CZ20024175A3 - Systems and methods for treating mucous membrane surface - Google Patents

Abstract

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

Description

Technical field

The present invention relates to systems and methods of treating diseases associated with the mucosal surface, such as the vaginal portion of the cervix. The systems and methods may include the use of an immune response modifying compound (IRM) selected from imidazoquinoline amines, imidazopyridine amines, 6.7 fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, and 1,2-bridged pharmaceutically acceptable imides. salts. In one optional embodiment, the invention provides systems and methods particularly useful for topical administration to the cervix for the treatment of cervical diseases such as cervical dysplasia including human papillomavirus (HPV) associated dysplasia.

The present invention is also directed to providing drug delivery and methods of use. Some aspects of the invention are directed to transporting a pharmacological agent to a selected location with minimal transport to areas surrounding the selected location. In some optional forms, the invention is particularly advantageous for topical administration of the uterus.

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throat pharmacological agents

BACKGROUND OF THE INVENTION

Many imidazoquinoline amines, imidazopyridine amines, 6.7 fused cycloalkylimidazopyridine amines, 1.2 bridged imidazoquinoline amines, thiazolo and oxazoloquinolamines and pyridinamines, imidazonaphthyridine and antiviraminimide antitumor compounds have been shown to be active, cancer) activity, and has also been shown to be useful as adjuvants in vaccines to enhance the protective response of the immune system to vaccines. These compounds are therefore sometimes collectively called IRM (Modifying Immune Response) of the compound of the invention. The IRM compound may be selected from the group consisting of imidazoquinoline amines, imidazopyridine amines, 6.7 fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoquinoline amines, thiazoloquinoline amines, 1,2 bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. Methods for preparing such IRM compounds and pharmaceutical compositions containing them are disclosed, for example, in US Patent Nos. 4,689,338, 5,389,940,

5268376, 4929624, 5266575, 5352784, 5494916, 5482936, 5346905,

5395937, 5238944, 5525612, 5175296, 5693811, 5741908, 5939090,

6110929, 4988815, 5376076 and PCT publications WO 99/29693, WO

00/76505, WO 00/76518 and WO 00/76519. The entire contents of each of these patents and patent applications are incorporated herein by reference.

The immunostimulatory, antiviral, and antitumor activities of these compounds have been discussed in detail, and have been identified.

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certain specific diseases are susceptible to this treatment. These diseases include basal cell carcinoma, eczema, essential thrombocytopenia, hepatitis B, multiple sclerosis, neoplastic diseases, psoriasis, rheumatoid arthritis, type 1 herpes simplex, type 2 herpes simplex, and warts. One of these IRM compounds, known as imiquimod, has been marketed in a topical formulation under the name Aldara ™ 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 due in large part to an increase in the immune response due to the induction of various important cytokines (eg, interferon, interleukins, tumor necrosis factor, etc.). These compounds have been shown to stimulate rapid release of 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 activities of these IRM compounds. One of the predominant immunostimulatory responses to these compounds is the induction of interferon α (IFN) production, which is believed to be very important in the observed acute antiviral and antitumor activities. In addition, enhancement of cytokine expression, such as tumor necrosis factor (TNF), IL-1 and IL-β, also has potentially beneficial activities and is believed to contribute to the antiviral and antitumor properties of these compounds.

Although some of the beneficial effects of IRMs are known, the ability to provide therapeutic benefit by topical administration of IRMs to treat a particular disease at a particular location may be prevented due to tissue irritation, wash away, poor permeability, and unwanted transport into the systemic circulation of the topically administered compound. Therefore, there is a need for new methods, compositions and systems to provide the greatest therapeutic benefit of this class of compounds.

Topical administration of the pharmacological agent to the tissue surface can provide localized therapeutic benefit without concurrent systemic effects. However, topical administration is often difficult or impossible due to anatomical localization of the tissue. In some cases, administration of the agent to the overall anatomical region that includes or surrounds the target tissue may be an alternative to direct topical application. However, if the substance has irritating properties, this alternative entails the possibility of irritating the tissues surrounding the target tissue. In addition, if the agent is non-irritating, regional administration typically requires a larger volume or concentration of the agent to achieve a therapeutic result equivalent to that achieved by direct application to the target tissue.

The cervix is one example of target tissue to which it is difficult to apply a topical agent. In relation to standing position is. cervix located in the highest part of the vaginal cavity. However, while the cervix is located in the highest part of the vaginal cavity, age, the stage of the estrous cycle, pregnancy, and other factors cause variability in the location of the cervix in different women and in the same woman at different stages of life.

Certain diseases of the cervix can preferably be treated by topical administration of the pharmacological agent. Cervical dysplasia is an example of a pathological disease that can be effectively treated by direct delivery of the drug to the surface of the cervix, where abnormal cells are typically found. . Unfortunately, currently the most common vaginal drug delivery applicators are inadequate for application of the drug to the surface of the cervix. And because cervical dysplasia can lead to throat cancer that · it ·

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The uterine is not an applicator that is not the optimal, acceptable choice.

The currently available vaginal applicators are generally intended for application to the vaginal cavity and not for direct application to the cervix. In general, the length and configuration of the applicators are insufficient to ensure transport of the agent to the highest part of the vaginal cavity. Transporting the middle and lower parts of the vagina does not ensure that the substance reaches the cervical tissue in the upper part of the vagina. Moreover, with the exception of certain body orientations, gravity tends to divert the substance from the cervix. Normal outflow and outflow of fluids, both menstrual and non-menstrual, also removes substances from the cervix. Thus, any applicator that is not capable of repeatedly transporting the appropriate amount of agent to the highest end of the vaginal cavity carries the risk of suboptimal treatment.

Overcoming the inaccuracy of current vaginal applicators used to transport a substance to the cervix by transporting excess volume or drug concentration may be unacceptable because of the risk of adverse effects on surrounding tissues. However, the transport of reduced volumes or concentrations to avoid irritating surrounding tissue leads to the risk of serious consequences of ineffective treatment.

Therefore, there is a continuing need for improved delivery systems and methods for topical application of a pharmacological agent.

Description of the invention

One aspect of the invention includes a system for treating diseases associated with the mucosal surface. The system comprises an immune response modifying compound (IRM) selected from imidazoquinoline amines, imidazopyridine amines, 6, 7 fused cycloalkylimidazopyridine amines, 1, 2 bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. The system also includes an application device for applying an IRM compound to the mucosal surface.

Another aspect of the invention comprises a system for treating diseases associated with the mucosal surface. The system comprises an immune response modifying compound (IRM) selected from imidazoquinoline. amines, imidazopyridine amines, 6.7 fused cycloalkylimidazopyridine amines, imidazonaphthyridine amines, oxazoquinoline amines, thiazoloquinoline amines, 1,2 linking imidazoquinoline amines, and pharmaceutically acceptable salts thereof. The system also includes an application device for applying an IRM compound to the mucosal surface.

For example, the IRM compound may be 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine, or 4-amino-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-a] -c] -quinoline-1-ethanol, or

2-propyl [1,3)] thiazolo [4,5-c] quinolin-4-amine.

The system can be used to treat diseases associated with the mucosal surface on the cervix, optionally on the vaginal portion of the cervix. Exemplary diseases associated with the mucosal surface include cervical dysplasia and intraepithelial cervical neoplasia.

In an exemplary form, the applicator device may include a hollow tube and a piston displaceable through the tube.

Yet another aspect of the invention includes a method of treating a disease associated with the mucosal surface. The method comprises providing an immune response modifying agent (IRM) selected from imidazoquinoline amines, imidazopyridine amines, 6, 7 fused cycloalkylimidazopyridine amines,

imidazonaphthyridine amines, oxazoquinoline amines, thiazoloquinoline amines, 1,2 bridge-linked imidazoquinoline amines, and pharmaceutically acceptable salts thereof. The method also includes providing an application device for applying an IRM compound to the mucosal surface. In addition, the method further comprises applying the IRM compound to the mucosal surface by the delivery device.

The method may include inserting the delivery device into the vagina, positioning the distal end of the delivery device to the vaginal portion of the cervix, and applying the IRM compound to the vaginal portion of the cervix.

At least some of the embodiments of the invention provided herein provide drug delivery systems and methods suitable for topical administration of the agent to the target tissue. Systems and methods may be advantageous for intravaginal delivery of a pharmacological preparation. For example, some forms provide effective topical application of a pharmacological agent for the treatment or prevention of diseases including, for example, cervical dysplasia.

Other aspects will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of the invention. It will be appreciated that guidance will be provided in several cell-specified locations through a list of Examples of the Invention. In any event, the list provided serves only as a representative group; it is not intended as an exclusive list.

It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not limiting.

