. The cap 18 can also include a tab 180, which provides easier capture of the cap 18 when removing it from the tube 3.

The cap 18 may optionally include textures such as knurling, ridges, etc. to facilitate removal. (8)

Markings, such as a relief arrow, can be optionally added to the cap 18 to indicate the direction of unscrewing for removal to facilitate comfortable use of the device.

In Fig. 5, the push-out part 11 is distally advanced to a position that causes the release of a pharmacological agent from the compartment 20. In an arbitrary illustrated embodiment of the invention, when the push-out part 11 is distally advanced, the distal tip 16 of the piston 15 protrudes above the distal end 4 of the elongated tubes Me

Q. In addition, the distal tip 16 may be convex in shape or domed externally to ensure complete release of the agent from the chamber 20.

Fig. 1b is a close-up view of an optional embodiment of the proximal end 2 of the delivery means 10. B --

According to the shown embodiment of the invention, the platform 14 of the push-out part 11 forms a shoulder 25 in connection with the push-out end 12 of the push-out part 11. When the push-out part 11 is advanced distally within the lumen 6, the shoulder 25 can be reliably stopped by abutting the working end 5 of the elongated tube 3, which may indicate complete delivery of the pharmacological agent from the chamber 20 of the device 10.

Fig. 7 is a large plan of an arbitrary embodiment of the distal end 1 of the delivery means 10. As shown, the distal "

The end of the chamber 20 of the lumen 6 may include a converging cone 30. The outer surface 31 of the piston 15 may also have a converging cone 32 that may extend to the distal tip 16. The respective converging cones 30 and 32 may facilitate full delivery of the pharmacological agent contained within chamber 20 when ;" push-out part 11 is advanced distally. The piston 15 may also include an annular seal C3, such as an annular projection 34, which may be tightly fitted against the lumen 6 to ensure that a significant portion, preferably all, of the pharmacological agent is removed from the lumen b as the piston 15 is advanced.

Go! distally Thus, the lumen b can have at least two different diameters, the lumen diameter Gr and the delivery diameter Or. A typical diameter of the lumen can be from about 5 mm to about 15 mm and a typical delivery diameter can be from about 2 mm to about 1 mm. In an example of a delivery means 10 with a maximum compartment volume of about iml, the length of the elongated tube C can be about 12-20 cm, |y) can be about 10 mm, and Go can be about bmm. se) The outer surface 35 of the distal end 1 of the elongated tube C may also have a converging cone 36,

Ge) to facilitate the introduction of the distal end 1 of the device 10 into the vagina. After pushing the agent out of the chamber 20, the converging cone 36 can also ensure that all of the released agent remains at the delivery site.

For example, when delivering an agent to the cervix, the walls of the sheath surrounding the distal end 1 may fit snugly around the distal end 1 to wipe away any amount of agent remaining on the tip compared to applicators having a square-ended end (i.e. , a regular cylinder) head (F, or a square head with rounded ends. ka In use, the user can place the thumb and middle finger closest to the protrusions va and 8p6 of the manual adjustment 7 to hold the device 10 in the selected location, while the index finger of the user is placed on the platform 14 to the distally advanced push-out part 11 so that the distal tip 16 of the piston 15 removes the pharmacological agent from the chamber 20 to deliver the agent to an intravaginal location, such as the surface of the cervical mucosa.

Fig. 8 is an exploded perspective view of the components of an arbitrary alternative embodiment of an intravaginal delivery device 100. As shown, the delivery device 100 may include a proximal end 65, 101, a distal end 102, and a longitudinal X-X axis passing therethrough. The elongated tube 103 may have a delivery end 104, a working end 105, and a lumen 106 extending therethrough. The cap 108 can be force-fitted or screwed onto the distal end 102 of the device 100 as described above for the cap 18 of the device 10.

The working end 105 of the elongated tube 103 may include a retaining device 107, including a protrusion 118, to facilitate manipulation of the device 100 during use. In an arbitrary illustrated embodiment of the invention, the protrusion 118 may extend continuously around the perimeter of the working end 105.

However, it will be understood that there is no need for the protrusion 118 to be continuous and, in other embodiments, the protrusion 118 may be absent.

The push-out part 111 can be slidably inserted into the lumen 106 and can include 70 a push-out end 113, a movable end 114 and a rod 115 passing between them. The push-out end 113 may include a platform 116 for accommodating a user's thumb or finger to distally advance the push-out part 111 during use. The platform 116 may have a concave surface 117 to better conform to the user's finger or thumb. The piston 120 can be securely attached to the movable end 114 of the ejectable part 111 or the movable end 114 can be made detachable, which is inserted into the hole 122a in the end 122. The piston 120 can include a distal head 121. In some embodiments, the distal head 121 can be rounded or cover the outside with a dome to further guarantee complete expulsion of the agent.

Fig. 9 is a longitudinal section of the device 100 showing a chamber 130 for holding or receiving a predetermined amount of pharmacological agent when the ejectable part 111 is proximally directed within the lumen 106 of the elongated tube 103. Fig. 10 shows that when the ejectable part 111 is distally advanced, the distal head 121 of the piston 120 may extend beyond the distal end 102 of the elongated tube 103.

11 is a close-up view of the distal end 102 of a projection of the device 100, showing that the camera 130 may include a converging cone 131 at the distal end 102 of the lumen 106. An arbitrary converging cone 131 of the camera 130 may be configured with a corresponding converging cone 132 in the distal part of the piston 120. The converging surfaces 131 and 132 may facilitate the complete expulsion of i) the pharmacological agent contained within the chamber 130.

The piston 120 may also include an o-ring 133, such as an annular projection 134, which may fit snugly against the lumen 106 to ensure complete ejection of the agent as the piston 120 Ge! zo advances distally. The outer surface 135 of the distal end 102 of the elongated tube 103 may be tapered 136 for the reasons discussed above. Me

With respect to the device 10, in some arbitrary embodiments, the lumen 106 may include a stopper 140, such as a protrusion 141, that may extend into the lumen 106 to prevent proximal withdrawal of the piston 120. Whether the device 100 is pre-filled with the agent or filled by the user during use, -- the position of the stopper 140 can provide a fixed maximum volume of the chamber 130 to contain a predetermined amount of agent.

Fig. 12 shows a close-up view of an optional embodiment of the proximal end 101 of the device 100 of Fig. 10, which shows that when the ejectable part 111 is fully advanced distally, the platform 116 of the ejectable end 113 can be recessed within the working end 105 of the elongated tube 103 This feature reduces the likelihood that some or all of the pharmacological agent released from the chamber n) c 130 will be returned back into the chamber 130 after delivery by careless proximal retraction of the ejectable member 111 after the pharmacological agent has been removed. ;" Also, in some arbitrary implementations, the working end 105 of the elongated tube 103 and the ejectable end 113 of the ejectable part 111 may be designed to provide audible and/or tactile feedback to the user when the ejection of the agent is complete. According to this arbitrary

Go! variant embodiment, the working end 105 of the lumen 106 may include a projecting surface 145 of the type of rib 146 at a location closest to the platform 116 when the ejectable part 111 is fully advanced - distally. The platform 116 may be sized such that when the platform 116 is pushed distally through the rib 146, a click should be heard and movement through the rib 146 creates an audible click to indicate

The user about the complete expulsion of the agent. The rib 146 may also act to "lock" the push piece 111 in the distally advanced portion and may prevent proximal retraction.

Ge) of the pushed-out part 111.

