HRP20021024A2 - Systems and methods for treating mucosal surface - Google Patents

Description

The application is partly a continuation (CIP) of the concurrent patent application no. 09/676,339 filed Sep. 29, 2000, which is a continuation of application 09/479,578 filed Jan. 7, 2000 (now U.S. Patent No. 6,245,776) which was filed prior to application no. 60/115,253 filed Jan. 8, 1999. That application also shows the benefit of application no. 60/213,420, filed Jun. 22, 2000. In addition, the disclosure of each of the above applications is incorporated herein by reference.

Description of the invention

Field of invention

The present invention relates to systems and methods for treating conditions associated with mucosal surfaces, such as the vaginal portion of the cervix. Systems and methods may comprise a compound that is an immune response modifier (IRM) selected from imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, imidazonaphthidine amines, oxazoloquinoline amines and their pharmaceutically acceptable salts. In one possible embodiment, the invention provides systems and methods that are particularly suitable for topical use in the cervix, and for the treatment of cervical conditions such as cervical dysplasia, including dysplasia associated with human papillomavirus (HPV).

This invention is also directed to drug delivery means and methods of administration. Some aspects of the invention are directed to delivery to areas surrounding a selected location. In some parts, the invention is particularly suitable for topical delivery of a pharmacological agent to the cervix of the uterus.

Previous knowledge

Many imidazoquinoline-amines, 6,7-fused cycloalkylimidazopyridine-amines, 1,2-bridged imidazoquinoline-amines, thiazolo- and oxazoloquinoline-amines and pyrimidines, imidazonaphthidine- and tetrahydroimidazonaphthidine-amines have shown good immunostimulating, antiviral and antitumor (including anticancer) properties. activity, and have also been shown to be useful as vaccine adjuvants to enhance the vaccine response of the protective immune system. These compounds are further collectively referred to as "IRM" (immune response modifier) compounds of the invention. Compounds that are IRM can be selected from the group consisting of imidazoquinoline-amines, imidazopyridine-amines, 6,7-fused cycloalkylimidazopyridine-amines, imidazoquinoline-amines, 1,2-bridged imidazoquinoline-amines, and their pharmaceutically acceptable salts. Methods for preparing such IRMs and pharmaceutical compositions containing them are disclosed, for example, in U.S. Pat. Patents no. 4,689,338; 5,389,640; 5,268,376; 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 publication WO 99/29693; WO 00176505; WO 00/76518; and WO 00/76519. The entire disclosure of each of these patent applications is incorporated herein by reference.

The immunostimulating antiviral and antitumor activities of these compounds have been discussed in detail, and some specific diseases have been shown to respond to treatment with them, including the following: basal cell carcinoma, eczema, thrombocytopenia, hepatitis B, multiple sclerosis, neoplastic diseases, psoriasis, rheumatoid arthritis, herpes simplex type I and warts. One of these IRM compounds known as imiquimod is the commercial topical formulation of AldaraTM, for the treatment of anogenital warts associated with human papillomavirus.

It is believed that the mechanism of antiviral and antitumor activity of these IRM compounds is essentially an increase in the immune response due to the induction of various important cytokines (eg interferon, interleukin, tumor necrosis factor, etc.). Such compounds have been shown to stimulate the rapid release of some monocyte/macrophage derived cytokines and are also capable of stimulating B cells to secrete antibodies that play an important role in the antiviral and antitumor activity of IRM compounds. One of the main immunostimulatory responses to these compounds is the induction of interferon (IFN)-α production, which is believed to be very important in triggering the observed antiviral and antitumor activity. Moreover, upregulation of cytokines, such as tumor necrosis factor (TNF), IL-1 and IL-6, also has potential beneficial activity and is believed to contribute to the antiviral and antitumor activity of these compounds.

Although some beneficial effects of IRN are known, the ability to achieve a therapeutic effect with topical application of IRM for the treatment of some site-specific conditions may be obscured by tissue irritation, washout of the formulation, poor penetration, or unwanted systemic delivery of the topically administered compound. Therefore, there is a need for new methods, formulations and systems to obtain a greater therapeutic effect of this class of compounds.

Topical administration of a pharmacological agent to the tissue surface can lead to a localized therapeutic effect without a simultaneous systemic effect. However, topical administration is often difficult or impossible due to the anatomical location of the tissue. In some cases, administration of the agent to a general anatomical region that includes or surrounds the target tissue may be an alternative to direct topical administration. Additionally, even if the agent is non-irritating, regional application typically requires the use of a greater volume or concentration of the agent to achieve a therapeutic effect equivalent 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. In the standing position, the cervix is typically located relatively in the upper part of the vaginal cavity. However, although the cervix is located in the upper part of the vaginal cavity, age, the state of the estrogen cycle, pregnancy and other factors cause changes in the position of the cervix in different women and in the same woman at different stages of life.

Some conditions of the cervix can be conveniently treated by topical administration of a pharmacological agent. Cervical dysplasia is an example of a pathological condition that can be effectively treated by direct drug delivery to the surface of the cervix, where abnormal cells typically occur. Unfortunately, many now available vaginal drug delivery applicators are not suitable for delivering the drug to the surface of the cervix. As cervical dysplasia leads to cervical cancer, a suboptimal applicator is not an acceptable option.

Most of the current vaginal applicators for administration into the vaginal cavity are generally not for direct administration into the cervix. In general, the length and configuration of the applicator is not sufficient to ensure delivery of the agent to the upper parts of the vaginal cavity. Delivery to the middle and lower parts of the vagina does not ensure that the agent reaches the surface of the cervix in the upper part of the vagina. Additionally, with the exception of some body orientations, gravity causes the funds to drain from the cervix. Normal douching and swelling of fluids, menstrual and non-menstrual, also drain the substance from the cervix. Therefore, any applicator that can repeatedly deliver an adequate amount of agent to the upper part of the vaginal cavity reduces the risk of treatment.

Overcoming the inaccuracy of current vaginal applicators used to deliver the agent to the cervix, such that the volume or concentration of the drug is in excess, may be unacceptable due to the risk of unwanted effects on the surrounding tissues. However, delivering reduced volumes or concentrations while avoiding irritation of the surrounding tissue is risky due to the consequences of ineffective treatment.

Therefore, there is a constant need to improve delivery systems and methods of topical application of pharmacological agents.

Summary of the invention

One aspect of the invention includes a system for the treatment of conditions associated with the mucosal surface. The system contains a compound that is an immune response modifier (IRM) selected from imidazoquinoline-amines, imidazopyridine-amines, 6,7-fused cycloalkylimidazopyridine-amines, 1,2-bridged imidazoquinoline-amines, and pharmaceutically acceptable salts thereof. The system contains an applicator for administering the IPR compound to the mucosal surface.

A further aspect of the invention includes a system comprising a compound that is an immune response modifier (IRM) selected from imidazoquinoline-amines, imidazopyridine-amines, 6,7-fused cycloalkylimidazopyridine-amines, imidazonaphthydrin-amines, oxazoloquinoline-amines, thiazoloquinoline-amines, 1 ,2-bridged imidazoquinoline-amines, and their pharmaceutically acceptable salts. The system contains an applicator for administering the IPR compound to the mucosal surface.

For example, the compound IRM can be 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine or 4-amino-α,�α-dimethyl-2-ethoxymethyl-1H-imidazo[ 4,5-c]quinoline-1-ethanol or 2-propyl[1,3]thiazolo[4,5-c]quinoline-4-amine.

The system can be used for the treatment of conditions related to the surface of the mucous membrane, and it can be the vaginal part of the cervix. Examples of conditions associated with the mucosal surface include cervical dysplasia and intraepithelial neoplasia.

In one exemplary embodiment, the application device may include a hollow tube and a movable piston located within the tube.

In another aspect, the invention includes methods of treating conditions associated with the mucosal surface. The method comprises the use of an immune response modifier (IRM) selected from the following: imidazoquinoline-amine, imidazopyridine-amine, 6,7-fused cycloalkylimidazopyridine-amine, imidazonaphthydrine-amine, oxazoloquinoline-amine, thiazoloquinoline-amine, 1,2-bridged imidazoquinoline-amine , and their pharmaceutically acceptable salts. The method also includes an applicator for delivering the IRM compound to the mucosal surface. In addition, the method further includes the application of the IRM compound on the surface of the mucous membranes with an applicator.

The method may include placing the applicator in the vagina, placing the distal end of the applicator in the vicinity of the vaginal part of the cervix and applying the compound that is IRM in the vaginal part of the cervix.

At least some of the embodiments shown herein depict a drug delivery system and method suitable for topical administration of the agent to tissue. The systems and methods may be suitable for intravaginal delivery of a pharmacological formulation. For example, some entities are suitable for 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 set forth in the section that follows, and that section will be apparent from the description or may be learned by practice from the invention. It will be seen that some places throughout the specification have instructions by way of examples given. In any case, the examples given serve as a representative group and are not intended to be exclusive.

It should be understood that the following general description and the following detailed description are examples and serve as an explanation only, and are not restrictive.

The attached pictures form part of this specification, illustrate some parts of the invention and, together with the description, serve to explain the invention in principle.