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

Brief description of the pictures

Giant. IA a top view of a treatment system comprising a delivery device and a packaged container of an IRM compound;

Giant. 1B is a top view of a treatment system with several pre-filled containers with an IRM compound;

Giant. 2 is a schematic perspective view of components of an intravaginal transport device;

Giant. 3 is a view of the proximal end of an exemplary intravaginal transport device;

Giant. 4 is a longitudinal cross-sectional view of an exemplary intravaginal transport device taken through line 4-4 with a compression member retracted proximally;

Giant. 5 is a longitudinal cross-sectional view of an exemplary intravaginal transport device taken through line 4-4 with a compression member displaced distally;

Giant. 6 is a detailed view of the proximal end of the intravaginal transport device illustrated in FIG. 5;

Giant. 7 is a detailed view of the distal end of the intravaginal transport device illustrated in FIG. 5;

Giant. 8 is a schematic perspective view of the components of an optionally alternative form of intravaginal delivery device of the invention;

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Giant. 9 is a longitudinal cross-sectional intravaginal transport of FIG. retracted proximally;

Giant. 10 is a longitudinal cross-sectional intravaginal transport of FIG. displaced distally;

view of the device for 8 with a compression element view of the device for 8 with a compression element

Giant. 11 is a detailed view of the distal end of the intravaginal transport device illustrated in FIG. 10;

Giant. 12 is a detailed view of the proximal end of the intravaginal transport device illustrated in FIG. 10;

Giant. 13 is a perspective view of an alternative proximal end for an intravaginal transport device;

Giant. 14 is a perspective view of another alternative proximal end for an intravaginal transport device;

Giant. 15 is a longitudinal sectional view of an exemplary intravaginal transport device pre-filled with the formulation;

Giant. 16 is a graph comparing imiquimod transport of fur-free mouse skin in three pharmaceutical formulations containing 5% imiquimod;

Giant. 17 is a graph comparing the transport of imiquimod to the skin of haired mice in four pharmaceutical formulations containing different concentrations of imiquimod and isostearic acid;

9 «0900 9 · · 00» 00 ···· · · · · · · · · ·

9 9 9 · 9 99 ·· · 9 · 9 · 9 · 9

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Giant. 18 is a graph comparing the mean serum imiquimod concentration in rats following a single intravaginal dose of Formulation A or Formulation B; and

Giant. 19A and 19B provide bar graphs of pharmacokinetic comparison of imiquimod in rats following vaginal dosing of Formulation A or Formulation B.

Description of the Invention

Reference will now be made in detail to some exemplary embodiments of the invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numerals are used throughout the drawings to refer to like or similar parts.

The present invention may be directed, in part, to drug delivery devices and methods of delivering a pharmacological agent to a selected location. In some optional forms, containers may be particularly suitable for intravaginal delivery of a pharmacological agent. In optional embodiments, said containers may provide topical application of the pharmacological agent to an intravaginal location, such as the cervix, for the treatment of diseases including, for example, cervical dysplasia. The containers may generally be used to deliver the pharmacological agent in the necessary repetition and amount to obtain the desired therapeutic outcome.

Throughout the specification, guidance may be provided through lists of Examples of the Invention. In any event, the list provided serves only as a representative group. However, it is not meant to be exclusive.

As used herein, the term pharmacological agent includes any substance or combination of substances that may be used to diagnose, treat, treat, treat, relieving, preventing, or otherwise treating a patient's disease. The term disease refers to any infectious, non-infectious, pathological, physiological, biochemical or other condition of a patient that can be treated according to the invention. Throughout the specification, unless stated otherwise, the terms proximal and distal are relative terms. The term proximal refers to the location closest to the user (e.g., the hand of the user handling the cartridge) and the term distal refers to the location furthest from the user. Thus, in a typical embodiment of the invention, the proximal end of the delivery device will be closest to or grasped by the user ' s hand and the distal end of the instrument will be positioned closest to the tissue site to which the substance will be applied.

As used herein, a mucosal-associated disease means an inflammatory, infectious, neoplastic or other disease that affects the mucosal surface or is sufficiently close to the mucosal surface to be affected by a therapeutic or prophylactic agent applied topically to the mucosal surface.

Unless otherwise indicated, the term treat and its derivatives such as treatment, treatment, etc. are used generically herein to indicate the administration of a pharmacological agent for any reason to a patient and are not intended to distinguish a preventive, therapeutic, diagnostic procedure. The term therapeutically refers to the amount of therapeutic agent administered, such as cytokine induction, antiviral or antitumor activity. A therapeutically effective amount comprises a single dose of the agent used during treatment for a period of time to achieve the desired therapeutic effect.

palliative or other effective amount means to provide the desired φφ · · ΦΦ φ • φφφφφφφφφφφφφφφφφφφφφ φφφφφφφφ · · φ φ φφφφφφφφφφφφ Φ · φφ φφ φφ φφ

Some optional forms of the device and methods of the invention may be advantageous for transporting a substance to the cervix through the vagina to treat (ie, prevent, diagnose, alleviate, etc.) cervical disease. In certain optional embodiments, they may be. cartridges of the invention particularly useful for transporting an immune response modifying agent (IRM) to the cervix for the treatment of its disease. Examples of immune response modifiers useful in the invention include those disclosed, for example, in US Patent Nos. 4689338, 5389640, 5268376, 4929624, 5266575, 5352784, 5494916, 5482936, 5346905, 5395937, 5238944, 5525612, 5175296, 5693811, 5693811, 5693811 5741908, 5939090, 6110929, 4988815, 5376076 and PCT publications WO

99/29693, WO 00/76505, WO 00/76518 and WO 00/76519. The entire contents of each of these patents and patent applications are incorporated herein by reference. Some optional IRM compounds suitable for the invention include 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine (imiquimod) and compounds and preparations as disclosed in co-pending U.S. Serial No. 09/479578 and PCT publication WO 00/06577. The entire contents of each of these patents and patent applications are incorporated herein by reference.

Generally, the term user of referenced cartridges (also referred to herein as applicators) includes healthcare providers who administer the substance to a patient, or patients themselves who administer the substance to themselves.

In some optional embodiments, the cartridges can provide accurate transport of a predetermined amount of pharmacological agent to a selected location with a reduced likelihood of unwanted transport to surrounding tissues. The predetermined amount is typically a therapeutically effective amount for a single dose. Accurate application of the substance to the selected location can advantageously reduce the amount of substance required to achieve the desired concentration. · · · · · · · · · · · · · · · · · · · · · · ·

........ '' therapeutic result while minimizing the possibility of irritating adjacent tissues to the selected site of application.

For intravaginal applications, the reservoir can reduce unwanted side effects caused by the substance. For example, if drug transport is required only to the cervix, such as in the case of cervical disease, drug transport to sites other than the upper vaginal cavity may inadvertently expose the lower portion of the vaginal cavity and other surrounding tissues to the cloth. This not only exposes untargeted tissues to the substance but also potentially irritates the tissue with the substance or other components in the pharmacological preparation.

The intravaginal reservoirs may optionally provide accurate transport of a volume of the substance (or preparation thereof) that is smaller than the volumes typically used to administer other intravaginal drugs. In some optional embodiments, intravaginal containers may provide transport of about 0.01-10 ml, in other optional forms about 0.5 to 4 ml, and typically about 1.0 ml.

The containers may be prefilled with a therapeutically effective amount of a particular agent or filled by the user at the time of administration.

In the second situation, the containers may be configured to obtain a substance from its source (for example, aluminum tubes, plastic tubes, etc.), which may be attached to the container for filling. Some optional containers can typically provide a fixed maximum volume of fabric. Alternatively, or in addition, the containers may have an ascending marking for filling with an amount less than the maximum volume of the container.

A pre-filled container may be provided in an optional form to eliminate the possibility of filling the transport container.

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4 9 4 4 4 9 4 9 1 4 • 9 4 4 1 9 4 4 9 9 4 4 ♦ · .. ».. .. ..

the wrong amount of substance. In one optional form, the containers may be pre-filled with a composition comprising an amount of an immune response modifying compound (IRM) for a single dose treatment. The cartridge, whether pre-filled or not, may be packaged in an outer wrapper, such as a foil wrapper, which maintains sterility and may act as a moisture barrier.

The container may be manufactured by known methods including injection molding processes to form a plastic applicator from polymeric materials, such as high density polyethylene, low density polyethylene, linear low density polyethylene, or polypropylene.

Giant. IA shows a treatment system 400 comprising an applicator device 10 and a container 401 filled with a formulation in a container 402. The device 10 could be configured to be filled with the formulation contained in a container 401 by placing them to communicate with each other.

Giant. 1B shows a treatment system 400 wherein the formulation is contained in pre-filled cartridges 401a-401d that can be filled with the supply device 10 once in a while.