It will be taken into account that in addition to the diameter of the lumen | p and the delivery diameter Or, the lumen 106 also has a diameter Ro at the working end 105. The lumen 106, thus, may have a cone 150 extending between the diameter Ro and Gr. In an example delivery device 100 having a maximum chamber volume of approximately 1 mL, the length of the elongated tube 103 is approximately 15 to approximately 17 cm, I 5 is approximately 11-15 mm, and Or is approximately 1 F) 7-12 mm. In an arbitrary alternative embodiment of the invention, the portion of elongated tube 103 shown as having parallel sides (see, e.g., FIG. 9 ) extending from the proximal end to the distal end may alternatively have a taper converging from the proximal end to the distal end. This can usefully ensure that the delivery means is filled with the pharmacological agent from the proximal end of the elongated tube rather than from the distal end. That is, without the cone just described, attempts to push the piston distally through the non-coned tube after filling the composition may be hampered by air that may be trapped between the piston seal and the lumen wall. 65 By coning the elongated lumen as described, a gap may remain between the piston and the wall, which may allow air to escape as the piston is advanced distally. Such a taper may occur gradually along the length of the tube, or there may be a sharp taper near where the piston must be positioned to establish a predetermined volume at the distal end of the elongated tube.

Figure 13 shows another optional embodiment of the working end of an elongated tube suitable for means of intravaginal delivery 10, 100 according to the invention. According to this embodiment, the working end 201 of the elongated tube 200 may include a structure that provides an indicator 203 of the orientation of the device 200 around the longitudinal axis X-X. Thus, in the embodiment of the invention of Fig.13, the opposite sides 204 and 205 are linear, giving the working end an oval configuration in cross section. In this embodiment of the invention, the protrusion 206 may extend around the perimeter of the working end 201. However, it will be 7/0 understood that the protrusion may be completely absent or be discontinuous around the perimeter.

Figure 14 shows another optional embodiment of the working end of the elongated tube 300, suitable for a means of intravaginal delivery according to the invention. In this variant of the implementation of the invention, the working end 301 of the elongated tube 300 can include a structure that also provides an indicator 303 of the orientation of the device

Z00 around the longitudinal axis X-X. The working end 301 may include vertices 304a-3044. The walls ZO5a-zo5a of the working end 301 between the vertices 304a-3044 form a cone that extends from the diameter P o of the working end to the diameter I p of the lumen. In the given version of the invention, the nearest side of each of the walls ZO5a-305a may include a concave cavity ZOba-30ba, extending distally into the surface of the walls ZOba-zo5a, respectively. In addition, the platform 350 of the ejector part (not shown) may have a distally concave surface 351 and four vertices 352a-352a configured to be connected to the vertices ZOda-304a of the walls ZO5a-3054. A projection or shoulder (not shown in this embodiment) may or may not be present around the proximal edge of the working end 301 as described for devices 10 and 110.

An intravaginal delivery device can provide precise delivery of a volume of agent that is less than the volumes typically used for other vaginal treatments. Many vaginal applicators are designed to deliver approximately 5ml of agent and the delivery site is not localized, but rather delivery is to the vaginal cavity in general.

In arbitrary implementation options, such as shown in Fig.15, the applicator 10 can be filled in advance with i) product P to eliminate the possibility of incorrect filling of the applicator. However, if the device must be filled during use, a stopper-type design in the device can set a maximum volume, which can help eliminate the possibility of exceeding the prescribed dosage. Any of the aforementioned applicators may be of sufficient length to allow the distal end of the applicator to be located in, or very close to, the cervix, while the applicator portion passes through the vagina and the proximal end is placed externally. sheath. The length of the applicator can be designed to deliver the immune response modifier compound to the upper segment of the vaginal cavity while the proximal end is outside the vagina. --

For example, the length of the applicator may be sufficient to accommodate the anatomical features of women (in such a way that the treatment of women with longer vaginal cavities is not compromised.

In use, the intravaginal delivery device may be held by the proximal end between the thumb and middle finger and the platform of the ejectable part, pressed (ie, advanced distally) by the index finger to release the agent. "

In arbitrary implementations, the push-out part can be pre-installed within the lumen of the elongated tube, ready for use. If the means of delivery must be filled before use, . the distal end of the elongated tube may include an internal thread of the tube corresponding to an external thread of the medicament source, such as an aluminum tube, to provide isolation of the thread during delivery of the medicament from the source to the chamber of the delivery means.

Dispensers can be packed in a bag that provides aseptic conditions, as well as waterproofing. The package may be made of any material suitable for protecting the pharmacological agent, such as foil or multi-layered foil (eg metal and plastic layers). In some implementation options, the package can protect against moisture loss by the composition or oxidation of the composition. o The applicator device may be part of a system or component used in a method that includes additional parts or components. In one arbitrary embodiment of the invention, the systems and methods include an immune response modifier (IRM) compound for treating or preventing a condition associated with

Ge) on the surface of the mucous membrane. For example, the MIV compound can be included in a composition that can be applied to the surface of the cervical mucosa for the treatment of cervical conditions, including cervical dysplasias such as cervical intraepithelial neoplasia.

In some arbitrary implementations, certain compositions can be used to apply the compound

MIV to the surface of the mucous membrane. In some arbitrary implementations, compositions can be amplified

F) the therapeutic effectiveness of the immune response modifier, by increasing the penetration into the mucous membrane or increasing the duration of contact of the immune response modifier with the surface of the mucous membrane.

The pharmaceutical composition may contain a preservative system that makes the composition suitable for packaging in reusable containers.

Compounds of MIV

As noted above, many compounds are immune response modifiers, namely, |imidazoquinolinamine, imidazopyridinamine, 6b,7-condensed /cycloalkylimidazopyridinamine, 1,2-bridged imidazoquinolinamine, thiazolo- and oxazolo-quinolinamines and pyridinamines, imidazonaphthyridine I! tetrahydroimidazonaphthyrydynamin according to the present invention exhibit significant immunomodulating activity. Some optional compounds of the invention that are immune response modifiers include 1H-imidazo|4,5c)|quinoline-4-amines defined by one of Formulas I-M below:

MN, yu y; In and (KO as 1 and se in which o

Ki. selected from the group consisting of alkyl having from one to ten carbon atoms, hydroxyalkyl having from one to six carbon atoms, acyloxyalkyl in which the acyloxy residue is alkanoyloxy having from two to four carbon atoms or benzoyloxy, and the alkyl residue contains from Ge! from one to six carbon atoms, benzyl, (phenyl)ethyl, and phenyl, wherein said benzyl, (phenyl)ethyl, or phenyl is optionally substituted on the benzene ring by one or two residues independently selected from the group consisting of alkyl, having from one to four carbon atoms, alkoxy having from one to four carbon atoms and halogen, provided that, if said benzene ring is substituted by two of said residues, said residues together contain not more than six carbon atoms; - -

Coy is selected from the group consisting of hydrogen, alkyl of one to eight carbon atoms, benzyl, co(phenyl)ethyl, and phenyl, wherein benzyl, (phenyl)ethyl, or phenyl is optionally substituted on the benzene ring by one or two residues independently selected from a group consisting of alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms, and halogen, provided that, if said benzene ring is substituted with two of said residues, said residues together contain no more than, than " six carbon atoms; and with c each K. is independently selected from the group consisting of alkoxy having from one to four carbon atoms, halogen and alkyl having from one to four carbon atoms, and n is an integer from 0 to 2, for . . . . . . and the condition that, if n-2, then the mentioned K. groups together contain no more than six carbon atoms, 7 МН (о) 2 - (ав) » М (се) х те) 22 з (Ко) Мо бо б5 In which

Co is selected from the group consisting of straight or branched chain alkenyl having from two to ten carbon atoms and substituted straight or branched chain alkenyl having from two to ten carbon atoms, wherein the substituents are selected from the group consisting of from alkyl with a linear or branched chain having from one to four carbon atoms and cycloalkyl containing from three to six carbon atoms; and cycloalkyl containing from three to six carbon atoms substituted by straight or branched chain alkyl having from one to four carbon atoms; and