Short description of the pictures

FIGURE 1A is a plan view of a treatment system including an applicator and a container containing the IRM compound packaged together;

FIGURE 1B is a plan view of a treatment system with several pre-filled containers of IRM compound;

FIGURE 2 is an exploded perspective view of the components of an intravaginal delivery device;

FIGURE 3 is a proximal end of an exemplary intravaginal delivery device;

FIGURE 4 is a longitudinal section of an exemplary intravaginal delivery device taken along line 4-4 with the movable member drawn proximally;

FIGURE 5 is a longitudinal section of an exemplary intravaginal delivery device taken along line 4-4 with the movable member pushed distally;

FIGURE 6 is a close-up of the proximal end of the intravaginal delivery device illustrated in FIGURE 5;

FIGURE 7 is a close-up of the distal end of the intravaginal delivery device illustrated in FIGURE 5;

FIGURE 8 is a close-up perspective detail of the components with a possible alternative assembly of the device for intravaginal administration according to the invention;

FIGURE 9 is a longitudinal section of the intravaginal delivery device of FIGURE 8 with the movable member retracted proximally;

FIGURE 10 is a longitudinal section of the intravaginal delivery device of FIGURE 8 with the movable member advanced distally;

FIGURE 11 is a close-up of the distal end of the intravaginal delivery device illustrated in FIGURE 10;

FIGURE 12 is a close-up of the distal end of the intravaginal delivery device illustrated in FIGURE 10

FIGURE 13 is a side view of the components of an alternative proximal end of an intravaginal delivery device;

FIGURE 14 is a side view of the components of the following alternative proximal end of an intravaginal delivery device;

FIGURE 15 is a longitudinal section of an example of an intravaginal delivery device pre-filled with a formulation;

FIGURE 16 is a graph comparing the transport of imiquimod across the skin of a hairless mouse from three pharmaceutical formulations each containing imiquimod;

FIGURE 17 is a graph comparing the transport of imiquimod across glabrous skin and isostearic acid;

FIGURE 18 is a graph comparing the mean serum concentration of imiquimod in rats after a single intravaginal dose of Formulation A or Formulation B; you

FIGURES 19A and 19B show a pharmacokinetic comparison of imiquimod in rats following vaginal dosing of Formulation A or Formulation B.

Description of units

Some examples of units from the invention will now be detailed, examples of which are illustrated in the attached figures. Whenever possible, the same reference number will be used throughout the figures, and when the same or similar parts are cited.

This invention may be directed in part to drug applicators and methods of delivering a pharmacological agent to a specific site. In some alternative embodiments, the delivery device may be configured for intravaginal delivery of the pharmacological agent. In an alternative embodiment, the disclosed delivery device may be used for topical administration of a pharmacological agent intravaginally, such as to the cervix, and for the treatment of conditions including, for example, cervical dysplasia. In general, delivery devices can be used to deliver pharmacological agents as often and in amounts necessary to obtain a desired treatment result.

Through the specification, the interpretation can be shown by the given examples. In any case, the statements are only representative of the group. The allegations are not intended to be exclusive.

As used herein, the term "pharmacological agent" includes any agent or combination of agents that can be used to diagnose, treat, cure, ameliorate, prevent, or otherwise affect a patient's condition. The term "condition" refers to infectious, non-infectious, pathological, biochemical or other conditions in a patient's body that can be treated according to the invention.

Throughout the specification, unless otherwise indicated, the terms "proximal" and "distal" are relative terms. The term "proximal" refers to the location closest to the user (for example, the hand of the user handling the delivery device) and the term "distal" refers to the location farthest from the user. Therefore, in a typical embodiment, the proximal end of the delivery device will be closest to where the user's hand is located, and the distal end of the instrument will be located closest to the tissue site where the agent will be applied.

As used herein, a "mucosal-related condition" means an inflammatory, infectious, neoplastic, or other condition of the mucosal surface to be acted upon by a therapeutic or prophylactic agent applied topically to the mucosal surface.

Unless otherwise stated, the term "treat" and corresponding derivative terms such as "treatment," "treating," etc., are used herein generally to refer to the administration of a pharmaceutical agent for any reason to a patient and are not intended to distinguish between preventive, therapeutic , diagnostic, palliative or other procedure. The term "therapeutically effective amount" means an amount of agent administered to produce a desired therapeutic effect, such as cytokine induction, antiviral or antitumor activity. "Therapeutically effective amount" includes a single dose of an agent used in therapy over a period of time to achieve the desired therapeutic effect.

Some possible combinations of devices and methods of the invention may be suitable for delivering an agent to the uterine cervix via vaginal treatment (ie, prevention, diagnosis, improvement, etc.) of cervical conditions. In some possible embodiments, the delivery device of the invention may be particularly suitable for delivery of an immune response modifier (IRM) to the cervix, and for conditions of the cervix. Examples of immune response modifiers suitable for the invention include those disclosed in, for example, U.S. Pat. Patents no. 4,689,338; 5,389,640; 5,268,376; 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 publication WO 99/29693; WO 00176505; WO 00/76518; and WO 00/76519. The full disclosure of each of these patents and patent applications is incorporated herein by reference. Some possible IRMs suitable for the invention include 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine (imiquomod) and the compounds and formulations disclosed in concurrent US Pat. 09/479,578 and PCT Publication WO 00/06577. The full disclosure of each of these patents and applications is incorporated herein by reference.

Generally, the "user" of these delivery devices (also referred to as the applicator) includes the healthcare professional who applies the agent to the patient or the patient himself who administers the agent.

In some possible embodiments, the delivery device can accurately deliver a predetermined amount of pharmaceutical agent to a selected site with a reduced likelihood of unwanted delivery to surrounding tissue. Typically, a predetermined amount is a therapeutically effective unit dose. The correct application of the agent to a certain place achieves a therapeutic result, while reducing the possibility of tissue irritation in the vicinity of the selected application site.

In the case of intravaginal applicators for administration, unwanted side effects caused by the agent can be reduced. For example, when the delivery of the agent is desired only in the cervix, and due to the condition of the cervix, by delivering the agent to long places in the upper part of the vaginal cavity, the lower vaginal cavity or other surrounding tissues may be unnecessarily exposed to the agent. Not only is non-target tissue exposed to the agent, but there is also the possibility of tissue irritation caused by the agent or other components of the pharmacological formulation.

Intravaginal delivery devices can deliver a precise volume of agent (or formulation thereof) that is smaller than the volume typically used to administer other intravaginal drugs. In some embodiments, intravaginal dispersers can deliver from about 0.01-10 mL, in other possible embodiments about 0.5 to 4 mL, typically about 1.0 mL.

Delivery devices can be pre-filled with a therapeutically effective amount of a particular agent or filled by the user at the time of administration. In the latter case, they are configured to receive the agent from a source of the agent (eg, aluminum tubes, plastic tubes, etc.) from which the administration device can be filled. Some delivery devices may typically have a maximum volume of agent. Alternatively or in addition, delivery devices may have volume markings for filling amounts that are less than the maximum volume of the delivery device.

In a possible embodiment, a prefilled delivery device can eliminate the possibility of filling the delivery device with an incorrect amount of agent. In one possible embodiment, the devices may be filled with a formulation, including an immune response modifier (IRM) compound, required for a single treatment. Whether pre-filled or not, the device may be packaged in an outer envelope, such as foil, which maintains sterility and may act as a moisture barrier.

The device can be formed by known methods, including an over-mold process that forms a plastic applicator from polymeric materials such as high density polyethylene, low density polyethylene, linear density polyethylene, or polypropylene.

FIG. 1A shows a treatment system 400 including an application device 10 and a formulation container 401 packaged together in a package 402. The device 10 can be configured to be filled with formulation from the container 401, and by bringing them into contact with each other where flow can occur. .

FIG. 1B shows a treatment system 400 in which the formulation is pre-filled with cartridges 401a-401d that can be introduced into the delivery device 10 at some time.

FIGURES 2 and 4 show a possible assembly of an intravaginal delivery device 10 according to the invention. As illustrated, the device 10 may include a distal end 1, a proximal end 2, and a longitudinal axis X-X passing therethrough. FIGURE 2 is an enlarged perspective view of a device component 10 including an elongated tube 3 having a delivery end 4, an operating end 5 and a lumen 6 passing therethrough. The end opening 5 may include a place for placing the hand 7 such as rims 8a and 8b for holding the device 10 during use. In some embodiments, the elongated tube 3 may have a length of from about 6 cm to about 24 cm, typically from about 10 cm to about 18 cm.

The pressing member 11 may slide within the lumen 6 of the elongated tube 3 and may include a pressing end 12 and an actuating end 13. The pressing end 12 may include a platform 14 for accommodating a user's thumb or finger that distally actuates the pressing member 11 and may have a distal the tip 16 at the opposite end 17. The cap 18 attached to the distal end 4 of the device 10 can be removed by known methods such as screwing or friction.

FIGURE 4 is the distal end of the device 10, and FIGURE 4 is a longitudinal section of the device 10 taken along the line 4-4 of FIGURE 3. The piston 15 shown in FIGURE 4 is attached to the driving end 13 or the pressing member 11 and is placed in the first position that creates chamber 20 for receiving a previously determined amount of pharmacological agent.

In some possible embodiments, the chamber 20 will have a volume for the pharmacological agent of about 5 mL to 0.1 mL, typically about 2 mL to 0.5 mL, and may be about 1.0 mL. In one possible embodiment, the driving end 13 of the pressing member 11 can be repositioned in the bore 19 of the piston 15. Therefore, in that one embodiment, if the pressing member 11 is retracted proximally, the driving end 13 of the member 11 is free to withdraw from the bore 19, and the piston 15 will not be pulled proximally with the pressing member 11. This possible aspect can prevent penetration of the agent after expelling the agent from the chamber 20, and can also prevent tissue penetration into the delivery end 4 of the tube 3, and if the pressing member 11 is pulled proximally .

Additionally, in some additional embodiments, the lumen 6 may include an obstruction 40, such as a protrusion 41, that may extend into the lumen 6 to prevent proximal return of the plunger 15. Whether the device 10 is pre-filled with agent or the full user is in time of use, the position of the barrier 40 can ensure a fixed maximum volume of the chamber 20 in which a predetermined amount of the agent is contained. This obstacle can prevent the user from exceeding a certain dose of the agent 10, and when the device is filled with the agent before use.