Giant. 2 and 4 show an optional form of the intravaginal transport 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 extending therethrough. Giant. 2 is a schematic perspective view of components of the device 10 comprising an elongate tube 3 having a transport end 4, an operating end 5, and a lumen 6 passing therethrough. The operating end comprises a handle 7, such as opposed flanges 8a and 8b for gripping the device 10 during use. In some forms, the »» ········· «

· ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** Have an elongated tube of about 6 cm to about 24 cm, typically about 10 cm to about 18 cm.

The squeezing element 11 may be displaced in the lumen 6 of the elongated tube 3. and may include a squeezing end 12 and a displaced end 13. The squeezing element 12 may include a platform 14 for accommodating a user's thumb or finger to distally move the squeezing element 11 in the lumen 6. The cap 18 can be detachably attached to the distal end 4 of the device 10 using known arrangements such as threads or sliding attachments.

In FIG. 3 is a view of the distal end of the device 10, and FIG. 4 is a longitudinal cross-section of the device 10 taken through line 4-4 of FIG. 3. In FIG. 4, a piston 15 is fastened to the displaced end 13 of the squeezing element 11, which is located in a first position securing the chamber 20 to contain or obtain a predetermined amount of the pharmacological agent.

In some optional embodiments, the chamber 20 will provide a volume of pharmacological agent of about 5 ml and 0.1 ml, typically about 2 ml to 0.5 ml, and optionally about 1.0 ml. In an optional embodiment of the invention, the displaced end 13 of the compression element 11 may be removably disposed within the bore 19 of the piston 15. Thus, in this optional embodiment, if the compression element 11 is pulled proximally, the displaced end 13 of the compression element 11 may be pulled out of the bore 19 and 15, will not be drawn proximally by the compression member 11. The optional aspect may prevent aspiration of the substance after expelling the substance from the chamber 20 and may also prevent tissue aspiration into the transport end 4 of the tube 3 if the compression member 11 is drawn proximally.

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In addition, in some optional forms, the lumen 6 may include a stopper 40, such as a protrusion 41, which may protrude into the lumen 6 to prevent proximal retraction of the piston 15. While the device 10 is pre-filled with fabric or filled by the user at the time of use, to provide a fixed maximum volume of chamber 20 to contain a predetermined amount of substance. This stopper may advantageously prevent the user from exceeding a particular dose of the substance if the device 10 is filled with the substance by the user before use.

The cap 18 is shown attached to the transport end 4. The cap 18 may be slidable. Alternatively, or additionally, the cap 18 may include a shaft 18a that is slidably attached to the distal end 1 of the lumen 6. The distal end 1 of the lumen 6 may alternatively have a nut thread (not shown) that engages helically in a helical manner. a thread (not shown) that may be present on the outer surface of the stem 18a. The lid 18 may also include a tab 18b that provides easier grip on the lid 18 when removed from the tube 3. ·

The cap 18 may optionally include a texture, such as grooves, strips, etc., to facilitate removal. Markings, such as an elevated arrow, may optionally be added to the cap 18 to indicate the direction of unscrewing for removal and thus participate in the ease of use of the device.

In FIG. 5, the compression element 11 has been moved distally to a position that would cause the pharmacological agent to be expelled from the chamber 20. In an optional illustrated embodiment, when the compression element 11 is displaced distally, the distal tip 16 of the piston 15 projects beyond the distal end 4 of the elongated tube 3. In addition, the distal tip 16 may be convex or arched outward to further ensure complete expulsion of the fabric from the chamber 20.

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In FIG. 6 shows a detailed view of an optional form of the proximal end 2 of the transport device 10. In the illustrated embodiment, the platform 14 of the compression element 11 forms an arm 25 at the connection with the compression end 12 of the compression element 11. If the compression element 11 is distally displaced in the lumen 6, For example, the arm 25 may be positively stopped by abutting the operating end 5 of the elongated tube 3, which may indicate completion of the transport of the pharmacological agent from the chamber 20 of the device 10.

Giant. 7 is a detail of an optional form of the distal end 1 of the transport device 10. As illustrated, the distal end of the chamber 20 of the lumen 6 may include a converging cone 30. The outer surface 31 of the piston 15 may also have a converging cone 32 which may extend into the distal tip 16. Corresponding converging cones 30 and 32 may facilitate completion of the transport of the pharmacological agent contained in the chamber 20 when the compression element 11 is moved distally. The plunger 15 may also include a sealing ring 33, such as a peripheral skirt 34, which may conveniently fit to the lumen 6 to ensure that a significant portion, preferably all, of the pharmacological agent is removed from the lumen 6 as the piston 15 is moved distally. Thus, the lumen 6 may have at least two different diameters, the diameter of the lumen L _D may be about 5 to about 15 mm, and the typical transport diameter may be about 2 to about 10 mm. In the example of a transport device 10 with a maximum chamber volume of about 1 ml, the length of the elongated tube 3 may be about 12-20 cm, L _D may be about 10 mm, and D _d may be about 6 mm.

The outer surface 35 of the distal end 1 of the elongated tube 2 may also have a converging cone 36 to facilitate insertion of the distal end 1 of the device 10 into the vagina. Also, once the fabric has been expelled from the chamber 20, the converging cone can ensure that all the expelled fabric remains in the place where it has been transported. For example, at • ·· · • · ·. Delivery with applicators cylindrical vaginal distal hip

When used proximal to 10 in the left placed on p 11, so that the substance from com localization, uterine it.

Giant. 8 is sc alternative How is the illustration? The longitudinal axis 100 may have a thread passing through 10.

The surgical handle 107 of the mold device 1C may be omitted from the operating device.

In comparison with the uterine tip (i.e., right; the tip with rounded corners), the distal end 1 may also cover the tissue remaining on the tip.

: 1 Place the thumb and middle finger 8b of the handle 7 to hold the device while the user's index finger is

The physical displacement of the squeezing element 3 of the piston 15 expels the pharmacological import of the substance into an intravaginal example of the mucosal surface of the throat, a perspective view of the optional components. for intravaginal transport 100. an apparatus for intravaginal transport end 101, distal end 102 extending through. The elongated tube 103 104, the surgical end 105 and the lumen 105

108 may be a displaceable or liner end 102 of the cap 18 of the tubing device 103 may include an Ot 118 to facilitate handling thereof. In this optional illustrated extending continuously around the circumference, however, it will be appreciated that the fold 118 need not be a fold 118

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The compression member 111 may be slidably advanced into the lumen 106 and may include a compression end 113 and a shaft 115 extending between. The compression member 113 may include a platform 116 for accommodating a user's thumb or other finger to distally displace the compression member 111 during use. The platform 116 may have a concave surface 117 to better accommodate the thumb or other finger of the user. The piston 120 may be rigidly attached to the displaced end 114 of the compression member 111 or the displaced end 114 may be removably disposed within the bore 122a at the end 122. The piston 120 may include a distal tip 121. In some embodiments, the distal tip 121 may be distally convex or arched to further ensure complete displacement of the fabric.

Giant. 9 is a longitudinal cross-sectional view of the device 100 showing a chamber 130 for retaining or obtaining a predetermined amount of pharmacological agent after the compression element 111 has been drawn proximally into the lumen 106 of the extended tube 103. FIG. 10 illustrates that when the element is compressed. 111, the distal tip 121 of the piston 120 may extend beyond the distal end 102 of the extension tube 103.

Fig. 11 is a view of the horse of the "view" device 100 illustrating that the chamber 130 may include a converging cone 131 at the distal end 102 of the lumen 106.

The optional converging cone 131 of chamber 130 may be configured to mate with a corresponding converging cone 132 in the distal portion of the piston 120. The converging surfaces 131 and 132 may facilitate complete displacement of the pharmacological agent contained in the chamber 130.

The piston 120 may also include a sealing ring 133, such as a peripheral skirt 134, which can snugly engage the lumen 106 to ensure complete emptying of the fabric, such as

the piston 120 is displaced distally. The outer surface 135 of the distal end 102 of the elongated tube 103 is tapered into the cone 136 for the reasons discussed above.

As with the device 10, in some optional embodiments, the lumen 106 may include a stopper 140, such as a protrusion 141 that may protrude into the lumen 106 to prevent proximal retraction of the piston 15. While the device 100 is pre-filled with fabric or filled by the user at the time of use, the positioning of the stopper 140 may provide a fixed maximum volume of the chamber 130 to contain a predetermined amount of substance.

Giant. 12 is a detailed view of an optional embodiment of the proximal end 101 of the device 100 of FIG. 10 illustrating that when the compressing element 111 is fully displaced distally, the platform 116 of the compressing end 113 can be entrapped into the operating end 105 of the elongated tube 103. This feature reduces the likelihood that some or all of the pharmacological agents released from chamber 130 will be aspirated back into the chamber. 130 after delivery by inadvertently pulling in the compressing member 111 after the pharmacological agent has been expelled.