C2i1 is selected from the group consisting of hydrogen, straight or branched chain alkyl having from 7/0 one to eight carbon atoms, benzyl, (phenyl)ethyl, and phenyl, wherein benzyl, (phenyl)ethyl, or phenyl is optional substituted on the benzene ring by one or two residues independently selected from the group consisting of straight or branched chain alkyl having from one to four carbon atoms, straight or branched chain alkyl having from one to four carbon atoms, and halogen, provided that when the benzene ring is replaced by two such residues, the residues together contain not more than /5 six carbon atoms; and each Co is independently selected from the group consisting of straight or branched chain alkoxy having from one to four carbon atoms, halogen, and straight or branched chain alkyl having from one to four carbon atoms, and n is an integer from zero to 2, provided that, when n-2, said K»o groups together contain no more than six carbon atoms; s y M b U o (o) (o) (Kz 7 «- d) 2 P Z . "» where

Koz is selected from the group consisting of hydrogen, straight or branched chain alkyl having from one to eight carbon atoms, benzyl, (phenyl)ethyl, and phenyl, wherein benzyl, (phenyl)ethyl, or phenyl is optionally substituted on to the benzene ring by one or two residues independently selected from the group consisting of straight or branched chain alkyl having from one to four carbon atoms, straight or branched chain alkyl having from one to four carbon atoms, and halogen , provided that when the benzene ring is replaced by two such residues, the residues together contain no more than 5p six carbon atoms; and and, each Kz is independently selected from the group consisting of straight or branched chain alkoxy,

He having from one to four carbon atoms, halogen, and straight or branched chain alkyl having from one to four carbon atoms, and n is an integer from zero to 2, provided that when n is 2, said groups Kz together contain no more than six carbon atoms; ime) 60 b5 is) ; 75 Where are you from?

Ki4 means -SNKHUKU, where Ku is hydrogen or a carbon-carbon bond, provided that when Ku is hydrogen, Ku is alkoxy having from one to four carbon atoms, hydroxyalkoxy having from one to four carbon atoms , 1-alkynyl having from two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl in which the alkyl residue contains from one to four carbon atoms and the alkyl residue contains from one to four carbon atoms, 2-, 3-, or 4- pyridyl, with the further condition that when Ku is Ge! with a carbon-carbon bond, Ku and Ku together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and Me) hydroxyalkyl having from one to four carbon atoms; at

The code is selected from the group consisting of hydrogen, alkyl having one to four carbon atoms, phenyl, and substituted phenyl, wherein the substituents are selected from the group consisting of alkyl having one to four carbon atoms, alkoxy , which has from one to four carbon and halogen atoms; and co

K. is selected from the group consisting of hydrogen, straight-chain or branched-chain alkoxy having one to four carbon atoms, halogen, and straight-chain or branched-chain alkyl having one to four carbon atoms; « with MN; with and M

M ve her 35 - (av) and A c 15 bo de

Kv is selected from the group consisting of hydrogen; straight or branched chain alkyl having from one to ten carbon atoms and substituted straight or branched chain alkyl having from one to ten carbon atoms, wherein the substituents are selected from the group consisting of cycloalkyl containing from three up to six carbon atoms, and cycloalkyl, which contains from three to six carbon atoms, substituted by alkyl with a linear or branched chain, having from one to four carbon atoms; straight or branched chain alkenyl having from two to ten carbon atoms and substituted straight or branched chain alkenyl having from two to ten carbon atoms, wherein the substituents are selected from the group consisting of cycloalkyl having from three to of six carbon atoms, and cycloalkyl, which contains from three to six carbon atoms, substituted by a linear or branched chain alkyl having from one to four carbon atoms; hydroxyalkyl having from one to six carbon atoms; alkoxyalkyl, in which the alkoxyl residue contains from one to four carbon atoms, and the alkyl residue contains from one to six carbon atoms; acyloxyalkyl, in which the acyloxy residue is 70 alkanoyloxy having from two to four carbon atoms, or bezoyloxy, and the alkyl residue contains from one to six carbon atoms; benzyl; (phenyl)ethyl and phenyl; wherein said benzyl, (phenyl)ethyl or phenyl is optionally substituted on the benzene ring by one or two residues independently selected from the group consisting of alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms carbon, and halogen, provided that when said benzene ring is replaced by two said /5 Residues, the residues together contain no more than six carbon atoms;

Web. 2 X t- ! se 5 V» o de

Ke5 and Kt are independently selected from the group consisting of hydrogen, alkyl having from one to four Ge atoms! zo Carbon, phenyl and substituted phenyl, wherein the substituents are selected from the group consisting of alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms, and halogen; me)

X is selected from the group consisting of alkoxy having from one to four carbon atoms, o alkoxyalkyl in which the alkoxy moiety has from one to four carbon atoms, and the alkyl moiety has from one to four carbon atoms, hydroxyalkyl having from one to four atoms. (87 with 5 carbons, halo alkyl having from one to four carbon atoms, alkylamido in which the alkyl group contains from one to four carbon atoms, amino, substituted amino in which the substituents are alkyl or hydroxyalkyl having from one to four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, alkylthio, having from one to four carbon atoms; and

K5 is selected from the group consisting of hydrogen, straight or branched chain alkoxy having from one to four carbon atoms, halogen, and straight or branched chain alkyl having from one to four carbon atoms; or a pharmaceutically acceptable salt of any of the above compounds. and? Among compounds that are immune response modifiers (IRMs), preferred are the 6,7-fused cycloalkylimidazopyridinamines defined by Formula Mi below: 5 MI. - 2 (ав) зо см о M и Ф р '" with 16 bo . b5 in 1 where t is 1, 2 or 3;

Kv is selected from the group consisting of hydrogen; cyclic alkyl with three, four or five carbon atoms; straight or branched chain alkyl having from one to ten carbon atoms and Substituted straight or branched chain alkyl having from one to ten carbon atoms, wherein the substituents are selected from the group consisting of cycloalkyl having from three to of six carbon atoms, and cycloalkyl, which contains from three to six carbon atoms, substituted by a linear or branched chain alkyl having from one to four carbon atoms; fluoro- or chloroalkyl containing from one to ten carbon atoms and one or more fluorine or chlorine atoms; straight or branched chain alkenyl having from two to ten carbon atoms and substituted straight or branched alkenyl having from two to ten carbon atoms, wherein the substituents are selected from the group consisting of cycloalkyl containing from three to six carbon atoms, and cycloalkyl, which contains from three to six carbon atoms, substituted by alkyl with a linear or branched chain, having from one to four carbon atoms; hydroxyalkyl having from one to six carbon atoms; alkoxyalkyl, in which the alkyl residue contains from one 7/5 to four carbon atoms, and the alkyl residue contains from one to six carbon atoms; acyloxyalkyl, wherein the acyloxy moiety is alkanoyloxy having from two to four carbon atoms, or bezoyloxy, and the alkyl moiety has from one to six carbon atoms, provided that any such alkyl, substituted alkyl, alkenyl, substituted alkenyl, a hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group does not have a carbon atom directly bonded to a nitrogen atom completely replaced by carbon; benzyl; (phenyl)ethyl and phenyl; wherein said benzyl, (phenyl)ethyl or phenyl is optionally substituted on the benzene ring by one or two residues independently selected from the group consisting of alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms carbon, and halogen, provided that when said benzene ring is substituted by two said residues, the residues together contain no more than six carbon atoms; sch and -SNEHKU, oh where