The cap 18 is shown attached to the delivery end 4. The cap 18 may be frictionally coupled to the outer surface 35 of the delivery end 4. Alternatively or in addition, the cap 18 may include a base 18a that is frictionally coupled to the distal end 1 of the lumen 6. The distal end 1 of the lumen 6 may alternatively have a female thread (not shown) which may receive a male thread (not shown) and which may be present on the outer surface of the base 18a. The cap 18 may also include a tab 18b for easier grip of the cap 18 when removed from the tube 3.

The cap 18 may have a relief structure such as bumps or grooved surface etc. for easier removal. Markings such as engraved arrows may be provided on the cap 18 to indicate the direction of unfolding for removal thereby contributing to the ease of use of the device.

In FIG. 5, the pressing member 11 is distally advanced to a position that would cause the pharmacological agent to exit the chamber 20. In possible illustrated embodiments, when the pressing member 121 is advanced distally, the distal tip 16 of the piston 15 extends over the distal end 4 of the elongated tube 3 In addition, the distal tip 16 can be convexly or dome-shaped outwardly to further ensure complete expulsion of the agent from the chamber 20.

FIG. 6 is a close-up detail of a possible assembly of the proximal end 2 of the delivery device 10. In the illustrated embodiment, the platform 14 of the pressing member 11 forms a shoulder 25 at the junction with the pressing end 12 of the pressing member 11. When the pressing member 11 is advanced distally within the lumen 6, the shoulder 25 can fit against the operative end 5 of the extended tube 3, which can indicate the complete delivery of the pharmacological agent from the chamber 20 of the device 10.

FIGURE 7 is a close-up detail of a possible assembly of the distal end 1 of the delivery device 10. As illustrated, the distal end of the chamber 20 of the lumen 6 may include a taper 30. The outer surface 31 of the piston 15 may also have a taper 32 that extends to the distal tip 16. Appropriate the constrictions 30 and 32 may facilitate the complete delivery of the pharmacological agent contained in the chamber 20 when the pressing member 11 is advanced distally. Plunger 15 also includes a closure ring 33 such as a surrounding rim 34 that can be tightly fitted to lumen 6 to ensure that a significant portion, preferably complete, of the pharmacological agent is removed from lumen 6 as plunger 15 advances distally. Therefore, the lumen 6 can have at least two different diameters, the lumen diameter LD and the delivery diameter DD. A typical lumen diameter of the LD can be about 5 to about 15 mm, and a typical delivery diameter can be from about 2 to about 10 nm. In an example delivery device 10 with a maximum chamber volume of about 1 mL, the length of the extended tube 3 may be about 12-20 cm, the LD may be about 10 mm, and the DD may be about 6 mm.

The outer surface 15 of the distal end 1 of the elongated tube 3 may also have a groove 36 that facilitates the insertion of the distal end 1 of the device 10 into the vagina. After ejecting the agent from the container 20, the tapered portion 36 may also ensure that all of the administration agent remains at the delivery site. For example, when the agent is delivered to the cervix, the vaginal wall surrounding the distal tip 1 can be tightly wrapped around the distal tip 1 thereby removing any residual agent on the tip, unlike applicators that have sharp tip ends (ie, a straight cylinder) or tip sharp end with rounded corners.

During use, the user may place the thumb and middle finger proximally on the rims 8a and 8b of the hand space 7 to hold the device 10 in the selected location, while the user's index finger placed on the platform 14 distally actuates the pressing member 11 so that the distal tip 16 of the piston 15 displaces the pharmacological agent from container 20 to deliver the agent intravaginally, such as the mucosal surface of the cervix.

FIGURE 8 is an enlarged component side view of a possible alternative assembly of an intravaginal delivery device 100. As illustrated, the delivery device 100 may include a proximal end 101, a distal end 102, and a longitudinal axis X-X passing therethrough. The elongated tube 103 may have a delivery end 104, an operating end 105 and a lumen 106 passing therethrough. A sliding or threadable cap 108 is attached to the distal end 102 of the device 100 as described for the cap 18 of the device 10 .

The operating end 105 of the elongated tube 103 may include a hand accommodation location 107 including a tip 118 to facilitate handling of the device 100 during use. In a possible illustrated embodiment, the edge of the opening 118 may extend continuously around the periphery of the operative end 105. However, it will be appreciated that the edge 118 need not be continuous, and in other embodiments, the edge 188 may be omitted.

The pressing member 11 is slidably received in the lumen 106 and may include a pressing end 113, a moving end 114, and a rod 115 extending therebetween. The pressing member 113 may include a platform 116 to accommodate a user's thumb or finger for distal advancement of the pressing member 111 during use. The platform 116 may have a concave surface 117 for better accommodation of the user's fingertip or palm. The plunger 120 may be fixedly located on the actuating end 114 of the pressing member 111 or the actuating end 114 may be removable, located in a notch 122a at the end 122. The plunger 120 may include a distal tip 121. In some embodiments, the distal tip 121 may be distally recessed or have the shape of a dome to the outside, and to further ensure the exit of the means.

FIGURE 9 is a longitudinal cross-sectional view of the device 100 showing a chamber 130 for receiving a predetermined amount of pharmacological agent when the proximal pressing member 111 is retracted into the lumen 106 of the elongated tube 103. FIGURE 10 illustrates that as the pressing member 111 is advanced distally, the distal tip 121 of the piston 120 may extend over the distal end 102 of the extension tube 103.

FIGURE 11 is a close-up of the distal end 102 of the device 100 illustrating that the chamber 130 includes a constriction 131 at the distal end 102 of the lumen 106. The possible constriction 131 of the chamber 130 may be configured to match a corresponding constriction 132 in the distal portion of the piston 120. Curved surfaces 131 and 132 may facilitate complete output of the pharmacological agent contained in the chamber 130.

Plunger 120 may also include a closure ring 113 such as a surrounding rim 134 that may be firmly seated against lumen 106 to ensure complete exit of the agent upon distal advancement of the plunger. The outer surface 135 of the distal end 102 of the elongated tube 103 may have a taper 136 for the reason discussed above.

As with the device 10, in some possible embodiments the lumen 106 may include an obstruction 140 such as a protrusion 141 that may extend into the lumen 106 to prevent proximal return of the plunger 120. Regardless of whether the device 100 is pre-filled with agent or the user is fully in time of use, the position of the barrier 140 can ensure a fixed maximum volume of the chamber 120 in which a predetermined amount of the agent is contained.

FIGURE 12 is a close-up detail of a possible intact proximal end 101 of the device 100 of FIGURE 10 illustrating that by fully displacing the pressing member 11 distally, the platform 116 of the pressing end 113 can be interrupted within the operative end 105 of the elongated tube 103. This feature reduces the likelihood that any or all pharmacological agents that have exited the chamber 130 are sucked back into the chamber 130 after delivery, and by proximally pulling the pressing member 111 after exiting the pharmacological agent.

In some embodiments, the operative end 105 of the elongated tube 103 and the pressing end 113 of the pressing member 111 may also be designed to provide an audible or tactile signal to the user when the release of the agent is complete. According to this possible embodiment, the operative end 105 of the lumen 106 may include a projecting surface 145 such as grooves 146 at the location of the proximal platform 116, and when the pressing member 111 is fully displaced distally. The platform 116 may be received such that the platform 116, by pressing distally over the groove 146, forms a signal notifying the user that the agent has been properly extruded. The grooves may also act to "lock" the pressing member 111 in the distally advanced portion and may prevent proximal return of the pressing member 111.

It will be appreciated that in addition to the lumen diameter LD and the delivery diameter DD, the lumen 106 also has a diameter PO at the operative end 105. The lumen 106 may therefore have a taper 150 extending between the diameters PO and LD. In an example delivery device 100 having a maximum chamber volume of about 1 mL, the length of the extended tube 103 is about 15 to about 17 cm, the LD is about 11-15 mm, and the DD is about 7-12 mm.

In a possible alternative embodiment, the elongated tube portion 103 is shown as having parallel sliding sites (see, eg, FIG. 9 ) extending from the proximal end to the distal end. This may allow the delivery device to be filled with the pharmacological agent at the proximal end of the elongated tube rather than at the distal end. Without a constriction, as just described, an attempt to push the plunger at a distal site along an unconstricted tube, and after introducing the formulation, may be interrupted by air that may be trapped between the plunger and the lumen wall. By narrowing the elongated lumen, as described, a gap between the piston and the wall can be maintained, allowing air to escape through the distal advancement of the piston. Such tapering may be gradual along the length of the extended tube, or may be abrupt near the site of the piston which predetermines the volume at the distal end of the extended tube.

FIGURE 13 illustrates another possible operative end assembly of an elongated tube suitable for an intravaginal delivery device 10, 100 of the invention. According to this embodiment, the operative end 201 of the elongated tube 200 may be configured to allow the indicator 203 to orient the device 200 about the longitudinal axis X-X. Therefore, as a whole from FIGURE 13, opposite sides 204 and 205 are linear giving an oval cross-section operative end. In this embodiment, the edge opening 206 may extend around the perimeter of the operative end 201. It will be appreciated, however, that the edge opening may be gradually missing or interrupted around the perimeter.

FIGURE 14 illustrates another possible assembly of the operative end of an elongated tube 300 suitable for an intravaginal delivery device of the invention. In this embodiment, the operative end 301 of the elongated tube 300 may be configured to also have an indicator 303 for orientation of the device 100 about the longitudinal axis X-X. The operative end 301 may have angles 304a-304d. The walls 305a-305d of the operative end 301 between the corners 403a-403d of the joint drive the operative end of the diameter PO into the lumen of the diameter LD. In the illustrated embodiment, the proximal aspect of each wall 305a-305d may include a concave portion 306a-306d extending distally to the surface of the wall 305a-305d. In addition, the pressing member platform 350 (not shown) may distally have a concave surface 351 and four corners 352a-352d configured to correspond to the corners 304a-304d of the walls 305a-305d. A rim tip (not shown in its entirety) may or may not be present around the proximal edge of operative end 301, as described for device 10 and 110.