In some selectable firing forms, the operating end 105 of the elongated tube 103 and the compressing end 113 of the compression member 111 may be designed to provide audible or tactile feedback to the user upon complete displacement of the fabric. According to this optional embodiment, the operating end 105 of the lumen 106 may include a projecting surface 145, such as a strip 146 positioned proximal to the platform 116 when the compression member 111 is fully displaced distally. The platform 116 may be positioned such that the platform 116 is depressed distally behind the bar 146 and a click may be heard and movement behind the bar 146 creates a tangible click that informs the user that the fabric has been completely displaced. The strip 146 may also lock the compression member 111 in the distally displaced portion and may prevent proximal pulling of the compression member 111.

It will be appreciated that in addition to the lumen diameter L _D and the transport diameter D _d , the lumen 106 also has a diameter P _o at the operating end 105. Thus, the lumen 106 may have a cone 150 extending between the diameter P _o and L _d . In an example of a transport device 100 having a maximum chamber volume of about 1 ml, the length of the elongated tube 103 is about 15 to about 17 cm, L _D is about 11-15 mm, and D _d is about 712 mm.

In an optional alternative form, the region of the elongated tube 103, referred to as having parallel sides (see, e.g., Fig. 9) extending from the proximal end to the distal end, may have a converging cone from the proximal end to the distal end. This may advantageously provide for filling the delivery device with a pharmacological agent from the proximal end of the elongated tube rather than the distal end. That is, without the cone as described, it may be prevented from attempting to push the piston into place distally along the non-chamfered tube after filling with the formulation with air that can be trapped between the piston seal and the lumen wall. By beveling the elongated lumen as described, the gap between the piston and the wall can be maintained, which may allow air to escape as the piston is moved distally. Such a tapered bevel may be progressive along the length of the elongate tube, or it may be a steep tapered bevel, near the location where the piston is to be positioned to set a predetermined volume at the distal end of the elongated tube.

Giant. 13 illustrates another optional form of an operating end of an elongate tube for an intravaginal delivery device 10, 100 of the invention. In accordance with this embodiment, the operating end 201 of the elongate tube 200 may include:

......

a configuration that provides the orientation indicator 203 of the device 200 about the longitudinal axis X-X. In the embodiment of FIG. 13, the opposite sides 204 and 205 are therefore linear giving the operating end an oval cross-sectional configuration. In this form, the fold 206 may extend around the circumference of the operating end 201. However, it will be appreciated that the fold may be completely absent or be placed discontinuously around the circumference.

Giant. 14 illustrates another optional form of an operating end of an extension tube 300 suitable for the intravaginal transport device of the invention. In this form, the operating end 301 of the extension tube 300 may be in a configuration that also provides an indicator 303 for orienting the device 300 about the longitudinal axis XX. The operating end 301 may include corners 304a-304d. The walls 305a-305d of the operating end 301 between the corners 304a-304d form a converging cone moving from the operating end of the diameter P 0 _to the lumen of the diameter L _D. In an illustrated embodiment, the proximal aspect of each of the walls 305a-305d may include a concave cavity 306a-306d extending distally to the surface of the walls 305a305d. In addition, the compression member platform 350 (not shown) may have a distal concave surface 351 and four corners 352a-352d configured to mate with the corners 304a-304d of the walls 305a-3-0-Sd. The fold or bars (not shown in this form of the invention) may or may not. be present around the proximal edge of the operating end 301 as described for the devices 10 and 110.

The intravaginal delivery device can provide accurate transport of a volume of substance that is less than the volumes typically used for other vaginal drugs. Many vaginal applicators are designed to transport about 5 ml of substance and the application is not localized but rather delivered generally to the vaginal cavity.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · Φ · '· ·'

In optional embodiments, such as shown in FIG. 155, the applicator 10 may be pre-filled with product P to eliminate the possibility of improper filling of the applicator. However, if the device is to be filled at the time of use, a structure, such as a stopper on the device, can set a maximum volume that can help eliminate the possibility of exceeding a predetermined dose.

Any of the above applicators may be of sufficient length to allow the distal end of the applicator to be positioned at or very close to the cervix, while a portion of the applicator extends through the vagina and the proximal end is positioned outside the vagina. The length of the applicator may be configured to provide transport of the IRM compound to the uppermost end of the vaginal cavity while the proximal end is outside the vagina. For example, the length of the applicator may be sufficient to accommodate the anatomical variability between women so that treatment of women with longer vaginal cavities is not compromised.

In use, the intravaginal transport device may be maintained at the proximal end between the thumb and middle finger and the platform of the squeezing element is compressed (i.e. displaced distally) by the index finger to transport the substance.

In an optional form, the compression member may be pre-positioned in the lumen of the elongate tube ready for use. If the delivery device is to be filled prior to use, the distal end of the elongate tube may include a nut thread that helically engages the helical thread of the drug source, such as an aluminum tube, to provide a threaded seal when transferring the drug from the chamber source to the delivery device.

Applicators can be packaged in a pillow case to provide asepsis as well as serve as a barrier

9 9 • • 99 · against moisture. The cushion wrapper may be made of any material suitable for protecting the pharmacological material, such as foil or foil layers (for example, metal and plastic layers). In some embodiments, the package may be protected from moisture loss from the formulation or from oxidation of the formulation.

The applicator device may be part of a system or component used in a method comprising additional parts or components.

In one optional embodiment, the systems and methods include an immune response modifying compound (IRM) for treating or preventing mucosal surface-associated diseases. For example, the IRM compound may be a composition that can be applied to the mucosal surface of the cervix to treat cervical diseases including its dysplasia, such as intraepithelial neoplasia of the cervix.

In certain optional embodiments, certain formulations may be used for application to the mucosal surface of an IRM compound.

In some optional embodiments, they may increase the therapeutic efficacy of the IRM by facilitating permeability or increasing the duration of IRM contact with the mucosal surface. The pharmaceutical composition may contain a preservative system, which allows the compositions to be suitable for use in multiple dose containers.

mucosal preparations

IRM compounds

As noted above, many of the many IRM compounds, such as imidazoquinoline amines, imidazopyridine amines, 6.7 fused cycloalkylimidazopyridine amines, 1,2 bridged imidazoquinoline amines, thiazolo and oxazoquinoline amines, and pyridinamines, imidazonaphthyridine and tetrahydroimidazonines are the subject of the present invention. invention. significant immunomodulatory activity. Certain optional immune-modifying compounds. the answer, Φ ♦ *, which are the subject of the present invention include 1Himidazo [4,5-c] quinolin-4-amines defined by one of formulas I-V below:

I kde

R 11 is selected from the group consisting of alkyl of one to ten carbon atoms, hydroxyalkyl of one to six carbon atoms, acyloxyalkyl, acyloxy is alkanoyloxy of two to four carbon atoms, or benzoyloxy, and the alkyl group contains one to six carbon atoms, benzyl, (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring by one or two groups 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 proviso that if said benzene ring is substituted by two of said groups, then said groups of the s-pole contain no more than six carbon atoms;

R ₂₁ is selected from the group consisting of hydrogen, alkyl of one to eight carbon atoms, benzyl, (phenyl) ethyl and phenyl, wherein the benzyl, (phenyl) ethyl or phenyl substituents are optionally substituted on the benzene ring by one or two groups independently selected from groups containing alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, provided that if said benzene ring is substituted by two of said groups,

said groups together comprising no more than six carbon atoms; and each R _x is independently selected from the group consisting of alkoxy of one or four carbon atoms, halogen and alkyl of one to four carbon atoms, and n is an integer from 0 to 2 with the proviso that if n is 2, then said R 1 groups together contain no more than six carbon atoms;

R 12 is selected from the group consisting of straight or branched chain alkenyl of two to ten carbon atoms and alkenyl with a substituted straight or branched chain of two to ten carbon atoms, wherein the substituent is selected from the group consisting of straight or branched chain alkyl of one to four carbon atoms, and cycloalkyl of three to six carbon atoms substituted with a straight or branched chain alkyl of one to four carbon atoms; and

R 22 is selected from the group consisting of hydrogen, straight or branched chain alkyl having one to ten carbon atoms, benzyl, (phenyl) ethyl and phenyl wherein the benzyl, (phenyl) ethyl or phenyl substituents are optionally substituted on the benzene ring by one or two groups independently selected from the group consisting of straight chain or branched chain alkyl of one to four carbon atoms, straight chain or branched chain alkoxy containing »♦» »» »» »» »» »» »» »» »» » One to four carbon atoms and halogen, provided that if said benzene ring is substituted by two of said groups, said groups together contain no more than six carbon atoms; and each R ₂ is independently selected from the group consisting of straight or branched chain alkoxy of one to four carbon atoms, halogen and straight or branched chain alkyl of one to four carbon atoms, and n is an integer from 0 to 2 with the proviso that when n is 2, then said R ₂ groups together contain no more than six carbon atoms;