Ku is hydrogen or a carbon-carbon bond, with the proviso that when Ku is hydrogen, Ku is alkoxy having from one to four carbon atoms, hydroxyalkoxy having from one to four carbon atoms, 1-alkynyl having from two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl, in which Ge! zo alkyl residue contains from one to four carbon atoms, and the alkyl residue contains from one to four carbon atoms, 2-, 3-, or 4-pyridyl, with the further proviso that when Ku is a carbon-carbon Me bond, Ku and Kx together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl having from one to four carbon atoms, Kov selected from the group consisting of hydrogen, alkyl with a linear or branched chain having from one to eight carbon atoms, hydroxyalkyl with a linear or branched chain having from one to six carbon atoms, morpholinoalkyl, benzyl; (phenyl)ethyl and phenyl, wherein said benzyl, (phenyl)ethyl or phenyl is optionally substituted on the benzene ring by a residue selected from the group consisting of methyl, methoxy and halogen; and -FkKeHATXX), wherein Kv and Kt are independently selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms, phenyl, and substituted phenyl, wherein the substituents are selected from the group consisting of alkyl, with has from one to four carbon atoms, alkoxy having from one to four carbon atoms, and halogen; ;" X is selected from the group consisting of alkoxy having from one to four carbon atoms, alkoxyalkyl in which the alkyloxy moiety has from one to four carbon atoms, and alkyl

The residue contains from one to four carbon atoms, haloalkyl, which has from one to four carbon atoms, alkylamido, in which the alkyl group contains from one to four carbon atoms, amino, substituted amino, in which the substituents are alkyl or hydroxyalkyl, having from one to four carbon atoms, azido, - alkylthio, which has from one to four carbon atoms, and morpholinoalkyl, in which the alkyl residue o contains from one to four carbon atoms, and

Ke is selected from the group consisting of hydrogen, fluorine, chlorine, straight or branched chain alkyl having one to four carbon atoms, and straight or branched chain fluoro or chloroalkyl,

He) having from one to four carbon atoms and at least one fluorine or chlorine atom; and their pharmaceutically acceptable salts.

Among compounds that are immune response modifiers (IRMs), preference is given to imidazopyridinamines, as defined by the IRM Formula below:

F) name) 60 b5

5 "7 And? in which village

K.7 is selected from the group consisting of hydrogen; -SNoRuu, where Km" is selected from the group consisting of straight, branched or cyclic alkyl containing from one to ten carbon atoms, (8) straight or branched chain alkenyl containing from two to ten carbon atoms, hydroxyalkyl with a straight or branched chain having from one to six carbon atoms, alkoxyalkyl, in which the alkyl residue contains from one to four carbon atoms, and the alkyl residue contains from one to six carbon atoms, and phenylethyl; ,K;, where each K; is independently an alkyl with a straight, branched or cyclic chain having from one to six carbon atoms; me)

Co.; selected from the group consisting of hydrogen, straight-chain, branched or cyclic alkyl containing from one to eight carbon atoms, straight-chain or branched hydroxyalkyl having from one to six carbon atoms, alkoxyalkyl in which the alkyl residue contains from one to -

With four carbon atoms, and the alkyl residue contains from one to six carbon atoms, benzyl; co (phenyl)ethyl and phenyl, where said benzyl, (phenyl)ethyl or phenyl is optionally substituted on the benzene ring by a residue selected from the group consisting of methyl, methoxy and halogen; and morpholinalkyl, in which the alkyl residue contains from one to four carbon atoms;

Square; and K/7; independently selected from the group consisting of hydrogen and alkyl having from one to five carbon atoms, provided that Ka; and Kk taken together contain no more than six carbon atoms, and with the further proviso that when K77 is hydrogen, then Ka; is other than hydrogen, and Co; is other than hydrogen or morpholinealkyl, and with the further proviso that when Ku; is hydrogen, then Co; and Co.; are other than hydrogen; and their pharmaceutically acceptable salts.

Among compounds that are immune response modifiers (IRM), preference is given to 1,2-bridged imidazoquinolinamines defined by Formula MI below: (ee) - (av) (se) (Che) ko bo b5 to U ! V and Y in which c 7 is selected from the group consisting of: o - (Sno)p-, where p equals from 1 to 4; - (СНИ)А-С(КогЕХСН)»-, dea and B are integers, and an is from 0 to 3, Ko is hydrogen or alkyl having from one to four carbon atoms, and Ke is selected from the group that consists of alkyl having from one to four carbon atoms, hydroxy, -OKre, where Ke is alkyl having from one to four carbon atoms, and 5 -MKeov s, where Co, and K's are independently hydrogen or alkyl , having from one to four carbon atoms; and b" -"СНао)а-(Х)-(СНо).-, деа and Б are integers, and ан equals from О to З, and M is О, 5 or -МК)-, where К) is hydrogen or alkyl having from one to four carbon atoms; (ab) and wherein 4 is 0 or 1, and Ka is selected from the group consisting of alkyl having one to four carbon atoms, alkoxy, alkyl having one to four carbon atoms, and halogen, and their pharmaceutically acceptable salts. (uh)

Acceptable thiazolo- and oxazoloquinolinamine and pyridineamine compounds that are immune response modifiers (IRMs) include compounds of Formula IX: 70 MN, as c . "» M and M o 29 shk z and o Kb 19 (se) (Che) (F) to her IX because in which:

Kv is selected from the group consisting of oxygen, sulfur and selenium;

Eoo is selected from the group consisting of -hydrogen; 65 - alkyl; -alkyl-OH;

-haloalkyl; - alkenyl; -alkyl-X-alkyl; -alkyl-X-alkenyl; -alkenyl-X-alkyl; -alkenyl-X-alkenyl; -alkyl-M(Ka)"; -alkyl-M»z; 70 - alkyl-O-C(O)-M(K 59)2; -heterocyclyl; -alkyl-X-heterocyclyl; -alkenyl-X-heterocyclyl; - aryl; -alkyl-X-aryl; -alkenyl-X-aryl; -heteroaryl; -alkyl-X-heteroaryl; and -alkenyl-X-heteroaryl;

Ezv and Kdo - each independently is: -hydrogen; -x-alkyl; -halo; -haloalkyl; sch -MZh (Evoe)"; or, taken together, K z and Klo form a condensed aromatic, heteroaromatic, cycloalkyl or i) heterocyclic ring; X is selected from the group consisting of -О-, -5-, -МКво-, -С(О)-, -С(О)О-, -ОС(О) - and a bond; and each Kbo is independently H or S. dvalkil;

Acceptable imidazonanaphthyridine and tetrahydroimidazonanaphthyridine compounds, which are modifiers of immune He! of the answer (MIV), include the compounds of Formulas X and Xi, given below: F

MN. she is 2 - d)

M

". and | evil : s - » 110 (ee) shsh - («c) o 50

F x in which 5B A is -M-SK-АС-АСК -; - SK-MAST-ASK -; -SV-SK-AM-SK -; or "ST-SK-ASN-M -; K/4o is selected from the group consisting of: (F, -hydrogen; ka -C..»oralkyl or Sooralkenyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of: 60 -aryl; - heteroaryl; -heterocyclyl; -0-C. gralalkyl, -0-(C.-coalkyl)o--aryl; 65 -0-(C. oralalkyl)o 4-heteroaryl; -0-(C. oralalkyl)o heterocyclyl ;