An intravaginal delivery device may allow delivery of a precise volume of agent that is smaller than typically used for other vaginal drugs. Many vaginal applications deliver about 5 mL of the agent, and the application is not localized but is delivered generally into the vaginal cavity.

In a possible embodiment, as shown in FIG. 15, the applicator 10 may be pre-filled with product P, to eliminate the possibility of incorrect filling of the applicator. However, since the device needs to be charged during use, obstacles can be placed in the device on the maximum volume that can help eliminate the possibility of exceeding the previously determined dose.

Any of the aforementioned applicators may be of sufficient length to allow the distal end of the applicator to be located at or very close to the cervix while a portion of the applicator passes through the vagina and the proximal end is located outside the vagina. The length of the applicator can be configured to ensure delivery of the compound that is the IRM into the uppermost end of the vaginal cavity, while the proximal end is outside the vagina. For example, the length of the applicator can be sufficient to adapt to the anatomical diversity of women, so that the treatment is also possible for women with a longer vaginal cavity.

In use, the intavaginal delivery device can be held at the proximal end between the thumb and middle finger, and the platform of the pressing member released (ie, advanced distally) with the index finger to deliver the agent.

In possible embodiments, the pressing member may be pre-positioned within the lumen of the elongated tube and be ready for use. If the delivery device is filled prior to use, the distal end of the elongated tube may have female threads that match the male threads of the drug source, such as an aluminum tube, to provide a threaded seal as the drug is transferred from the source and chamber of the delivery device.

Devices can be packed in sealed bags, which ensures sterility and dryness. The sealed bag can be made of any suitable material for the protection of the pharmacological agent such as foils, foil laminates (eg metal and plastic layers). In some units, the wrapper can protect against loss of moisture from the formulation or against oxidation of the formulation.

The delivery device may be part of a system or component used in a method comprising an immune response modifier (IRM) compound for the treatment and prevention of mucosal surface-related conditions. For example, a compound that is an IRM can be a formulation that can be applied to the mucosal surface of the cervix for the treatment of conditions of the cervix including cervical dysplasia such as cervical intraepithelial neoplasia.

In some units, some formulations can be used to apply compounds that are IRM to the mucosal surface. In some possible embodiments, the formulations may accelerate the therapeutic efficacy of IRM by facilitating mucosal permeability or increasing the duration of IRM contact with the mucosal surface. A pharmaceutical formulation may contain a preservative to keep the formulation suitable for packaging in multiple containers.

Compounds that are IRM

As indicated above, many imidazolinoline amines, imidazopyridine amines, 6,7-fused cycloalkyl imidazopyridine amines, 1,2-bridged imidazoquinoline amines, thiazolo- and oxazoloquinoline amines and pyrimidines, imidazonaphtidine- and tetrahydroimidazonaphtidine-amines are IRMs. from this invention that have significant immunomodulating activity. Some possible immune response modifiers of the invention include 1H-imidazo[4,5-c]-quinolin-4-amines defined by formulas I-V below:

[image]

where

R11 is selected from the group consisting of: alkyl of one to ten carbon atoms, hydroxyalkyl of one to six carbon atoms, acyloxyalkyl in which the acyloxyl part is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl residue contains one to six carbon atoms, benzyl (phenyl)ethyl and phenyl, and said benzyl (phenyl)ethyl or phenyl may be substituted on the benzene ring with one or two substituents independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen , with the limitation that when said benzene ring is substituted with two of said residues, then said residues together have no more than six carbon atoms;

R21 selected from the group consisting of: hydrogen, alkyl of one to eight carbon atoms, benzyl (phenyl)ethyl and phenyl, and benzyl (phenyl)ethyl or phenyl may be substituted on the benzene ring with one or two residues independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the limitation that when said benzene ring is substituted with two of said residues, then said residues together have no more than six carbon atoms; you

each R1 is independently selected from the group consisting of: alkoxy of one to four carbon atoms, halogen and alkyl of one to four carbon atoms, and n is an integer from 0 to 2, with the restriction that when n is 2, then said R1 groups together have no more than six carbon atoms;

[image]

where

R12 selected from the group consisting of a straight or branched alkenyl chain consisting of one to ten carbon atoms and a substituted straight alkenyl chain consisting of one to ten carbon atoms, wherein the substituent is selected from the group consisting of a straight or branched alkyl chain which consists of one to four carbon atoms and cycloalkyl containing three to six carbon atoms; cycloalkyl containing three to six carbon atoms substituted by a straight or branched alkyl chain consisting of one to four carbon atoms; you

R22 selected from the group consisting of: hydrogen, straight-chain or branched alkyl of one to eight carbon atoms, benzyl (phenyl)ethyl and phenyl, and benzyl (phenyl)ethyl or phenyl may be substituted on the benzene ring with one or two residues which are independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the limitation that when said benzene ring is substituted with two of said residues, then said residues together have no more than six carbon atoms; you

each R2 is independently selected from the group consisting of straight-chain or branched-chain alkoxy containing from one to four carbon atoms, halogen, and straight-chain or branched-chain alkyl from one to four carbon atoms, and n is an integer from 0 to 2, with the restriction that when n is 2, then said R1 groups together have no more than six carbon atoms;

[image]

where

R23 selected from the group consisting of hydrogen, a straight or branched alkyl chain consisting of one to eight carbon atoms, benzyl (phenyl)ethyl and phenyl, and benzyl (phenyl)ethyl and phenyl may be substituted on the benzene ring with one or two residues which are independently selected from the group consisting of a straight or branched alkyl chain of one to four carbon atoms, a straight or branched alkoxy chain of one to four carbon atoms, and a halogen, with the limitation that when said benzene ring is substituted with two of said residues, then said the residues together have not more than six carbon atoms; you

each R3 is independently selected from the group consisting of straight-chain or branched-chain alkoxy containing from one to four carbon atoms, halogen, and straight-chain or branched-chain alkyl from one to four carbon atoms, and n is an integer from 0 to 2, with the restriction that when n is 2, then said R1 groups together have no more than six carbon atoms;

[image]

where

R14-CHRxRy wherein Ry is hydrogen or a carbon-carbon bond with the restriction that when Ry is hydrogen, Rx is alkoxy of one to four carbon atoms, hydroxy alkoxy of one to four carbon atoms, 1-alkylnyl of two to ten carbon atoms, tetrahydropyranyl . substituents independently selected from the group consisting of hydroxy, hydroxyalkyl of one to four carbon atoms; you

R24 selected from the group consisting of: hydrogen, alkyl of one to four carbon atoms, phenyl and substituted phenyl, wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen; you

R4 is selected from the group consisting of hydrogen, straight-chain or branched-chain alkoxy containing from one to four carbon atoms, halogen and straight-chain or branched-chain alkyl from one to four carbon atoms

[image]

where

R15 selected from the group consisting of hydrogen, a straight or branched alkyl chain consisting of one to ten carbon atoms, and a substituted straight or branched alkyl chain consisting of one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl which has three to six carbon atoms substituted with a straight or branched alkyl chain consisting of one to ten carbon atoms; a straight or branched alkenyl chain consisting of one to ten carbon atoms, and a substituted straight or branched alkenyl chain consisting of one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy radical contains one to four carbon atoms and the alkyl radical contains one to six carbon atoms; acyloxyalkyl wherein the acyloxyl moiety contains one to six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl and phenyl may be substituted on the benzene ring with one or two residues independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the limitation that when said benzene ring is substituted with two of said residues, then said residues together have no more than six carbon atoms; you

R25 is

[image]

where

are RS and RT independently selected from the group consisting of hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl, wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms , and hydrogen;

X is selected from the group consisting of said phenyl selected from the group consisting of: hydrogen, alkyl of one to four carbon atoms, phenyl and substituted phenyl, wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and a halogen; you

R4 is selected from the group consisting of hydrogen, straight-chain or branched-chain alkoxy containing from one to four carbon atoms, halogen and straight-chain or branched-chain alkyl from one to four carbon atoms, alkoxy from one to four carbon atoms, wherein the alkoxy residue contains from one to four carbon atoms carbon, and the alkyl residue contains from one to four carbon atoms, hydroxyalkyl from one to four carbon atoms, haloalkyl from one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, chlorine, hydroxy, 1-morpholino, 1-pyrrolidino, alkylthio of one to four carbon atoms, and

R5 is selected from the group consisting of hydrogen, a straight or branched alkyl chain containing one to four carbon atoms, halogen, and a straight or branched alkyl chain containing one to four carbon atoms;

or a pharmaceutically acceptable salt of any of the foregoing.