R 12 is selected from the group consisting of hydrogen, straight or branched chain alkyl having one to eight carbon atoms, benzyl, (phenyl) ethyl and phenyl wherein the benzyl, (phenyl) ethyl or phenyl substituents are optionally substituted on the benzene ring by one or two groups independently selected from the group consisting of straight or branched chain alkyl of one to four carbon atoms, straight or branched chain alkoxy of one to four carbon atoms and halogen, provided that if said benzene ring is substituted by two of said groups, then said groups together contain not more than six carbon atoms; and * · ♦ ··· · * · ·· ·

each R ₃ is independently selected from the group consisting of straight or branched chain alkoxy of one to four carbon atoms, halogen and straight or branched chain alkyl of one to four carbon atoms, and is an integer from 0 to 2 subject to, that if n is 2, then said R ₃ groups together contain no more than six carbon atoms;

nh ₂

IV where

R ₁₄ is -CHR _x R _y , wherein R _y is hydrogen, or a carbon-carbon bond, with the proviso that when R _y is hydrogen, R _x is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl, wherein the alkoxy group contains one to four carbon atoms and the alkyl group contains one to four carbon atoms, 2-, 3- or 4-pyridyl, and with the proviso that when R _y is the carbon-carbon bond, R _y and R _x together form a tetrahydrofuranyl group optionally substituted with one or two substituents independently selected from hydroxy and hydroxyalkyl of one to four carbon atoms;

R 24 is 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 of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and »« · · · · · · · · ·

R ₄ is selected from the group consisting of hydrogen, straight or branched chain alkoxy containing one to four carbon atoms, halogen and straight or branched chain alkyl

cycloalkyl cycloalkyl wherein

R 18 is selected from the group consisting of hydrogen, straight or branched chain alkyl having from one to ten carbon atoms and alkyl with substituted straight or branched chain containing from one to ten carbon atoms, wherein the substituent is selected from the group consisting of three to six carbon atoms and containing three to six carbon atoms substituted with a straight or branched chain alkyl of one to four carbon atoms; straight chained or branched alkenyl of two to ten carbon atoms and alkenyl substituted with unbranched or branched chain of 2 to 10 carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl having three carbon atoms and cycloalkyl carbon atoms substituted with a branched chain containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy group contains one to four carbon atoms and the alkyl group contains one to six carbon atoms; acyloxyalkyl, wherein the acyloxy group is alkanoyloxy of two or four carbon atoms or benzoyloxy, and the alkyl group contains one to six carbon atoms; benzyl, (phenyl) ethyl and phenyl, az containing three to alkyl with unbranched six six or ♦

said benzyl, (phenyl) ethyl or phenyl substituents are optionally substituted on the benzene ring by one or two groups independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, provided that when said benzene ring is substituted with two of said groups, then said groups together contain no more than six carbon atoms; and

R25 is where

R _S and R _T are independently selected from 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 ;

X is selected from the group consisting of alkoxy of one to four carbon atoms, alkoxyalkyl wherein the alkoxy group contains one to four carbon atoms and the alkyl group contains one to four carbon atoms; (C 1 -C 4) hydroxyalkyl, (C 1 -C 4) haloalkyl, alkylamido wherein the alkyl group contains one to four carbon atoms, an amino group, a substituted amino group wherein the substituent is an alkyl or hydroxyalkyl of one to four carbon atoms, azido, chloro, hydroxy, morpholino, 1-pyrrolidino, alkylthio of one to four carbon atoms; and

R ₅ is selected from the group consisting of hydrogen, straight or branched chain alkoxy of one to four carbon atoms, halogen and straight or branched chain alkyl of one to four carbon atoms;

or a pharmaceutically acceptable salt of any of the foregoing compounds.

Preferred 6,7-fused cycloalkylimidazopyridine amine IRM compounds are defined by Formula VI below:

wherein 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; straight or branched chain alkyl of one to ten carbon atoms and alkyl with substituted straight or branched chain of one to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl of three to six carbon atoms and cycloalkyl of three to six carbon atoms substituted with unbranched alkyl

0000 * 0 0 0 0

0000

substituted with one to one or branched chain of one to four carbon atoms; fluoro or chloroalkyl containing one to ten carbon atoms and one or more fluorine or chlorine atoms; straight or branched chain alkenyl of two to ten carbon atoms, wherein the substituent is selected from the group consisting of cycloalkyl of three to six carbon atoms of straight or branched chain four carbon atoms; hydroxyalkyl of one to six carbon atoms, alkoxyalkyl wherein the alkoxy group contains one to four carbon atoms and the alkyl group contains one to six carbon atoms; acyloxyalkyl, wherein the acyloxy group is alkanoyloxy of two or four carbon atoms or benzoyloxy, and the alkyl group contains one to six carbon atoms, with the proviso that any such alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl group does not have fully a carbon-substituted carbon atom attached directly to the nitrogen atom; benzyl;

(phenyl) ethyl; and phenyl; said benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring with one or two groups independently selected from the group consisting of alkyl of one to four carbon atoms, alkoxy-s-i-middle-to-four-four carbon "atoms" and "halogen" with the proviso that if said benzene ring is substituted by two of said groups, then said groups together contain no more than six carbon atoms;

and CHR _x R _y , where

R _y is hydrogen, or a carbon-carbon bond, with the proviso that when R _y is hydrogen, R _x is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1-alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl, wherein the alkoxy group contains one to four '''' to ' to ' ** atoms and the alkyl group contains one to four carbon atoms, 2-, 3- or 4-pyridyl, and with the proviso that if R _y is a carbon-carbon bond, R _y and R _x together form a tetrahydrofuranyl group optionally substituted with one or two substituents independently selected from hydroxy and hydroxyalkyl of one to four carbon atoms;

R ₂ 6 is selected from the group consisting of hydrogen, alkyl straight or branched chain containing one to eight carbon atoms, hydroxyalkyl with a straight or branched chain containing one to six carbon atoms, morpholino olinoalkyl, benzyl, (phenyl) ethyl and phenyl, the benzyl the (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring by a group selected from methyl, methoxy and halogen; and

-C (Rs) (Rt) (X) wherein R _S and R _T are independently selected from 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;

X is selected from the group consisting of alkoxy of one to four carbon atoms, alkoxyalkyl wherein the alkoxy group contains one to four carbon atoms and the alkyl group contains one to four carbon atoms; haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino group, substituted amino group wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, alkylthio of one to four carbon atoms; · · »* * * * ·

R 5 is selected from the group consisting of hydrogen, fluoro, chloro, straight or branched chain alkyl of one to four carbon atoms, and fluoro- or chloroalkyl of straight chain or branched chain of one to four carbon atoms and at least one fluorine or chlorine atom;

and pharmaceutically acceptable salts thereof.

Preferred imidazopyridine amines defined by Formula VII below:

IRM compounds are

alkoxyalkyl, where carbon atoms and carbon atoms,

VII

R 17 is selected from the group consisting of hydrogen, -CH ₂ R _W , wherein R _w is selected from the group consisting of straight chain, branched or cyclic alkyl having from one to ten carbon atoms, straight chained or branched alkenyl containing from two to about ten carbon atoms, straight or branched chain hydroxyalkyl containing one to six carbon atoms, the alkoxy group containing one to four alkyl groups containing one to six, and phenylethyl; and -CH = R _Z R _Z wherein each R _Z is independently straight chain alkyl, branched or cyclic chain containing one to six carbon atoms;

R ₂₇ is selected from the group consisting of hydrogen, straight or branched chain alkyl having one to eight carbon atoms, straight or branched chain hydroxyalkyl having one to six carbon atoms, alkoxyalkyl wherein

99-9 9 9 99 9 0

9 9 9 ·

0 9 · * · _Λ • · * ϊ 1

Q Ε7 · · »

00 00 09 00 99 the alkoxy group contains one to four carbon atoms and the alkyl group contains one to six carbon atoms, benzyl, (phenyl) ethyl and phenyl, wherein the benzyl, (phenyl) ethyl or phenyl substituent is optionally substituted on the benzene ring by a group selected from the group consisting of methyl, methoxy and halogen; and morpholinoalkyl, wherein the alkyl group contains one to four carbon atoms;

R _{@ 7} and R @ ₇₇ are independently selected from the group consisting of hydrogen and alkyl of one to five carbon atoms with the proviso that R ₆₇ and R ₇₇ together contain no more than six carbon atoms and with the further proviso that when R ₇₇ H, then R ₆₇ is not hydrogen and R ₂₇ is neither hydrogen nor morpholinoalkyl and with the further proviso that if R _{67 is} hydrogen then R ₇₇ and R ₂₇ are not hydrogen;

and pharmaceutically acceptable salts thereof.