-S..»ralkoxycarbonyl; -5(0)0-2-C1-zoalkyl; -5(0)0-2-(C1-gralalkyl)o--aryl; -5(0)0.2-(C4 oralalkyl)o 4-heteroaryl; -5(0)0.2-(C4 oralalkyl)o 4-heterocyclyl; -M(Kz10)2; -Mz; oKso; 70 - halogen; -MO"; -OH; and -ZN; and -C4.»oalkyl-MEK2310-0-X-Clio or -Co-alkenyl-MK310-2-X-Caio, where O is -CO- or -505-; X is a bond, -O- or 75. 7MR310- and Clio is aryl; heteroaryl; heterocyclyl; or -C.4 alkyl or -Cozodalkenyl unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl; -heteroaryl; -heterocyclyl; -0-S. gralalkyl, -O-(C..hoalkyl)o--aryl; -O-(C. oralalkyl)o 4-heteroaryl; -O-(C. oralalkyl)o 4-heterocyclyl; -S..»ralkoxycarbonyl; ch -5(0)0-2-C1-zoalkyl; -5(0)0-2-(C1-gralalkyl)o--aryl; i) -5(0)0.2-(C4.oralalkyl)o4-heteroaryl; -5(0)0.2-(C4 oralalkyl)o 4-heterocyclyl; -M(Kz10)2; Ф -МКз510-СО-0-С 4 oralalkyl; -Ma; Ge) oKso; o - halogen; -MO"; "- "on; G" c) -VN; or Klio "- s 7 (0) 0-1 her ( a 1-6 (I o sei 0)2 o 50 1 y (Che) where M is -M- or -SK-;

The circle is selected from the group consisting of: -hydrogen; -C..1oalkyl; -C2 1oalkenyl; o - aryl; name) -S. zoalkyl-O-C. zoalkyl; -C4 1ralkyl-O-Co 4ralkenyl; and 60 -C..1oalkyl or C» zralkenyl substituted by one or more substituents selected from the group consisting of: -OH; - halogen; -M(Kz10)2; 65 -CO-M (Kz10)2; -b0-S. hoalkilu;

-Mz; - aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each C 4 o is independently selected from the group consisting of hydrogen and C 4 alkyl; and each K is independently selected from the group consisting of hydrogen, C..alkyl, C.4.1oalkyl, halogen, and trifluoromethyl, 70 or pharmaceutically acceptable salts thereof.

MN; "

Vp sch o (22) and x F «c) de

B is -MA-C(B)»-C(B)2- (B) 2-; "С(В)"-МВ-С(В) 2-С(ВО)2-; "C(B)"-C(B)2-MA-C(B) 2- or -"C(K)"-C(B)2-C(B)2-MV-; -

K/11 is selected from the group consisting of: so -hydrogen, -S..»oralkyle or

Co.oralkenyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl; shsh -heteroaryl; - -heterocyclyl; and -0-C. oral alkyl; -O-(C. gvalkyl)o--aryl; -O-(C. oralalkyl)o 4-heteroaryl;

Go! -O-(C. oralalkyl)o 4-heterocyclyl; -S..»ralkoxycarbonyl; - -5(0)0-2-C1-zoalkyl; o -5(0)0-2-(C1-gralalkyl)o--aryl; -5(0)0.2-(C4 oralalkyl)o 4-heteroaryl; and, -5(0)0.2-(C4 oralalkyl)o4-heterocyclyl;

Ge) -M(Kz314)2; -Mz; oKso; 5B - halogen; -MO";

F) -on; and ka -ZN; -C4 ovalkyl-MEKz44-2-X-K444 or -Co odalkenyl-MEKz344-2)-X-Calyl4, where C) is -CO- or -505-; X is a bond, -O- or bo 0 7MEz11- and Cll1 is aryl; heteroaryl; heterocyclyl; or -S. Goalkill or

Psoralkenyl, which is unsubstituted or substituted by one or more substituents selected from the group consisting of: -aryl, -heteroaryl; 65 -heterocyclyl; -0-S. pharyngitis;

-O-(C..coalkyl)o--aryl; -O-(C. oralalkyl)o 4-heteroaryl; -O-(C. oralalkyl)o 4-heterocyclyl; -S..»ralkoxycarbonyl; -5(0)0-2-C1-zoalkyl; -5(0)0-2(C,1-ooalkyl)o--aryl; -5(0)O2(Si oralalkyl)o 4-heteroaryl; -5(0)0.2-(C4 oralalkyl)o 4-heterocyclyl; 70 - M(Kz314)2; -MKz544-СО-0-С 4 oralalkyl; -Mz; oXO - halogen; -MO"; -OH; and -ZN; or K.44 is t u. and 4 sch zv (Or o sn 216 i " MV) 2 311) "c) where U is -M- or -SK-; "-

K211 is selected from the group consisting of:

From - inOodnyu; co -C.4 1oalkyl; -C5 loalkenyl; - aryl; « -C4 1ralkil-O-S. 40-alkyl; -WITH. 4oalkyl-O-C»o 4o-alkenyl; and C c -C..1oalkyl or C.40-alkenyl substituted by one or more substituents selected from the group consisting of: -OH; - halogen; 15 - M(Kz314)2;

Со-СО-М(Вз1)"; - -b0-S. hoalkilu; -Ma; o - aryl; co 020 -heteroaryl; -heterocyclyl; sr -CO-aryl; and -CO-heteroaryl; each Kaz41 is independently selected from the group consisting of hydrogen and C4 alkyl; and each K is independently 255 selected from the group consisting of hydrogen, C 41-0 alkyl, C 1-6 alkoxy, halogen, and trifluoromethyl, and their

GF) pharmaceutically acceptable salts.

The compounds mentioned above are disclosed in the patents and applications cited above in the Background of the Invention section, all of which are incorporated herein by reference.

Substituents K.4-K.414, indicated above, are generally referred to here as "1-substituents". Preferred 1-substituents are 60 alkyl containing from one to six carbon atoms and hydroxyalkyl containing from one to six carbon atoms. Optional 1-substituents are 2-methylpropyl or 2-hydroxy-2-methylpropyl.

The substituents K24-K2i14 above are generally referred to herein as "2-substituents". Optional 2-substituents are hydrogen, alkyl having from one to six carbon atoms, alkoxyalkyl in which the alkyl moiety contains from one to four carbon atoms and the alkyl moiety contains from one to four carbon atoms, and hydroxyalkyl which has from one to four carbon atoms. Optional 2-substituents are hydrogen, methyl, butyl, propylhydroxymethyl, ethoxymethyl or methoxyethyl.

In examples where n can be zero, one or two, n is preferably zero or one.

Immune Response Modifier (IRM) Pharmaceutical Prescriptions

The amount of an MIV compound that will be therapeutically effective in a given situation will depend on such things as the activity of the particular compound, the route of administration, the particular prescription of the composition, and the condition being treated. Thus, it is virtually impossible to identify specific quantities to introduce here; however, one skilled in the art is able to determine appropriate therapeutically effective amounts based on the data presented herein, information available in the art relevant to these compounds, and standard testing. 70 The pharmaceutical compositions described below can be used for local administration of an immune response modifier. Many compositions are particularly useful for topical application to mucosal surfaces. In some embodiments, the compositions can affect the pharmacokinetics of the immune response modifier by reducing the concentration of the immune response modifier and thus provide a pharmacodynamic effect similar to other compositions having a higher concentration of the immune response modifier.

In general, the pharmaceutical composition of the invention includes an MIV, a fatty acid, a preservative and optionally an agent that improves viscosity, such as a carbomer. Modifiers of the immune response can be made using methods previously described in the above patents, as well as in US patents Mo 4,988,815; 5,367,076; 5,175,296; 5,395,937; and 5,741,908, incorporated herein by reference). Unless otherwise specified, all percentages are percentages by mass based on the total weight of the composition.

The amount of immune response modifier presented in the pharmaceutical composition of the invention will be the amount effective for treating the condition, preventing the recurrence of the condition, or promoting the immune response.

The amount of immune response modifier is preferably from about 0.195 to about 995 of the total weight of the composition. Optionally, the amount of the immune response modifier does not exceed about 5wt.9o and most preferably is from about 0.1 to about Zwt.95 for application to the surface of the mucous membrane.