Preferred 6,7-fused cycloalkylimizadopyridine amines which are IRM are defined by formula VI below:

[image]

where m is 1, 2 or 3;

R 16 is selected from the group consisting of hydrogen, cyclic alkyl of three, four or five carbon atoms; a straight or branched alkyl chain containing one to ten carbon atoms and a substituted straight or branched alkyl chain containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl having three to six carbon atoms and cycloalkyl having three to six carbon atoms substituted by a straight or branched alkyl chain containing one to four carbon atoms; fluorine or chloroalkyl having from one to ten carbon atoms and one or more fluorine or chlorine atoms; a straight or branched alkenyl chain containing one to ten carbon atoms and a substituted straight or branched alkenyl chain containing one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl having three to six carbon atoms and cycloalkyl having three to six carbon atoms substituted by a straight or branched alkyl chain containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy radical contains from one to four carbon atoms and the alkyl radical contains from one to six carbon atoms; acyloxyalkyl wherein the acyloxy radical is alkanoyloxy of two to four carbon atoms or benzyloxy and the alkyl radical contains one to six carbon atoms, with the limitation that any such alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group does not have a complete a substituted carbon atom attached directly to a nitrogen atom; benzyl, (phenyl)ethyl phenyl; said benzyl, (phenyl)ethyl and phenyl substituent may be substituted on the benzene ring by one or two residues independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen with the limitation that when is the benzene ring substituted by two said residues, then the residues together do not contain more than six carbon atoms; you

-CHRXRY

whereby

Ry is hydrogen or a carbon-carbon bond with the restriction that when Ry is hydrogen, RX is alkoxy of one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, 1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy residue is contains one to four carbon atoms and the alkyl residue contains one to four carbon atoms, 2-,3-, or 4-pyridyl, and with the further limitation that when RY is a carbon-carbon bond, RY and RX together form a tetrahydrofuranyl group that can be substituted with one or more substituents independently selected from the group consisting of hydroxy and hydroxyalkyl of one to four carbon atoms,

R 26 is selected from the group consisting of hydrogen, a straight or branched alkyl chain containing one to eight carbon atoms, a straight or branched hydroxyalkyl chain containing one to six carbon atoms, morpholinoalkyl, benzyl, (phenyl)ethyl and phenyl, and benzyl, ( the phenyl)ethyl or phenyl substituent may be substituted on the benzene ring with a residue selected from the group consisting of methyl, methoxy and halogen; you

-C(RS)(RT)(X), wherein RS and RT are independently selected from the group consisting of hydrogen, alkyl of one to eight carbon atoms, phenyl and substituted phenyl, wherein the substituent is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy from one to four carbon atoms, and halogen;

X is selected from the group consisting of Alkoxy having one to four carbon atoms, Alkoxyalkyl wherein the alkoxyl residue contains one to four carbon atoms and the alkyl residue contains one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amide substituted with amino, wherein the substituent is alkyl or hydroxylalkyl of one to four carbon atoms, azido, alkylthio of one to four carbon atoms, and morpholinoalkyl, wherein the alkyl residue contains one to four carbon atoms, and

R6 is selected from the group consisting of hydrogen, fluorine, chlorine, a straight or branched alkyl chain containing one to four carbon atoms, a straight or branched chloro- or fluoroalkyl chain containing one to four carbon atoms and at least one fluorine or chlorine atom;

and corresponding pharmaceutically acceptable salts.

Preferred imidazopyridiamines which are IRM are defined by the formula below

[image]

where

R 17 is selected from the group consisting of hydrogen; -CH2RW, wherein RW is selected from the group consisting of straight-chain, branched or cyclic alkyl having one to ten carbon atoms, straight or branched alkenyl chain having two to ten carbon atoms, straight or branched hydroxyalkyl chain having one to six carbon atoms , alkoxyalkyl wherein the alkyl residue contains one to six carbon atoms and the alkyl residue contains one to four carbon atoms, and phenylethyl; and -CH=CRZRZ wherein each RZ is independently straight chain or cyclic alkyls of one to six carbon atoms;

R27 is selected from the group consisting of hydrogen, a straight or branched alkyl chain containing one to eight carbon atoms, a straight or branched hydroxyalkyl chain containing one to six carbon atoms, alkoxyalkyl wherein the alkyl residue contains one to six carbon atoms and the alkyl residue contains one to six carbon atoms, benzyl, (phenyl)ethyl and phenyl, and the benzyl, (phenyl)ethyl or phenyl substituent may be substituted with a benzene ring with a residue selected from the group consisting of methyl, methoxy and halogen, and morpholinoalkyl, at wherein the alkyl residue contains one to six carbon atoms, and with the further limitation that when R67 is hydrogen, then R77 and R27 are not hydrogen;

and corresponding pharmaceutically acceptable salts.

Preferred 1,2-imidazoquylolinamines which are IRM are defined by formula VIII below:

[image]

in which it is

Z selected from the group consisting of:

-(CH2)p- where p is from 1 to 4;

-(CH2)a-C(RDRE)(CH2)b-, where a and b are integers and a+b is from 0 to 3, RD is hydrogen or alkyl with one to four carbon atoms, and RE is selected from the group consist of alkyl of one to four carbon atoms, hydroxy, -ORF wherein RF is alkyl of one to four carbon atoms, and NRGR'G wherein RG and R'G are independently hydrogen or alkyl of one to four carbon atoms; you

-(CH2)a-(Y)-(CH2)b-, where a and b are integers, and a+b is from 0 to 3, RD is hydrogen or alkyl with one to four carbon atoms, and Y is O, S or -NRJ where RJ is hydrogen or alkyl of one to four carbon atoms;

and wherein q is 0 or 1, and R8 is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen,

and appropriate pharmaceutically acceptable salts.

Suitable thiazolo- and oxazolo quinolinamines and pridynamines include compounds of Formula IX:

[image]

where

R 19 is selected from the group consisting of oxygen, sulfur and selenium;

R29 is selected from the group they comprise

- hydrogen,

-alkyl,

-alkyl-OH,

-haloalkyl,

-alkenyl,

-alkyl-X-alkyl,

-alkyl-X-alkenyl,

-alkenyl-X-alkyl,

-alkenyl-X-alkenyl,

-alkyl-N(R59)2,

-alkyl-N3,

-alkyl-O-C(O)-N(R59)2,

-heterocyclyl,

alkyl-X-heterocyclyl,

alkenyl-X-heterocyclyl,

-aryl,

-alkyl-X-aryl,

-heteroaryl,

alkyl-X-heteroaryl,

alkenyl-X-heteroaryl,

R39 and R49 are independently:

- hydrogen,

-X-alkyl,

-halogen,

-haloalkyl,

-N(R59)2,

or R39 and R49 taken together form a fused aromatic heterocyclic ring,

X is selected from the group consisting of -O-, -S-, -NR59-. -C(O)-. -C(O)O-, -OC(O)- and bond, and

each R 59 is independently H or C 1-8 alkyl.

Suitable imidazonaphthyrines and tetrahydroimidazonaphthyrines which are IRM are those of formulas X and XI below:

[image]

where

And it is =N-CR=CR-CR=; =CR-N=CR-CR=; =CR-CR=N-CR=; or =CR-CR=CR-N=;

R110 is selected from the following groups:

- hydrogen:

- C1-20 alkyl or C1-20 alkenyl which is unsubstituted or substituted with one or more substituents from the following group:

-aryl,

-heteroaryl,

-heterocyclyl

-O-C1-20 alkyl,

-O-(C1-20 alkyl)0-1-aryl,

-O-(C1-20 alkyl)0-1-heteroaryl,

-O-(C1-20 alkyl)0-1-heterocyclyl,

-C1-20 alkoxycarbonyl,

-S(O)0-2-C1-20 alkyl,

-S(O)0-2-(C1-20 alkyl)0-1-aryl,

-S(O)0-2-(C1-20 alkyl)0-1-heteroaryl,

-S(O)0-2-(C1-20 alkyl)0-1-heterocyclyl,

-N(R310)2,

-N3,

-oxo,

-halogen,

-NO2,

- Oh, you

-SH; you

-C1-20 alkyl-NR310-Q-X-R410 or -C2-20 alkenyl-NR310-Q-X-R4, where Q is -CO- or -SO2-; X is a bond, -O- or NR310, and R410 is aryl, heteroaryl, heterocyclyl, or C1-20 alkyl or -C2-20 alkenyl which is unsubstituted or substituted with one or more substituents from the following group:

-aryl,

-heteroaryl,

-heterocyclyl,

-O-C1-20 alkyl,

-O-(C1-20 alkyl)0-1-aryl,

-O-(C1-20 alkyl)0-1-heteroaryl,

-O-(C1-20 alkyl)0-1-heterocyclyl,

-C1-20 alkoxycarbonyl,

-S(O)0-2-C1-20 alkyl,

-S(O)0-2-(C1-20 alkyl)0-1-aryl,

-S(O)0-2-(C1-20 alkyl)0-1-heteroaryl,

-S(O)0-2-(C1-20 alkyl)0-1-heterocyclyl,

-N(R310)2,

-NR310-CO-O-C1-20 alkyl,

-N3,

-oxo,

-halogen,

-NO2,

- Oh, you

-SH; or R4 is

[image]

wherein Y is -N- or -CR-;

R210 is selected from the following group:

- hydrogen,

-C1-10 alkyl,

-C2-10 alkenyl,

-aryl;

-C1-10 alkyl-O-C1-10 alkyl,

-C1-10 alkyl-O-C2-10 alkenyl, and

-C1-10 alkyl-O-C2-10 alkenyl substituted with one or more substituents selected from the following group

-OH,

-halogen,

-N(R310)2,

-CO-N(R3)2,

-CO-C1-10 alkyl,

-N3,

-aryl,

-heteroaryl,

-heterocyclyl,

-CO-aryl, te

-CO-heteroaryl,

each R 310 is independently selected from the following group: hydrogen and C 1-10 alkyl; you

each R is independently selected from the group consisting of hydrogen

and C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl;

or corresponding pharmaceutically acceptable salts.