Preferred 1,2-bridged imidazoquinoline amine IRM compounds are defined by Formula VIII below:

where

Z is selected from the group consisting of

- (CH ₂ ) _p - wherein p is 1 to 4;

- (CH ₂ ) _and -C (R _d Re) (CH ₂ ) b -, where a and b are integers and a + b is 0 to 3, R _d is hydrogen or alkyl of one or four carbon atoms

4 * and R _E is selected from the group consisting of alkyl of one to four carbon atoms, hydroxy, -OR _F , wherein R _F is alkyl of one to four carbon atoms and -NR 8 R ' _{G /} wherein R q and R' _G 'are independently hydrogen or alkyl of one or four carbon atoms; and

- (CH ₂ ) _a - (Y) - (CH ₂ ) _b -, wherein a and b are integers and a + b is 0 to 3, and Y is O, S or -NR j -, wherein R j is hydrogen or alkyl with one or four carbon atoms;

and wherein q is 0 or 1 and R ₈ is selected from the group consisting of alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen and pharmaceutically acceptable salts thereof.

Suitable thiazolo- and oxazoloquinolamine and pyridinamine compounds include those defined by Formula IX:

K49

LX where

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

R ₂₉ is selected from the group consisting of

-hydrogen;

To · toto · »toto toto toto toto toto toto toto · · · · to to to to to to to to to to to to to to to to to * ·. «.. .. .. ..

-alkyl;

-alkyl-OH;

-haloalkyl;

-alkenyl;

-alkyl-X-alkyl;

-alkyl-X-alkenyl;

-alkenyl-X-alkyl;

-alkenyl-X-alkenyl;

-alkyl-N (R ₅₉ ) ₂ ;

- alkyl-N ₃ ;

-alkyl-OC (O) -N (R ₅₉ ) ₂ ;

-heterocyclyl;

-alkyl-X-heterocyclyl;

-alkenyl-X-heterocyclyl;

-aryl;

-alkyl-X-aryl;

-alkenyl-X-aryl;

-heteroaryl;

-alkyl-X-heteroaryl; and -alkenyl-X-heteroaryl;

R ₃₉ and R ₄₉ are each independently:

—— hydrogen; ---------------- ------ - --------- ------ ----- - - ..... ....... - - -X-alkyl;

-Hello;

-haloalkyl;

-N (R ₅₉ ) ₂ ;

or when taken together, R ₃₉ and R _{49 form a} fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring;

X is selected from the group consisting of -O-, -S-, -NR59-, -C (O) -, C (O) O-, -OC (O) -, and a bond; and • 9,999 ·· ····

9 «♦ ···

9 9 9 · 9 9 9 *

9 9 9 9 9

Each R ₅₉ is independently H or C _1-8 alkyl; 9 9 9 9 9 9 9 9 9 R ₉ is independently H or C _1-8 alkyl;

t

Suitable imidazonaphthyridine and tetrahydroimidazonaphthyririne IRM compounds are those defined by Formula X and XI below:

X where

A is = N-CR = CR-CR =; = CR-N = CR-CR =; = CR-CR = N-CR =; or = CR-CR = CR-N =;

Rno is selected from the group consisting of:

-hydrogen;

-C 1-2 alkyl or C 2-20 alkenyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of: ---- --- aryl;

-heteroaryl;

-heterocyclyl;

-O-C 1-20 alkyl;

-O- (C 1-2 alkyl) 0-1 -aryl;

-O- (C 1-20 alkyl) 0-1-heteroaryl;

-O- (C 1-20 alkyl) 0-1-heterocyclyl;

-C 1-2 alkoxycarbonyl;

-S (O) 0-2-C 1-2 -alkyl;

-S (O) 0-2- (C 1-20 -alkyl) _0-1 -aryl;

-S (o) 0-2 "(C 1-2 -alkyl) 0-1-heteroaryl;

• Φ φ φ φ φ φ φ φ φ φ φ · ·

ΦΦΦ F ΦΦΦ ΦΦΦ Φ Φ Φ Φ Φ · · · · · · · · · · · · ·

-S (Ο) 0-2- (Ci-2o alkyl) ₀ -ι-heterocyclyl;

-N (R ₁₀ ) 2;

-N ₃ ;

-OXO;

-halogen;

-NO ₂ ;

-OH; and -SH; and

-C 2o _{alkyl-NR3-and O} --OX R4io or - C _2-2 alkenyl-NR ₃ QXR-io io ₄ wherein Q is -CO- or -S0 ₂ -; X is a bond, -O- or -NR ₃₁₀ - and R ₄₁₀ is aryl; heteroaryl; heterocyclyl; or -C _1-2 alkyl or

C 2-20 alkenyl which is unsubstituted or substituted with one or more substituents selected from the group consisting of: -aryl;

-heteroaryl;

-heterocyclyl;

-O-C 1-20 alkyl;

-O- (C 1-20 alkyl) 0-1 -aryl;

-O- (C 1-20 alkyl) 0-1-heteroaryl;

-O- (C 1-20 alkyl) 0-1-heterocyclyl;

------- - - - - ---- - ------- -S (O) 0-2-C 1-20 -alkyl;

-S (O) 0-2- (C 1-20 -alkyl) 0-1 -aryl;

-S (O) 0-2- (C 1-20 -alkyl) 0-1-heteroaryl;

-S (O) 0-2- (C 1-20 -alkyl) 0-1-heterocyclyl;

“N (R ₃ io) 2, ·

-NR _{3 10} CO-O-C 1-2 alkyl;

-N ₃ ;

-OXO;

-halogen;

-NO ₂ ;

-OH; and ·· * ···

Φ · ····

4 ·

4 4

4 44 • 44 • 44

-SH; or R410 is

wherein Y is -N- or -CR-;

R ₂ io is selected from the group consisting of:

-hydrogen;

-C1-10 alkyl;

-C2-10 alkenyl;

-aryl;

-C1-10 alkyl-O-C1-10 alkyl;

-C1-10 _{alkyl-0-C2-IO} alkenyl; and

-C-10 alkyl or _C2-IO alkenyl substituted by one or more substituents selected from the group consisting of:

-OH;

-halogen;

-N (R310) 2;

-CO-N (R ₃ io) _2;

-CO-C 1-10 alkyl -N ₃ ;

-aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

-CO-heteroaryl;

each R 310 is independently selected from the group consisting of hydrogen and Οχ. Alkyl; and

each R is independently selected from hydrogen, C ₁₀ alkyl, C _x-IO alkoxy, halogen or trifluoromethyl and methyl, or a pharmaceutically acceptable salt thereof.

XI where

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

R m is selected from the group consisting of:

-hydrogen;

-C ₂₀ alkyl, or c _{2. 20} alkenyl which is not substituted or substituted with one or more substituents selected from the group consisting of:

-aryl;

-heteroaryl;

-heterocyclyl;

-O-C 1-20 alkyl;

-O- (C _1-20 alkyl) 0-1 aryl;

-O- (C _1-20 alkyl) 0-1 heteroaryl;

-O- (C _1-20 alkyl) 0-1 heterocyclyl;

-Cx-20 alkoxycarbonyl;

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

-S (O) 0-2- (C _1-2 -alkyl) 0-1 aryl;

-S (O) 0-2- (C _1-2 -alkyl) 6-χ-heteroaryl;

-S (O) 0-2- (C _1-2 -alkyl) 6-χ-heterocyclyl;

-N (R3 11) 2;

-N ₃ ;

• · ·

-0X0;

-halogen;

-NO ₂ ;

-OH; and -SH; and

-C ₂₀ alkyl-NR311-QX-R411 or -C _{second 2} o alkenyl-NR ₃₁₁ -QXR ₄₁₁ , wherein Q is -CO- or -SO ₂ ; X is a bond, -O- or -NR ₃₁₁ - _and R _41X is aryl; hetroaryl; heterocyclyl; or C _1-20 alkyl or

-C ₂ . ₂₀ alkenyl which is unsubstituted or substituted by one or more substituents selected from the group consisting of:

-aryl;

-heteroaryl;

-heterocyclyl;

-O-C _1-20 alkyl;

-O- (C _01.20 alkyl) 0-1-aryl;

-O- (C _1-20 alkyl) _-O -heteroaryl;

-O- (C 1-20 alkyl) _-O -heterocyclyl;

-Whose. ₂ o alkoxycarbonyl;

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

-S (O) 0-2- (C _1-20 -alkyl) _0-1 -aryl;

-S (O) 0-2- (C 1-20 -alkyl) _0-1 -heteroaryl;

-S (O) 0-2- (C _1-20 -alkyl) _0-1 -heterocyclyl;

-N (R ₃ N) _2;

-NR ₃ h-CO-O-C _1-2 alkyl;

-N ₃ ;

-0X0;

-halogen;

-NO ₂ ;

-OH; and

-SH; or R ₄ n is • · · «·

wherein Y is -N- or -CR-;

R ₂ n is selected from the group consisting of:

-hydrogen;

-C1-10 alkyl;

-C2-20 alkenyl;

-aryl;

-C 1-10 alkyl-O-C 1-10 alkyl;

-C 10 _{alkyl-0-C2-IO} alkenyl; and

-C 10 alkyl, or c _{2. 2} o alkenyl substituted with one or more substituents selected from the group consisting of:

-OH;

-halogen;

-N (R 3h) ₂ ;

-CO-N (R ₃ h) ₂ ;

-CO-C 1-10 alkyl;

-N ₃ ;

-aryl;

-heteroaryl;

-heterocyclyl;

-CO-aryl; and

-CO-heteroaryl;

R311 is independently selected from hydrogen and _Ci-I0 alkyl; and • · · · · ·

each R is independently selected from the group consisting of hydrogen, C _1-10 alkyl, C 1-10 alkoxy, halogen and trifluoromethyl, and pharmaceutical salts thereof.