As a rule, the pharmaceutical composition of the invention is an oil/water emulsion. Oil component i) of the composition includes MIV and fatty acid. The fatty acid is present in the composition in an amount sufficient to solubilize the MIV. In general, this is about 2905-4595, usually about 1095-3095, and preferably about 1595-1895, of the total weight of the composition. Fatty acids such as isostearic acid are acceptable for He! from compositions. Alternatively, the immune response modifier can be dissolved in carboxylic acids with linear chains containing from six to eight carbon atoms. Me

The pharmaceutical composition of the invention may also include an emulsifier such as a nonionic surfactant. at

Acceptable surfactants include, for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4-oleate, polyoxyethylene(4)lauryl ether, etc. For some compositions, surfactants of the Poloxamer 77 type (for example, Ripgopis E68 from VAZE, I pdm/idzsnatep, Germany) and sorbitan trioleate (for example, Zrap so 85 from Zidt Spetisai, So, Zi otsiv, MO) and sorbitan trioleate are preferred, either alone or in combinations Nonionic surfactant is usually present in an amount of about 0.595-1095 of the total weight of the composition. In preferred embodiments, the total emulsifier content does not exceed approximately 595% of the total weight of the composition, more preferably approximately 3.595% of the total weight of the composition. "

The composition of the invention may also include a viscosity-increasing agent, such as a carbomer, which has predominantly mucoadhesive properties. The carbomer may be present in an amount of about 0.195-895, preferably about 0.595-495, more preferably about 0.5-395, and most preferably about 1.095 of the total;" masses of composition. Acceptable carbomers include polyacrylic acids of the type Sagroro!i 934P, Sagroroi! 971 R,

Sagroroi! 940 and Sagroroi 974R from V.R. Sooagis The preferred carbomer is Sagroroi 974R.

In some optional embodiments, the composition may also include a chelating agent. Functions

Go! of the chelating agent consist in the binding of metal ions. If present, non-chelated metal ions can inhibit gel formation by inhibiting ionization that facilitates gel formation in the carbomer-containing composition. An optional chelating agent is disodium ethylenediaminetetraacetate (EDTA) in a concentration of about 0.0001-0.595, usually about 0.0005-0.195 of the total weight of the composition.

A preservative such as methylparaben, sorbic acid, propylene glycol, etc. may also be added. In one optional embodiment of the invention, each of methylparaben and sorbic acid

Ge) are provided in concentrations of about 0.0595-0.395, preferably about 0.1595 of the total weight of the composition, and propylene glycol is present in amounts up to about 3095, preferably about 595. It has been found that this combination of preservatives preferably meets the requirements of Rgezeguayop EPesiimepezz Tevzi (PET ), dv 1997 Eigoreap RpNaptasoreia. Tevi 5.1.3 EFPisasu Apitisgoriai Rgezegmayop - Thorisa! Rgeragayope - A

Sptiegia. This makes it possible to obtain a composition that is acceptable for use in a multi-dose dispenser without

F) adverse effect on the stability of the composition. Methylparaben and sorbic acid can be dissolved in propylene glycol before adding to the composition.

The remainder of the pharmaceutical composition may include water to provide a composition that can be washed off the mucosal surface by normal physiological clearance mechanisms.

In addition to providing mucoadhesive properties of the composition, carbomer also increases viscosity, forming a stabilizing gel. Many factors, such as the amount of oil phase, the pharmacological agent and the amount of carbomer used will affect the pH at which gel formation occurs. In some compositions, the presence of metal ions and surfactants increases the pH at which the carbomer forms 65 Gel. Thus, in the absence of a chelating agent, or in the presence of an increased amount of surfactants, the pH value at which the carbomer forms a gel can be increased. Thus, it may be necessary to add an organic or inorganic base or other substance to promote gel formation. Acceptable inorganic bases include, for example, KOH, MaNH, etc., the pH for the pharmaceutical composition of the invention is usually about pH 3.0-7.0, preferably about pH 2.0-6.0.

Applications on the surface of the mucous membrane.

According to the invention, the compositions can be applied locally, especially to non-keratinized epithelial surfaces such as mucosal surfaces. Mucosal surfaces include mucous membranes such as buccal, gingival, nasal, tracheal, bronchial, gastrointestinal, rectal, urethral, 7/0 ureteral, vaginal, cervical, uterine, etc. Depending on the concentration of the immune response modifier, the composition and surface of the mucous membrane, the therapeutic effect of the immune response modifier may extend only to the surface layers of the mucous membrane or to deeper tissues.

In one embodiment of the invention, the disclosed immune response modifiers can be applied topically to the vaginal or supravaginal region of the cervix for dysplasias such as cervical/5 intraepithelial neoplasia. In some embodiments, the aforementioned compositions are particularly advantageous for cervical application of the immune response modifier for a period of time sufficient to achieve the desired therapeutic effect without unwanted systemic absorption of the immune response modifier.

Cervical intraepithelial neoplasia (CIN)

Approximately 16,000 new cases of aggressive cervical cancer are diagnosed each year in the U.S., despite comprehensive screening of women for predictable cellular changes. There are approximately 3,000 deaths from cervical cancer in the United States, and this is usually secondary to failure to detect a primary malignancy in time. The Pap smear is a screening test that has been adopted since the 1950s as a way to detect abnormal cells in the cervix, including inflammation and dysplasia, which includes cervical cancer. This screening test has been widely used in industrialized countries and has had a strong impact on cervical cancer-related mortality. Abnormal smear

Papanicolaou - rapid and accurate monitoring of the progression of the disease with the potential for therapeutic intervention i) for the destruction or removal of malignant or pre-malignant tissues. These surgeries are expensive, inconvenient, and associated with injury rates ranging from 2 to 2395. Recently, injury rates approaching 1095 have been reported after laser treatment. b z The herpes virus was previously considered the etiological agent of cervical cancer. However, there was a gradual transition of this point of view from herpes virus to human papillomavirus (HPV), when it was shown that the cytopathic action of Me

NRM in experimental systems is very accurately imitated in human diseases. Improved experimental methods during the recent past allowed to determine the characteristics of the full spectrum of NRU subtypes, which led to the conclusion that a high degree of risk in infection with different types of HRM (for example, HRM 16, 18,07

Зз5 Less often 31, 33, 35, 45) is a likely exclusive initiation factor (ie, an oncogenic agent) for cervical dysplasia and subsequent cancers. The HRM mechanism of the transformation of a normal cell into a dysplastic one is associated with NRU encoded oncogenic proteins (Eb and E7) of high-risk genotypes, which bind the cellular gene for suppressing tumor products p5Z and KB, which leads to a failure of the cell cycle control mechanism, in which roZ and Co. play an important role. In addition, the use of these molecular methods led to the epidemiological observation that HRM was isolated from approximately 9,395 cervical tumors, and this further strengthened the generally accepted conclusion that HRM infection is the most important initiating factor in cervical cancer. :z» Usually sexually active women are exposed to HRM, but it does not necessarily lead to dysplasia or cancer. Infected women in whom viral DNA persists have approximately five times the chance of persistent dysplasia compared to women whose bodies are able to destroy the virus. Importance

Go! of the cell-mediated immune response (CMI) to HRM infection is illustrated by the observation that the antibody-mediated immune response is not effective in eliminating established infections, as demonstrated by the fact that patients with cervical cancer often show high levels of antibodies against viral EB and E7 proteins. This specific humoral immune response probably reflects a large external influence of the 5p antigen in increasing the tumor burden. In contrast to the apparently insignificant effect of the humoral and immune response, the cell-mediated immune response (Tp-1 type of response) is effective in controlling development

Tumors. The reverse development of intraepithelial damage is accompanied by the formation of a cellular infiltrate consisting of СО4" T-cells, СХО8" T-cells, natural killer MK-cells and macrophages. This inflammatory infiltrate is, of course, associated with tumor regression, which is different from that for women, 5 whose body is not able to increase this inflammatory response, which leads to the progression of the disease. In addition, patients with defects in cell-mediated immunity have an increased rate of cervical cancer development, (F, while those with defects in antibody production do not show the same susceptibility. ka In one optional embodiment of the invention, the inventors propose local application of MIV for atraumatic treatment of the cervix, including cervical intraepithelial neoplasia (CIN). v Intravaginal application of MIV

In order to obtain a beneficial therapeutic or prophylactic effect in cervical diseases, intravaginal application of the immune response modifier disclosed in this application is desirable. The immune response modifier can be administered through a dosed composition or dispenser that ensures contact of the immune response modifier with the surface of the cervical mucosa for a period of time sufficient to provide the desired therapeutic effect. Any of the dispensers described herein or shown in the drawings may be used for the application of MIV.