[image]

where

B is -NH-C(R)2-C(R)2-C(R)2-; -C(R)2--NHC(R)2-C(R)2-; C(R)2-C(R)2-NH-C(R)2-; or -C(R)2-C(R)2-C(R)2-NH-;

R111 is selected from the following group:

- hydrogen,

- C1-20 alkyl or C1-20 alkenyl which is unsubstituted or substituted with one or more substituents from the following group:

-aryl,

-heteroaryl,

-heterocyclyl,

-O-C1-20 alkyl,

-O-(C1-20 alkyl)0-1-aryl,

-O-(C1-20 alkyl)0-1-heteroaryl,

-O-(C1-20 alkyl)0-1-heterocyclyl,

-C1-20 alkoxycarbonyl,

-S(O)0-2-C1-20 alkyl,

-S(O)0-2-(C1-20 alkyl)0-1-aryl,

-S(O)0-2-(C1-20 alkyl)0-1-heteroaryl,

-S(O)0-2-(C1-20 alkyl)0-1-heterocyclyl,

-N(R311)2,

-N3,

oxo,

-halogen,

-NO2,

- Oh, you

-SH; you

-C1-20 alkyl-NR3-Q-X-R4 or -C2-20 alkenyl-NR311-Q-X-R411, wherein Q is -CO- or -SO2-; X is a bond, -O- or NR311, and R411 is aryl, heteroaryl, heterocyclyl, or C1-20 alkyl or

C2-20 alkenyl which is unsubstituted or substituted with one or more substituents from the following group:

-aryl,

-heteroaryl,

-heterocyclyl,

-O-C1-20 alkyl,

-O-(C1-20 alkyl)0-1-aryl,

-O-(C1-20 alkyl)0-1-heteroaryl,

-O-(C1-20 alkyl)0-1-heterocyclyl,

-C1-20 alkoxycarbonyl,

-S(O)0-2-C1-20 alkyl,

-S(O)0-2-(C1-20 alkyl)0-1-aryl,

-S(O)0-2-(C1-20 alkyl)0-1-heteroaryl,

-S(O)0-2-(C1-20 alkyl)0-1-heterocyclyl,

-N(R311)2,

-NR311-CO-O-C1-20 alkyl,

-N3,

-oxo,

-halogen,

-NO2,

- Oh, you

-SH; or R411 is

[image]

wherein Y is -N- or -CR-;

R211 is selected from the following group:

- hydrogen:

-C1-10 alkyl

-C2-10 alkenyl,

-aryl,

-C1-10 alkyl-O-C1-10 alkyl,

-C1-10 alkyl-O-C2-10 alkenyl, and

-C1-10 alkyl-O-C2-10 alkenyl substituted with one or more substituents selected from the following group

-OH,

-halogen,

-N(R311)2,

-CO-N(R311)2,

-CO-C1-10 alkyl,

-N3,

-aryl,

-heteroaryl,

-heterocyclyl,

-CO-aryl, te

-CO-heteroaryl,

each R 311 is independently selected from the following group: hydrogen and C 1-10 alkyl; you

each R is independently selected from the following group: hydrogen and

C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl;

and corresponding pharmaceutically acceptable salts.

The above compounds are disclosed in the patents and applications cited above in the prior art, all of which are incorporated herein by reference.

The above substituents R11-R111 are generally designated herein as "1-substituents". Preferred 1-substituents are alkyl containing one to six carbon atoms and hydroxyalkyl containing one to six carbon atoms. 1-Substituent can be 1-methylpropyl or 2-hydroxy-2-methylpropyl.

The above substituents R21-R211 are generally referred to herein as "2-substituents". 2-Substituents are hydrogen, alkyl of one to six carbon atoms, alkoxyalkyl, wherein the alkyl residue contains one to four carbon atoms, and the alkyl residue contains one to four carbon atoms, and hydroxyalkyl of one to four carbon atoms. 2-Substituent can be hydrogen, methyl, butyl, propyl, hydroxymethyl, ethoxymethyl or methyloxyethyl.

In cases where n is zero, one or two, n is preferably zero or one.

Pharmaceutical formulations with IRM

The amount of an IRM compound that will be therapeutically effective in a specific case will depend on such things as the activity of the particular compound, the route of administration, the particular formulation, and the condition being treated. Therefore, it is not practical to provide a specific amount for administration herein, however, those skilled in the art will be able to determine suitable pharmaceutically effective amounts based on the instructions provided herein, available information on the compounds listed, and routine testing.

The pharmaceutical formulations described below can be used for topical administration to the mucosal surface. In some embodiments, the formulations can affect the pharmacokinetics of IRM by reducing the concentration of IRM leading to similar pharmacodynamic effects as other formulations having higher concentrations of IRM.

In general, the pharmaceutical formulation of the invention includes an IRM, a fatty acid, a preservative system and a viscosity increasing agent such as a carbomer may be present. An IRM can be prepared using the methods previously described in the prior art chapter, as well as in U.S. Pat. Patents no. 4,988,815; 5,367,076; 5,175,269; 5,395,937; and 5,741,908, the disclosures of which are incorporated herein by reference. Unless otherwise specified, all percentages are percentages by weight based on the total weight of the formulation.

The amount of IRM present in the pharmaceutical formulation of the invention will be an effective amount to treat the target condition, to prevent the return of the condition, or to achieve immunity to the condition. The amount of IRM is preferably from about 0.1% to about 9% by weight based on the total weight of the formulation. The amount of IRM may not exceed about 5% by weight, and the most preferred is about 0.1 to about 3% by weight for application on the mucosal surface.

Typically, the pharmaceutical formulation of the invention is an oil-in-water emulsion. The oil component of the formulation includes IRM and fatty acid. The fatty acid is present in the formulation in an amount sufficient to render the IRM soluble. This is generally about 2% to about 45%, typically about 10% to about 30%, and preferably about 15% to about 18% based on the total weight of the formulation. Fatty acids such as isostearic acid are suitable for formulations. Alternatively, IRM can be dissolved in a linear chain carboxylic acid of six to eight carbon atoms.

A pharmaceutical formulation of the invention may also include an emulsifier such as a nonionic surfactant. Suitable surfactants include, for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4-oleate, polyoxyethylene(4)lauryl ether, etc. For some formulations, surfactants such as poloxamers are preferred surfactants (eg, Plumoric F68 from BASF, Ludwigshafen, Germany) and sorbitan thiooleate (eg, Span 85 from Signa Chemical Co., St. Louis, MO) alone or in combination. The nonionic surfactant is typically present in an amount of about 0.5% to about 10% of the total weight of the formulation. In preferred units, the total emulsifier content does not exceed about 5% of the total mass of the formulation, and more preferably about 3.5% of the total mass of the formulation.

Formulations of the invention may also include viscosity-increasing agents such as carbomer, which preferably has mucoadhesive properties. The carbomer may be present in amounts from about 0.1% to about 8%, preferably from about 0.5% to about 4%, more preferably from about 0.5% to about 3%, and most preferably from about 1.0% of the total weight of the formulation. Suitable carbomers include polyacrylic acids such as Carbopol 934P, Carbopol 971P, Carbopol 940 and Carbopol 974P from B.F. Goodrich. The preferred carbomer is Carbopol 974P.

In some preferred embodiments, the formulation may also include a chelating agent. Chelating agents form a chelate with the methane ion. If a non-chelated metal is present, it can reduce gelation by reducing the ionization that facilitates gelation in the carbomer contained in the formulation. A possible chelating agent is disodium ethylenediaminetetraacetate (EDTA) in a concentration of about 0.0001 to about 0.5%, typically about 0.0005 to about 0.1% by total weight of the formulation.

A preservative may also be added such as methylparaben, sorbic acid, propylene glycol, etc. In one possible embodiment, methylparaben and sorbic acid are both present at a concentration of about 0.05% to about 0.3%, preferably about 0.15% of the total weight of the formulation and propylene glycol is present at a concentration of about 30%, preferably about 5%. This combination of preservatives was found to be good in the Preservation Effectiveness Test (PET), 1997 European Pharmacopeia, Test 5.1.3 Efficacy Antimicrobial Preservation - Topical Preparatios - A Criteria. This keeps the formulation suitable for use in a multi-dose device without adversely affecting the stability of the formulation. Methylparaben and sorbic acid may be dissolved in propylene glycol prior to addition to the formulation.

The remainder of the pharmaceutical formulation may contain water to enable the formulation to be washed off the mucosal surface by normal physiological flushing mechanisms.

In addition to obtaining mucoadhesive properties, carbomer also increases viscosity by forming a stabilizing gel. Many factors, such as the amount of oil phase, the amount of drug, the amount of carbomer used will affect the pH value at which the gel is formed. In some formulations, the presence of metal ions and surfactants increase the pH at which the carbomer forms a gel. Therefore, in the absence of a chelating agent or the presence of an increased level of surfactant, the pH at which the carbomer forms a gel will increase. Therefore, it may be necessary to add an organic or inorganic base or other substance to facilitate gel formation. Suitable inorganic bases include, for example, KOH, NaOH, etc. The pH of the pharmaceutical formulation of the invention is typically from about pH 3.0 to about pH 7.0, preferably about pH 4.0 to about pH 6.0.

Application to the surface of the mucous membrane

According to the invention, the compositions can be applied topically, especially to non-granular epithelial surfaces such as mucosal surfaces. Mucous surfaces include mucous membranes such as buccal, gingival, nasal, tracheal, bronchial, gastointestinal, rectal, urethral, ureteral, vaginal, cervical, uterine, etc. Depending on the concentration of IRM, formulation composition, mucosal surface, the therapeutic effect of IRM can be provided only on the superficial layers of the mucosal surface or deep in the surface.

In one embodiment, the disclosed IRMs can be administered topically to the vaginal or supravaginal region of the cervix for the treatment of dysplastic conditions such as cervical intraepithelial neoplasia. In some units, the formulations described above are particularly suitable for cervical application of IRM in a period sufficient to obtain the desired therapeutic effect without unwanted systemic absorption of IRM.

Cervical intraepithelial neoplasia (CIN)

Every year in the U.S.A. approximately 16,000 new cases of invasive cervical cancer were diagnosed despite intensive screening of women diagnosed with cellular changes. There are also about 3,000 deaths from cervical cancer in the U.S. alone, and these are usually secondary because primary cancer lesions are not detected in time.