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

The substituents R 11 -R 11 mentioned above are generally referred to herein as 1-substituents. Preferred 1-substituents are alkyl of one to six carbon atoms and hydroxyalkyl of one to six carbon atoms. Optionally, 1-substituents are 2-methylpropyl or 2-hydroxy-2-methylpropyl.

The substituents R21-R21 mentioned above are generally referred to herein as " 2-substituents. &Quot; Optional 2-substituents are hydrogen, alkyl of one to six carbon atoms, alkoxyalkyl wherein the alkoxy group contains one to four carbon atoms, and the alkyl group contains one to four carbon atoms, and the hydroxyalkyl group contains one to four carbon atoms. Optionally it is

The 2-substituent is hydrogen, methyl, butyl, propyl hydroxymethyl, ethoxymethyl or methoxymethyl.

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

Preparations with IRM compounds

The amount of IRM compound that will be therapeutically effective in a specific situation will depend on such things as activity. the particular compound, the route of administration, the particular composition and the disease to be treated. As such, it is not practical here to identify the administration of a specific amount; however, those skilled in the art will be able to determine appropriate therapeutically effective amounts based on the instructions provided herein, information available in the art regarding these compounds, and routine testing.

The pharmaceutical compositions described below can be used for topical administration of an IRM compound. Many of the compositions provided are particularly advantageous for topical administration to the mucosal surface. In some embodiments, the composition may affect the pharmacokinetics of the IRM compound so that a reduced concentration of the IRM compound provides similar pharmacodynamic effects to those of other formulations having a higher IRM compound concentration.

The pharmaceutical composition of the invention generally comprises an IRM compound, a fatty acid, a preservative system and an optional viscosity enhancer, such as a carbomer. IRM compounds can be prepared using the methods described previously in the patents listed in the Background section above, as well as in US Patent Nos. 4,988,815; 5367076; 5,175,296; 5,395,937; and 5741908, the disclosure of which is hereby incorporated herein by reference. Unless otherwise specified, all weight percentages are based on the total weight of the preparation.

The amount of IRM compound present in the pharmaceutical composition of the invention will be an amount effective to treat the target disease, prevent disease recurrence, or promote immune immunity. The amount of IRM compound is preferably about 0.1% to about 9% by weight based on the total weight of the formulation. Optionally, the amount of IRM compound does not exceed 5% by weight and is preferably about 3% by weight for administration to mucosal surfaces.

about 0.1 to the subject of the invention is

Oil component of the preparation

Pharmaceutical composition, typically oil in aqueous emulsion.

it comprises an IRM compound and a fatty acid. The fatty acid is present in the formulation in an amount sufficient to solubilize the IRM compound. 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 composition. Alternatively, the IRM compound may be solubilized in linear chain carboxylic acids having six to eight carbon atoms.

The pharmaceutical composition of the invention may also contain an emulsifying agent, such as a nonionic surfactant. Suitable surfactants include, for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4 oleate, polyoxyethylene (4) lauryl ether, etc. For some compositions, surfactants such as Poloxamers (e.g. Pluronic F68 available from BASF, Ludwigshafen, Germany) and sorbitan are preferred. trioleate (e.g. Span 85 available from Sigma Chemical Co., St. Louis, MO), alone or in combination. The nonionic surfactant is typically present in an amount of from about 0.5% to about 10% of the total weight of the composition. In preferred embodiments, the total emulsifier content does not exceed about 5% of the total weight of the formulation and is more preferably about 3.5% of the total weight of the formulation.

The composition of the invention may also contain a viscosity enhancing agent, such as a carbomer, preferably having mucoadhesive properties. The carbomer may be present in an amount of about 0.1% to about 8%, preferably about 0.5% to about 4%, more preferably about 0.5% to about 3%, and most preferably about 1% of the total weight of the composition. Suitable carbomers include polyacrylic acids such as Carbopol 971P, Carbopol 940 and Carbopol 974P available

• · · · · · · · · · · ·

from B. F. Goodrich. Carbopol 974P.

A preferred carbomer is

In some optional embodiments, the composition may include a chelating agent. The chelating agent has the effect of chelating metal ions. If metal ions are present, they can inhibit gel formation by suppressing ionization, which facilitates gel formation in the carbomer-containing formulation. An optional chelating agent is sodium ethylenediaminotetraacetic acid (EDTA) at a concentration of about 0.0001 to about 0.5%, topically about 0.0005 to about 0.1% of the total weight of the formulation.

preferably about 5% preservatives

A preservative such as methylparaben, sorbic acid, propylene glycol, etc. may also be added. In one optional embodiment of the invention methylparaben and sorbic acid are provided, each at a concentration of about 0.05% to about 0.3%, preferably about 0%. , 15% of the total weight of the preparation and propylene glycol is present in amounts up to about 30%. It has been discovered that this combination preferably meets the Preservation Effectiveness Test (PET), 1997 European

Pharmacopeia, Test 5.1.3. Efficacy Antimicrobial Preservation Topical Preparations - A Criteria). This makes the formulation suitable for use in a multi-dose applicator without adversely affecting the stability of the formulation. Methylparaben and sorbic acid may be solubilized in propylene glycol prior to addition to the formulation.

The remainder of the pharmaceutical composition may include water to ensure that the composition can be washed away from the mucosal surface by normal physiological cleansing mechanisms.

• • • • • • • •

In addition to providing mucoadhesive properties, the carbomer also increases viscosity by forming a stabilizing gel. Many factors, such as the amount of oil phase, the amount of drug, and the amount of carbomer used affect the pH at which the gel is formed. In some formulations, the presence of metal ions and surfactants increases the pH at which the carbomer forms a gel. Thus, in the absence of a chelating agent or in the presence of elevated surfactant levels, the pH at which the carbomer forms a gel may be increased. Thus, 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 for the pharmaceutical composition of the invention is typically about pH 3.0 to about pH 7.0, preferably about pH 4.0 to about pH 6.0.

applied topically, surfaces such as nasal, rectal,

Application to the Mucosal Surface According to the invention, the compositions can be especially for non-horned epithelial surfaces such as mucosal surfaces. Mucosal surfaces of the mucous membrane such as buccal, gingival, tracheal, bronchial, gastrointestinal, urethral, vaginal, cervical, uterine, etc. Depending on the concentration of the IRM, formulation, mucosal surface, the therapeutic effect of the IRM compound can only reach the superficial layers of the mucosal surface or to the tissues deep to the surface.

In one embodiment, said IRMs can be topically applied to the vaginal or supravaginal region of the cervix to treat dysplastic diseases, such as intraepithelial dysplasia of the cervix.

In some embodiments, the above-described compositions are particularly preferred for cervical administration of an IRM compound after administration

• • · ·· · · · · · · φ ♦ · «« «* · · · · ¹ • # · * · * period sufficient to obtain the desired therapeutic effect without undesired systemic absorption of the IRM compound.

Intraepithelial cervical neoplasia (CIN)

Despite extensive searches for women to detect predictive cell changes, approximately 16,000 new cases of invasive cervical cancer are diagnosed each year in the United States. There are also around 3,000 cervical cancer deaths in the United States, and this is usually a secondary phenomenon due to the lack of early detection of primary tumor lesions.

The Papanicolau test (Pap ster) is a screening test that has been adopted since 1950 as a method for detecting abnormal cervical cells including inflammation and dysplasia including cervical cancer. This screening test has been widely accepted in industrialized countries and has had a major impact on cervical cancer mortality. Abnormal Pap smear offers accurate observation of disease progression with potential for therapeutic interventions such as destruction or excision of tumor or precancerous tissues. These excisional treatments are expensive, inconvenient, and are associated with a percentage of failure ranging from 2 to 23% and with a documented higher failure rate in more advanced lesions. More recently, a failure rate of approximately 10% after laser treatment has been documented.