In addition to the applicators already described, the immune response modifier can be formulated as a suppository and can be administered intravaginally using a suppository applicator. An acceptable suppository applicator includes known cardboard tubes for dispensing the medication in the vaginal cavity.

The compositions of the invention may also be administered using a cylinder-type applicator such as described herein or shown in the figures. An example of a suitable cylindrical applicator can be found in (US Patent No. 5,282,789, the disclosure of which is incorporated herein by reference).

In an optional embodiment of the invention, the immune response modifier can be administered directly to the mucous membrane of the cervical canal. In one such embodiment of the invention, the immune response modifier can be applied topically to the cervical mucosa using a direct cervical applicator, as previously described, or using a cervical cap. One example of an acceptable cervical cap is found in (US Patent No. 4,858,624, the disclosure of which is incorporated herein by reference). Acceptable immune response modifier compositions for direct cervical applications are disclosed above and in the examples below. In general, an MIV composition according to any of the compositions 7/5 AA in the examples below can be placed in the concave region of a cervical cap that is applied directly above the cervix. These compositions can also be used with other types of applicator designs, including those shown in the pictures and described in this application. Optionally, the immune response modifier composition may include a viscosity agent such as carbomer to increase the residence time of the immune response modifier on the cervix.

The following examples provide further description of immune response modifier compositions and methods in accordance with the invention. The examples, however, are not intended to limit the compositions and methods.

Examples

Example 1. Safety assessment. pharmacokinetics (PK) and pharmacodynamics (PD) of 1--2-methylpropyl-1H-imidazo|4,5-C)quinolin-4-amine ((MICVIMODU), used for application to the cervix

Methods

The study evaluated five single, randomized, placebo-controlled (8) increasing doses of imiquimod: 50, 100, 150, 200, and 250 mg of imiquimod as a cream applied to the cervix over a period of eight hours. The components of the imiquimod formulation used in this study (Formulation A) are presented in the Table below. Each dose group consisted of 8 subjects (b active and 2 placebo), two Ge! 3 subjects were treated with the main dose, and the remaining six subjects were treated after an acceptable response to the main dose. Safety was assessed by recording adverse effects, laboratory tests, and colposcopy with Me photodocumentation of the cervix before dosing and 24 hours after dosing, and 48 hours after dosing, if appropriate. Systemic exposure (PC) was determined by measuring the amount of imiquimod and metabolites 48 hours after dosing, and PD response was determined by serological analysis for cytokines: -- tumor necrosis factor-o (TME-o), interferon-o (IEM-o) , agonists of interleukin-1 (I-1KA), co-interleukin-b6 (1/-6), neopterin (MRT) and 2 5 oligoadenylate synthetase (2, 5 AB) receptors during dosage dosing and selected time periods within 48 hours after dosing. Statistical processing of side effect assessment and demographic studies, laboratory tests, health signs, and ECG were performed using the methods of Rizpeg Ehasi,

MUysohop o Kapk-Zyt and Kgyvskaii UMaiivz, respectively. Cytokine changes between dose groups were compared using UMiisohop Kapk-Zyt, and changes from baseline were assessed using Zreactap Kapk shsh with Soiteiayop. and Results "" Thirty-nine generally healthy, surgically sterilized 18-50-year-old women within 25,905 ideal body weights were included in the study. All women had normal baseline colposcopy findings with normal and borderline dyskaryosis on cervical histology. Adverse events were recorded in each of the 39 o subjects, the most common adverse event (92905) was mild fever. No differences were observed between groups for subjects who had one or more adverse events or attributed adverse effects that were possibly or probably related to the medication. (Two serious adverse events were observed, which were intercurrent and related to tibial fracture and surgical treatment). Statistically significant changes in some laboratory parameters and pulse rate were observed, which were not considered clinically significant. No ECG or physical differences were observed

Ge) tests. Pelvic and colposcopic examinations showed few reactions of cervical changes in the form of minor vesicles or ulcers in 2 of the 6 who received a dose of 25 Ω. These reactions were observed within 48 hours. No (>5 ng/ml) imiquimod serological levels were detected. Significant changes in baseline values were observed for IRM and 1--6 in the group receiving 25O0mg, in the MR group, 2 5Az and I-1KA in the groups receiving 15O0mg, 200mg and 250mg. iF) Studies have shown that single doses of imiquimod up to 250 mg when applied to the cervix for 8 hours in healthy volunteers are safe with minimal systemic external effects. Cervical application of a dose of 150 mg increases the systemic concentration of some cytokines. 60 centuries

Cetyl alcohol 2.2

Sorbtan monostearate 05 o

Example 2

Production of a pharmaceutical composition V

This example describes a new composition for vaginal application, which is a stable composition with high viscosity, and also meets the criteria of the EP test for storage efficiency. The mass ratio (905) of the components of this composition (Composition B) is shown in Table 2 below.

Imiquimod was dissolved in isostearic acid with Zrap 85. Rishgopis Eb68, EDTA, Sagroro!i 974P, propylene glycol, sorbic acid and methylparaben were dissolved in water. After emulsification to form an oil-in-water emulsion, sodium hydroxide was added to achieve a pH of about 5.2. The pH range for this composition may be approximately 4.8 to 6.0. school

F zo

F o - zv so "

Example C - c Production of pharmaceutical compositions C-E Pharmaceutical compositions C-E were made from the components listed below in Table 3. The method of production of compositions C-E was the same as that disclosed for the production of composition B in Example 2. what else.

Fo vDA 1 o t vo

Example 4 6E Transport of imiquimod through the hairless skin of a mouse from compositions A and B containing 5 wt. 90 imiquimod.

Fig. 16 is a graph of the results of studying the penetration of imiquimod from compositions A and B, examples 1 and 2 using hairless mouse skin according to the procedure described in US Patent 5,238,944, the full disclosure of which is incorporated herein by reference.

Briefly, hairless mouse skin was removed from 5- to 7-week-old female hairless mice (obtained from Charles

Rivera). The skin was kept on ice until use. The mouse skin was placed in a clitic diffuser of the type described in (US Patent 5,238,944). Mouse skin was placed with the epidermal side up between the upper and lower layers of cells held together with a hinge clamp.

The cells of the lower part of the skin were completely covered with 0.1M NS. receptor fluid so that the receptor fluid was in contact with the skin. The receptor fluid was mixed using a magnetic stirrer. 70 Approximately 100-5mg of the test composition was applied to the epidermal (top) layer of the skin to cover in one even layer only that area of the skin that would be in contact with the receptor fluid when the skin was placed in the cell diffuser. The compositions were applied to the skin before adding the receptor fluid to the lower layers of skin cells.