The Papanicolaou test (Pap stain) is a screening test that has been accepted since the 1950s as a method of detecting abnormal cells of the cervix, including inflammation and dysplasia, which includes cervical cancer. This screening test is widely accepted in industrialized countries and has an impact on cervical cancer mortality. Abnormal Pap staining accelerates rapid observation of disease progression with possible therapeutic intervention of destruction or excision of cancerous or precancerous tissue. These excision treatments are expensive, uncomfortable, and associated with failure rates ranging from 2 to 23%, and are more unsuccessful for more advanced lesions. It has recently been shown that the failure rate after laser treatment is around 10%.

Herpes virus was originally thought to be the etiological agent for cervical cancer. However, there is a gradual shift in attention from herpes virus to human papillomavirus (HPV) as the cytopathic effects of HPV in an experimental system have been shown to mimic very well what is seen in human disease. Improved experimental methods in the recent past allow the characterization of the full spectrum of HPV subtypes, which is resulted in the conclusion that high-risk HPV types (e.g. HPV 16, 18 and less often 31, 33, 35, 45) are most likely the only initial factors (i.e. oncogenic agent) of cervical dysplasia and then cancer. Mechanisms of HPV transformation of normal cells into dysplastic cells related is with HPV-encoded octoproteins (E6 and E7) from the high-risk genotype that bind to the products of the p53 and Rb suppressor genes of cell tumors resulting from the breakdown of the cell cycle control mechanism in which p53 and Rb play an important role. In addition, the application of molecular methods has resulted by the epidemiological observation that HPV is isolated from approximately 93% of cervical tumors, which is further reinforced by the general with the accepted conclusion that HPV infection is the most important irritant for cervical cancer.

HPV exposure is common in sexually active women, but does not always lead to dysplasia or cancer in most exposed women. Infected women who permanently harbor the viral DNA are about five times more likely to develop permanent dysplasia compared to women who can stop the virus. The importance of the cell-maintained immune response (CMI) to HPV infection is illustrated by the observation that an antibody-maintained immune response is ineffective in clearing an established infection, as demonstrated by the fact that patients with invasive cervical cancer often have high levels of antibodies to the viral E6 and E7 proteins. This specific antibody response probably indicates a long-term exposure to the antigen, as opposed to an increased tumor burden. In contrast to the apparent inconsistent effect of the humoral immune response, the cell-mediated immune response (Th-1-type response) is effective in controlling tumor progression. Regression of intraepithelial lesions is accompanied by a cellular infiltrate consisting of CD4+ T-cells, CD8+ T-cells, natural killer (NK) cells and macrophages. This inflammatory infiltrate is usually associated with tumor regression, in contrast to women who lack the ability to elicit an inflammatory response and experience disease progression. In addition, patients with a lack of cells to maintain immunity have an increased incidence of cervical cancer, while those with a defect in antibody production do not.

In one embodiment, the inventors envision the topical application of IRM for non-invasive conditions of the cervix including cervical antiepithelial neoplasia (CIN).

Intravaginal applicators for IRM

In order to obtain a suitable therapeutic or prophylactic effect of the condition of the cervix, intravaginal application of IRM is preferred. IRM can be applied through a dosed formulation or a device that ensures contact of IRM with the surface of the cervical mucosa for a sufficient period to obtain the desired therapeutic effect. Any device (ie, applicator) described herein and/or shown in the drawings may be used to administer IRM.

In addition to the applicators already described, IRM can be formulated as a suppository and administered vaginally using a suppository applicator. A suitable suppository applicator includes known applicators for delivering medication into the vaginal cavity. Formulations of the invention may also be administered using barrel-type applicators such as those described herein and/or shown in the drawings. An example of a suitable barrel-type applicator can be found in U.S. Pat. Patent no. 5,282,789, which disclosure is incorporated herein by reference.

In a possible unit, IRM can be given directly to the mucous membrane of the cervix. In one such embodiment, the IRM can be delivered topically to the cervical mucosa using a direct cervical applicator, as previously described, or using a cervical cap. One example of a suitable cervical cap is found in U.S. Pat. patent no. 4,858,624, the disclosure of which is incorporated herein by reference. Suitable IRM formulations for direct cervical application are shown above and in the Examples below. In general, an IRM formulated suitable for any of the compositions A-J of the Examples below can be placed in the concave portion of the cervical cap which is then directly applied to the cervix. These formulations may also be used with other types of delivery devices including those shown in the drawings and described herein. The IRM can be formulated to include a viscosity agent, such as carbomer, to increase the residence time of the IRM in the cervix.

The following examples further describe the IRM formulations and methods of the invention. However, the Examples are not intended to limit the formulations and methods.

EXAMPLES

EXAMPLE 1

EVALUATION OF SAFETY, PHARMACOKINETICS (PK) AND PHARMACODYNAMICS (PD) OF 1-(2-METHYLPROPYL)-1H-IMIDAZO[4,5-C]QUINOLINE-4-AMINE (IMIQUIMOD) USED TO THE CERVIX

Methods

It was a single-dose, randomized, double-blind, placebo-controlled trial of progress that evaluated five doses of imiquimod. 50, 100, 150, 200 and 250 mg of imiquimod in the cream formulation was applied to the cervix for eight hours. The ingredients of the imiquidmod cream formulation used in this study (Formulation A) are shown in Table I below. Each dose group contained 8 subjects (6 active and 2 placebo), with two subjects treated as dose leaders and the other six of subjects was treated after an acceptable response in dose leaders. Safety was assessed based on adverse effects (AEs), laboratory tests, and colposcopy with photodocumentation of the cervix before the dose and 24 hours after the dose, and if necessary 48 hours after the dose. Systemic exposure (PK) was determined by measuring imiquimod and metabolites during 48 hours post-dose and PD response was determined by serum cytokine analysis; tumor necrosis factor-α (TNF-α), interferon-α (IFN-α), interleukin-1 receptor agonist (IL-1RA), interleukin-6 (IL-6), neoperin (NPT) and 2'5'- oligoadenylate synthetase (2'5' AS) during dosing and selected time for 48 hours after dosing. Statistical tests for AE assessment and demographic, laboratory, vital signs, and ECG are Fisher extract, Wilcoxon rank sum, and Kruskall Wallis test. Cytokine administrations between dose groups were compared using the Wilcoxon rank sum, and changes from baseline were assessed using the Spearman rank correction.

the results

Thirty-nine, generally healthy surgically sterilized 18-50 year old women 25% within the ideal body weight were included in the study. All women had a normal result of the baseline colonoscopy and a normal borderline value of dyskaryosis of the cervical histology. AEs were reported for all 39 subjects with mildly elevated temperature as the most common occurrence (92%). There was no difference between groups in subjects who had multiple manifestations, or an AE attributed to possible or probable drug-relatedness. (The two serious AEs that did occur were increased manifestation associated with fracture of the joint and post-operative condition). Statistically significant changes in some laboratory parameters were observed, and the change in heart rate was not considered clinically significant. No differences were observed in ECG physical examinations. Pelvic and colonoscopy studies showed a small reaction in 2 of 6 subjects who received 250 mg, who had changes in small vesicles or small ulcers on the cervix. These reactions stopped within 48 hours. No quantifiable amount of imiquimod was detected in serum (>5 ng/mL). Significant changes from baseline were seen in IFN and IL-6 in the 250 mg group and in NPT. 2'5' AS and IL-1RA in the 150 mg, 200 mg and 250 mg groups.

Studies show that single doses of imiquimod up to 250 mg applied to the cervix over 8 hours in healthy volunteers are safe with minimal systemic exposure. Application to the cervix in doses ≥ 150 mg increases the systemic concentration of some cytokines.

TABLE 1

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EXAMPLE 2

PREPARATION OF PHARMACEUTICAL FORMULATION B

This example describes a new pharmaceutical formulation for vaginal use, which is a stable formulation of high viscosity and well preserved to pass the EP preservation efficiency test (PET) criterion. The w/w% of the ingredients of this formulation (Formulation B) is shown in Table 2 below.

Imiquimod is dissolved in isostearic acid with Span 85. Plunoric F68, EDTA, Carbopol 974P, polyethylene glycol, sorbic acid, and methylparaben are dissolved in water. After emulsification, an oil-in-water emulsion was formed, sodium hydroxy was added to reach a pH of about 5.2. The pH range for that formulation can be around 4.8 to 6.0.

TABLE 2

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EXAMPLE 3

PREPARATION OF PHARMACEUTICAL FORMULATIONS C-F

Pharmaceutical formulations C-F are prepared with the components listed in Table 3 below. The method of preparation of Formulation C-F is the same as shown for the preparation of Formulation B of Example 2

TABLE 3

[image] PG* propylene glycol

EXAMPLE 4

TRANSPORT OF IMIQUIMOD THROUGH SKIN OF HAIRLESS MOUSE FROM TWO FORMULATIONS A AND B, BOTH WITH 5% W/W IMIQUIMOD

FIGURE 16 is a graph of the results of penetration testing of imiquimod Formulations A and B Examples 1 and 2, using hairless mouse skin according to the procedure described in U.S. Patent No. 5,238,944, the entire disclosure of which is incorporated herein by reference.

Briefly, 5- to 7-week-old female hairless mice were skinned (supplied by Charles River). The skin was kept on ice until use. The skin is attached to a diffusion cell of the type shown in U.S. Pat. Patent no. 5,238,944. The skin is joined on the epidermal side between the upper and lower part of the cell, which is held together by a ball clamp.

The lower part of the cell under the attached skin is completely filled with 0.1 M HCl receptor fluid so that the receptor fluid has contact with the skin. The receptor fluid was mixed using a magnetic stirrer and a magnetic stirrer.

Approximately 100±5 mg of the formulation to be tested was applied to the epidermal (upper) side of the skin so that it covers the area of the skin that will be in contact with the receptor fluid in a uniform layer, and after attaching the skin to the diffusion cell. The formulation was applied to the skin before the receptor fluid was added to the cells beneath the skin.