The cells were then placed in a chamber at a constant temperature (3122). To maintain a constant temperature, a heat exchanger connected to a constant temperature bath with a fan for air circulation was used in the chamber. The receptor fluid was stirred using a magnetic stirrer throughout the experiment to ensure sample homogeneity and reduce the diffusion barrier layer on the dermal side of the skin. At specified time intervals (1, 2, 4, 6, 8, 12 and 24 hours), the full volume of the receptor fluid was withdrawn and immediately replaced with fresh receptor fluid. The extracted receptor fluid was analyzed for imiquimod content by conventional high-performance chromatography as follows:

Detector: UV at 258nm; Mobile phase: 25/75 acetonitrile/water containing 195 triethylamine, 0.290 1-octanesulfonate with pH adjusted to 2.0 with НзРО); Stationary phase: C8 7 degrees EX-C8 5;

Flow rate 2ml/min; Execution time: approximately 10 minutes.

The cumulative amount of penetration of the composition was plotted against time to obtain a constant He value

Speed at

Example 5

Transport of imiquimod through the hairless skin of mice from C-E compositions containing 1 wt. 9b5 and 90 wt. imiquimod and different concentrations of isostearic acid

Table 4 below provides the imiquimod concentration, isostearic acid concentration, viscosity, pH, and (o) established transport rate (μg/hr) of compositions C-E across hairless mouse skin.

Graphical results are presented in Fig.17. The procedure used to study the permeation of F through the skin was the same as that disclosed in Example 4. («c - " from the response (wt. o) acid (wt. 95) (x10-5 centipoise) |(μg/h) vv h z s Example 6 :z» Comparison of the pharmacokinetics of imiquimod in rats after a single dose of vaginal application of composition A and composition B

Imiquimod serum concentration versus time profiles were compared in hysterectomized rats after a single dose of intravaginal composition A or composition B. The two compositions 5wt.9o were dosed to provide a dose level of Zbmg/kg. After dosing, each rat was secured to prevent removal of the composition by licking. After six hours, the vagina was washed. Blood samples were collected before dosing and at 0.5, 1, 2, 3, 4 and 24 hours after administration of the composition. Because of the higher viscosity of composition B, intravaginal administration to rats was much easier, and retention of composition B was better than that of composition A.

Ge; Serum was analyzed for imiquimod by high-performance liquid chromatography (HPLC). Values of imiquimod concentrations in serum versus time are shown in Fig. 18. The time to reach the maximum concentration of imiquimod in serum (Tlakh) was similar (1 hour) for both compositions. However, the maximum concentration of imiquimod (Cmax) for composition B was approximately 1.6 times greater than for composition A, and the corresponding area under the curve against time (AOC) was 3.3 times greater (Fig. 19A and 198). Based on these data, (F) the rate and extent of absorption of imiquimod was greater for composition B than for composition A.

GI Example 7

Production of the pharmaceutical composition in Mas.bo ratio of components for composition C are shown in Table 5. The oil phase was prepared as follows. Imiquimod (20g) was slowly added with stirring to isostearic acid (3000g). The mixture was stirred and heated, if necessary, to 559C to facilitate dissolution of imiquimod. After complete dissolution, heating was stopped. Sorbitan trioleate (200g) was added and thoroughly mixed. Carbomer 974 was slowly added with stirring. Stirring was continued until the 65 carbomer was uniformly distributed in the oil phase. The oil phase was then cooled to a temperature less than 3090,

The aqueous phase was prepared in the following way. Sorbic acid (30.0g) and methylparaben (40.0g) were added with stirring to propylene glycol (1000g). The starting mixture was stirred and gently heated (4590) until a solution was formed. The heat source has been removed. Roiachateg 188 (500g) was added to the solution. The resulting mixture was stirred until the Royahateg was completely wet. The resulting aqueous mixture was added to a solution of disodium EDTA (10.0 g) in purified water (13950 g). The resulting mixture was stirred until a clear solution was obtained.

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, and then sodium hydroxide solution was added. The resulting 7/0 mixture was stirred for at least 30 minutes until a homogeneous cream with a glossy surface was obtained. The pH was determined and adjusted, if necessary, to 5.6-5.8 with sodium hydroxide solution.

Example 8

Production of pharmaceutical compositions N.-.)

Pharmaceutical compositions H-) were prepared using the method of Example 7. Mass.90 components in 7/5 Compositions are shown in Table 5 below.

Component 2 sy PI Po I POLYA sch zv o

F zo

F o

Based on the foregoing discussion, it has been determined that the imidazoquinolinamines, imidazopyridinamines, - 35 6b,7-fused cycloalkylimidazopyridinamines, and 1,2-linked imidazoquinolinamines of the present invention may be useful in the treatment of mucosal diseases, including cervical dysplasia. In addition, the disclosed pharmaceutical compositions may be particularly useful for topical application of an immune response modifier to the mucosal surface.

It is apparent from the foregoing detailed description and examples that modifications and variations may be made in the compounds, compositions, devices, systems, and methods disclosed herein. Other implementation options will be obvious to specialists in this field. It is clear that the technical requirements and examples should be considered only as a demonstration. with

Claims (1)

The formula of the invention (ee) and . - : . 1. A system for the treatment of a condition associated with the surface of the mucous membrane of the cervix or the vaginal part of the cervix, the system comprising a pharmaceutical composition and an applicator device for applying the composition to the surface of the mucosa, wherein said composition contains: (a) a modifier compound | immune response (miv) selected from imidazoquinolinamines, imidazopyridinamines, se) 6b,7-condensed cycloalkylimidazopyridinamines, 1,2-bridged imidazoquinolinamines and their pharmaceutically acceptable salts; (b) a fatty acid and (c) a preservative containing propylene glycol, wherein the applicator device is pre-filled with a therapeutically effective amount of the immune response modifier compound. 2. The system according to claim 1, in which the compound of the immune response modifier is imidazonaphthyridinamine or its GF) pharmaceutically acceptable salt. GF Z. The system according to claim 1, in which the applicator device additionally contains measuring marks to assist the user in determining the amount of the immune response modifier compound in the applicator device. 4. The system of claim 1, wherein the condition associated with the mucosal surface is cervical dysplasia. bo 5. The system of claim 1, wherein the condition associated with the mucosal surface is cervical intraepithelial neoplasia. 6. The system according to claim 1, in which the applicator device comprises: - a hollow tube having a distal delivery end and a proximal end and - a piston sliding within the tube. 65 7. The system of claim b, wherein the device further comprises a part configured to cause movement of the piston toward the distal end. 8. The system of claim 7, wherein the device is configured to limit backward movement of the part toward the proximal end when the piston is positioned adjacent the distal end. 9. The system according to claim 7, in which the piston is removably connected to the part. 10. The system according to claim 7, in which the part slides in a hollow tube. 11. The system according to claim 7, in which the device additionally includes a stopper that limits the return movement of the piston to the proximal end. 12. The system of claim 6, wherein the piston includes a portion extending from the distal end when the piston 70 is located in the most distant position from the proximal end. 13. The system of claim 6, wherein the distal end is tapered on its outer surface. 14. The system according to claim 7, in which the part has a length shorter than the distance between the proximal end and the piston when it is located in the most distant position from the proximal end. 15. The system of claim 1, wherein the applicator device is formed from high density polyethylene or low density polyethylene, linear low density polyethylene or polypropylene. 7 y y shi y y 16. The system according to claim 1, in which the lumen of the hollow tube has at least two different diameters. 17. The system according to claim 1, in which the hollow tube has a length of 6 to 24 cm. 18. The system according to claim 1, in which the diameter of the lumen of the hollow tube is from 5 to 15 mm. 19. The system of claim 1, wherein the delivery diameter of the distal end is from 2 to 12 mm. 20. The system according to claim 1, in which the applicator device provides delivery from 0.1 to 10 ml of the pharmaceutical composition. c) 6) (o) (o) "c) "- d) - and? (ee) - («c) se) iChe) ime) 60 b5