The cell is placed in a chamber with a constant temperature (31°C). To keep the temperature constant, the chamber used a heat exchanger attached to the diffusion cell. The receptor fluid was mixed using a magnetic stirrer throughout the experiment to ensure sample uniformity and reduce the diffusion barrier layer on the dermal layer of the skin. At specific time intervals (1, 2, 4, 6, 8, 12 and 24 hours) the entire volume of receptor fluid was immediately removed and replaced with fresh receptor fluid. The prescribed prescription liquid was analyzed for imiquiod content by conventional high-pressure chromatography:

Detector: UV at 258 nm; mobile phase: 25/75 acetonitrile/water containing 1% triethylamine, 0.2% 1-octane sulfonate with oH adjusted to 2.0 with H3PO4; stationary phase: C8Zorbax RX-C8 5 m; flow rate: 2 mL/min; time approximately 10 minutes.

The dependence of the cumulative penetrated amount on time is plotted so that the steady state velocity is obtained.

EXAMPLE 5

TRANSPORT OF IMIQUIMOD THROUGH SKIN OF HAIRLESS MOUSE FROM FORMULATIONS C-F WITH 1% W/W AND 3% W/W IMIQUIMOD AND WITH DIFFERENT CONCENTRATIONS OF ISOSTEARIC ACID (ISA)

Table 4 below shows the imiquimod concentration, isostearic acid concentration, viscosity, pH, and steady state rate (mg/h) of Formulation C-F across hairless mouse skin.

The results are shown as a graph in FIGURE 17. The procedure used for the penetration test is the same as in Example 4.

TABLE 4

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EXAMPLE 6

PHARMACOKINETIC COMPARISON OF IMIQUIVOMOD IN RATS AFTER SINGLE DOSE VAGINAL ADMINISTRATION OF FORMULATION A AND FORMULATION B

A graph of imiquimod serum concentration versus time was compared in ovariectomized rats after a single intravaginal dose of Formulation A or Formulation B. The two 5% w/w formulations were dosed so that the dose difference was 35 mg/kg. After dosing, each rat was fitted with a collar to prevent removal of the formulation by licking. After about six hours, the vagina was washed and the collars were removed. Blood samples were collected before dosing, and 0.5, 1, 2, 3, 4 and 24 hours after dosing. Due to the higher viscosity of Formulation B, intravaginal administration to rats was significantly easier and retention of Formulation B was more favorable than Formulation A.

Imiquimod was analyzed in serum by HPLC. The mean imiquimod concentration versus time is shown in FIGURE 18. The time to reach the maximum imiquimod serum concentration (Tmax) is similar (1 h) for both formulations. However, the maximum concentration of imiquimod (cmax) for Formulation B is approximately 1.6 times higher than Formulation A, and the specific area under the curve versus time (AUC) is 3.3 times higher (FIGS. 19A and 19B). Based on these data, the rate and extent of absorption of imiquimod is greater for Formulation B than for Formulation A.

EXAMPLE 7

PREPARATION OF PHARMACEUTICAL FORMULATION G

The weight percentages (w/w%) of the ingredients are shown in Table 5.

The oil phase was prepared as follows: Imiquimod (20.0 g) was slowly added to isostearic acid (3000 g) with stirring. The mixture was stirred and heated if necessary to 55°C to facilitate dissolution of imiquimod. After complete melting, the heating is turned off. Sorbitan trioleate (200 g) was added and mixed well. Carbomer 974 was slowly added with stirring. Mixing was continued until the carbomer was uniformly dispersed in the oil phase. The oil phase was then allowed to cool to less than 30°C.

The aqueous phase was prepared as follows: Sorbic acid (30.0 g) and methylparaben (40.0 g) were added with stirring to propylene glycol (1000 g). The resulting mixture was stirred and heated (<45°C) until a solution was formed. The heat source has been removed. Polaxamer 188 (500 mg) was added to the solution. The resulting mixture was mixed until the poloxamer was completely wet. The resulting mixture was then 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 formed.

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

EXAMPLE 8

PREPARATION OF PHARMACEUTICAL FORMULATIONS H-J

Pharmaceutical formulations H-J were prepared using the methods of Example 7. The w/w % of the ingredients in the formulations are shown in Table 5 below.

TABLE 5

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It will be apparent from the foregoing discussion that the imidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridiamines, and 1,2-bridged imidazoquinoline amines of the present invention may be useful for the treatment of mucosal conditions associated with cervical dysplasia. In addition, the presented pharmaceutical formulations may be particularly suitable for topical application of IRM to the mucosal surface.

It will be apparent from the foregoing detailed description of the examples that modifications and variations may be introduced with the compounds, formulations, devices, systems and methods disclosed herein. Other units will be clear to experts. The specifications and Examples are intended to be considered as examples only.

Claims (41)

1. A system for the treatment of conditions related to the surface of the mucous membrane, characterized by the fact that the system contains: a compound that is an immune response modifier (IRM) selected from imidazoquinoline-amines, imidazopyridine-amines, 6,7-fused cycloalkylimidazopyridine-amines, 1,2-bridged imidazoquinoline-amines, and their pharmaceutically acceptable salts, and a device for applying (applicator) the compound that is IRM to the surface of the mucous membrane. 2. The system of claim 1, characterized in that the compound which is the IRM is 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine. 3. The system of claim 1, characterized in that the compound which is the IRM is 4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol. 4. The system from claim 1, characterized in that the system further contains a pharmaceutical formulation containing: - compound that is IRM; - at least one fatty acid; you - preservation system containing propylene glycol. 5. The system of claim 1, characterized in that the applicator is pre-filled with a therapeutically effective amount of the compound that is IRM. 6. The system of claim 1, characterized in that the compound that is IRM is contained in a container separate from the device. 7. The system of patent claim 1, characterized by the fact that it further contains measurement marks on the device for application, and to help in determining the amount of compound that is IRM for the device for application. 8. The system from patent claim 1, characterized in that the condition associated with the surface of the mucous membrane is dysplasia of the cervix. 9. The system from claim 1, characterized in that the surface of the mucous membrane is on the cervix. 10. System from patent claim 9, characterized in that the surface of the mucous membrane is on the vaginal part of the cervix. 11. The system of claim 10, characterized in that the condition associated with the mucosal surface is intraepithelial neoplasia of the cervix. 12. System from claim 1, characterized in that the application device contains: a hollow tube containing a distal end for delivery and a proximal end, and piston that slides inside the tube. 13. The system of claim 12, further comprising a member configured to cause movement of the piston toward the distal end. 14. The system of claim 13, wherein the device is configured to limit return of the member toward the proximal end when the plunger is positioned adjacent the distal end. 15. The system of claim 13, characterized in that the piston connected to the member is detachable. 16. The system of claim 13, characterized in that the member is slidably received in the hollow tube. 17. The system of claim 12, characterized in that it further comprises an obstacle that limits the return of the piston towards the proximal end. 18. The system of claim 12, characterized in that the piston includes a portion extending from the distal end, and when the piston is located at its farthest point from the proximal end. 19. The system of claim 12, characterized in that the distal end is tapered on the outer surface. 20. The system from claim 13, characterized in that the length of the member is less than the distance between the proximal end and the piston, and when the piston is located at its furthest point from the proximal end. 21. A system for the treatment of conditions related to the mucosal surface, characterized in that the system contains: a compound that is an immune response modifier (IRM) selected from imidazoquinoline-amine, imidazopyridine-amine, 6,7-fused cycloalkylimidazopyridine-amine, imidazonaphthydrine-amine, oxazoloquinoline-amine, thiazoloquinoline-amine, 1,2-bridged imidazoquinoline-amine, and of their pharmaceutically acceptable salts, and a device for applying a compound that is IRM to the surface of the mucous membrane. 22. The system of claim 21, characterized in that the compound which is the IRM is 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine. 23. The system of claim 21, characterized in that the compound which is the IRM is 4-amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol. 24. The system of claim 21, characterized in that the compound which is the IRM is 2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine. 25. The system from claim 21, characterized in that the system further contains a pharmaceutical formulation containing: - compound that is IRM; - at least one fatty acid; you - preservation system containing propylene glycol. 26. The system of claim 21, characterized in that the applicator is pre-filled with a therapeutically effective amount of the compound that is IRM. 27. The system of claim 21, characterized in that the compound that is IRM is contained in a container separate from the device. 28. The system of claim 21, characterized in that it further contains measuring marks on the device for application, and to assist in determining the amount of compound that is IRM for the application device. 29. The system of claim 21, characterized in that the condition associated with the mucosal surface is cervical dysplasia. 30. The system from claim 21, characterized in that the mucosal surface is on the cervix. 31. System from patent claim 30, characterized in that the surface of the mucous membrane is on the vaginal part of the cervix. 32. The system of claim 31, characterized in that the condition associated with the mucosal surface is intraepithelial neoplasia of the cervix. 33. System from patent claim 21, characterized in that the application device contains: a hollow tube containing a distal end for delivery and a proximal end, and piston that slides inside the tube. 34. The system of claim 33, further comprising a member configured to cause movement of the piston toward the distal end. 35. The system of claim 34, wherein the device is configured to limit return of the member toward the proximal end when the plunger is positioned adjacent the distal end. 36. The system of claim 34, wherein the piston connected to the member is detachable. 37. The system of claim 34, characterized in that the member is slidably received in the hollow tube. 38. The system of claim 33, characterized in that it further comprises an obstacle that limits the return of the piston towards the proximal end. 39. The system of claim 33, characterized in that the piston includes a portion extending from the distal end, and when the piston is located at its farthest point from the proximal end. 40. The system of claim 33, characterized in that the distal end is tapered on the outer surface. 41. The system of claim 34, characterized in that the length of the member is less than the distance between the proximal end and the piston, and when the piston is located at its furthest point from the proximal end.