It was originally thought that the etiological agent for cervical cancer is a virus. herpes. Gradually, however, there was a gradual shift in view of the etiological role from herpes virus to human papillomavirus (HPV) when the cytopathic effects of HPV in experimental systems that closely mimic the effects seen in human diseases were demonstrated. Improved experimental methods have allowed the characterization of the full spectrum of HPV subtypes in the recent past, which has led to V · · · · · ···

concluded that high-risk HPV types (for example, HPV 16, 18 and less frequently 31, 33, 35, 45) are very likely to be the exclusive initiation factor (ie, an oncogenic substance) for cervical dysplasia and subsequent cervical cancer. The mechanism of transformation of a normal cell by HPV to a dysplastic cell is associated with HPV encoded proteins (E6 and E7) from high-risk genotypes binding the cell products of tumor suppressing p53 and Rb genes, thereby disrupting the cell cycle control mechanism in which p53 and Rb an important role. Moreover, the application of these molecular methods led to the epidemiological observation that HPV is isolated from approximately 93% of cervical cancer, further supporting the generally accepted conclusion that HPV infection is the most important initiating factor for cervical cancer.

Exposure to HPV is common in sexually active women, but this exposure does not always lead to dysplasia or cancer in most exposed women. Infected women who are persistent carriers of viral DNA are approximately five times more likely to develop persistent dysplasia compared to women who are able to eradicate the virus. The importance of a cell-mediated response (CMI) to HPV infection is illustrated by the observation that an antibody-mediated immune response is not effective to eliminate ongoing infection, as demonstrated by the fact that patients with invasive cervical cancer often show high levels of antibodies against viral proteins E6 and E7. This particular antibody response is likely to reflect extensive antigen exposure in spite of increasing tumor burden. Despite the apparent insignificant effect of the humoral immune response, the cell-mediated immune response (Th-1 type response) appears to be effective in controlling tumor progression. The regression of intraepithelial lesions is accompanied by a cellular infiltrate composed of CD4 + T cells, 4 9

CD8 + T cells, natural killer (NK cells) and macrophages. Cellular infiltrate has usually been associated with tumor regression, which is in contrast to women who lack the ability of this inflammatory response and who progress to disease. In addition, patients with a defect in cell-mediated immunity are at increased risk of cervical cancer, while patients with defects in antibody production do not show the same susceptibility.

In one optional embodiment, the inventors envisage topical application of IRM compounds for non-invasive treatment of cervical diseases including cervical intraepithelial neoplasia (CIN).

Intravaginal Applicators for IRM Compounds

To obtain a beneficial therapeutic or prophylactic effect on cervical disease, it is preferred to administer the IRM compound herein. The IRM compound may be administered via a metered formulation or applicator that provides contact of the IRM compound with the mucosal surface of the cervix for a period of time sufficient to provide the desired therapeutic effect. Any applicators described and / or disclosed herein may be used to administer an IRM compound.

In addition to the applicators already described, the IRM compound may be formulated as a suppository and administered intravaginally using a suppository applicator. A suitable suppository applicator includes known tubular cardboard paper applicators for delivery of drugs to the vaginal cavity. The compositions of the invention may also be administered using keg-type applicators, such as those described and / or shown in the figures. An example of a suitable barrel-type applicator may be found in U.S. Patent No. 5,282,789, the disclosure of which is hereby incorporated by reference.

• aaa a

• aa ·

0 0 0

0 0 • · o ·· ·

In an optional embodiment, the IRM compound may be administered directly to the mucosa of the invention and in the Examples of the IRM compound the cervical mucosa. In one such form, the IRM compound can be applied topically to the cervix using a direct cervical applicator as previously described, or using a cervical cap. One example of a suitable cervical cap is disclosed in U.S. Patent No. 4,858,624, the disclosure of which is hereby incorporated by reference. Suitable IRM compounds for direct cervical applications are listed above for embodiments of the invention set forth below. Generally formulated based on any of the formulations A-J in the Examples below, it can be placed in the concave region of the cervical cap, which is then directly applied over the cervix. These formulations can also be applied using other types of applicator devices including the applicator devices shown in the figures and described herein. The IRM compound is optionally formulated with a viscosity agent, such as a carbomer, to increase the contact time of the IRM compound at the cervix.

The following Examples are provided to further describe the compositions and methods of the invention. However, the examples are not intended to be limiting compositions and methods.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Evaluation of safety, pharmacokinetics (PK) and pharmacodynamics (PD) of 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine (imiquimod) applied to the cervix

4 4 ···

4 ·

4 4 4

4444 4 4 4 44

Methodology

This was a single-dose, randomized, double-blind, placebo-controlled study in which five doses of imiquimod were evaluated. 50, 100, 150, 200 and 250 mg of imiquimod in cream formulations were applied to the cervix for 8 hours. The components of the cream preparation with imiquimod used in this study (Formulation A) are listed in Table I below. Each dose group was composed of 8 subjects (6 active and 2 placebo) with two subjects treated as pilot patients, and the remaining six subjects were treated after an acceptable response of the pilot subjects. Safety was assessed by adverse events, laboratory tests and colposcopy with photodocumentation of the cervix before and 24 hours after dosing and, if required, 48 hours after dosing. Systemic exposure (PK) was determined by measuring imiquimod and metabolites within 48 hours after dosing and PD response was determined by analyzing serum for cytokines: tumor necrosis factor-α (TNF-α), interferon α (IFN-α), an interleukin receptor agonist 1 (IL-1RA), interleukin-6 (IL-6), neopterin (NPT) and 2 '5' oligoadenylate synthetase (2 '5' AS) during dosing and selected times within 48 hours post dosing. Statistical tests to assess adverse reactions and demography, laboratory tests, vital signs and ECG were Fisher's exact test, Wilcoxon Rank-Sum test and Kruskall Wallis test, respectively. Changes in cytokines between different dose groups were compared using the Wilcoxon Rank-Sum assay and changes from baseline were evaluated using the Spearman Rank Correlation assay.

Results

The study included 39 generally healthy, surgically sterilized women aged 18-50 years in the range of 25% of ideal body weight. All women had normal baseline colposcopy and borderline dyskariosis in throat histology.

• 9 »

99 Uterine. Adverse reactions were reported in each of the 39 subjects with a slight increase in temperature as the most common adverse event (92%). There were no differences between groups with respect to subjects who experienced one or more of the adverse reactions, or adverse reactions attributable to the drug as possible or likely. There were two serious adverse reactions that were intercurrent events associated with a broken ankle and its surgical solution). Statistically significant changes in some laboratory parameters and pulse rate were reported that were not considered clinically significant. No physical ECG or physical examination was detected during the physical examination. Pelvic and colposcopic examination revealed small reactions in 2 of 6 patients at the 250 mg dose with changes in the cervix in terms of small blisters or minor ulcers. These reactions disappeared within 48 hours. No quantifiable (greater than 5 ng / ml) serum levels of imiquimod were detected. Significant changes from baseline were seen for IFN and IL-6 in the 250 mg dose group and for NPT, 2'5 'AS and IL-1RA in the 150 mg, 200 mg and 250 mg dose groups.

The study showed that single doses of imiquimod up to 250 mg applied to the cervix for 8 hours are safe with minimal systemic effects in healthy volunteers. Cervical administration of doses above 150 mg increases the systemic concentration of certain cytokines.

«· ····»

9

9 • • • • • •

0 0 9 *

9 99 99

Table 1

Folders Preparation A (% w / w) Imiquimod 5.0 Isostearic acid 25.0 Benzyl alcohol 2,0 Cetyl alcohol 2.2 Stearyl alcohol 3.1 White petrolatum 3.0 Polysorbate 60 3.4 Sorbitan monostearate 0.6 Glycerine 2,0 Methyl paraben 0.2 Propyl paraben 0.02 Water 52.98 Xanthan rubber 0.5 pH 5.1 Viscosity (cps) 0.33 X 10 ⁵

Example 2 Preparation of Pharmaceutical Formulation B

This example describes a new formulation for vaginal administration that is a stable formulation with high viscosity and is well preserved to meet the criteria of the EP Preservation Effectiveness Test (PET). The w / w% values of the ingredients of this formulation (Formulation B) are shown in Table 2 below.

Imiquimod was dissolved in isostearic acid with Span 85. Pluronic F68, EDTA, Carbopol 974P, propylene glycol, sorbic acid and methyl paraben were dissolved in water. After emulsification to form a water-in-oil emulsion, sodium hydroxide was added to achieve a pH of about 5.2. The pH range for this formulation may be about 4.8-6.0.

• ff ffff ·· • ff ffffffff

• · ff ff ffff

Table 2

Folders Preparation B (% w / w) Imiquimod 5.0 Isostearic acid 28.0 Pluronic F68 2.98 Purified water 43.78 Carbopol 974P 1.7 At ₂ EDTA 0.05 Propylene glycol 15 Dec Sorbic acid 0.15 Metylparaben 0.15 Sleep 85 2.02 5N NaOH 1.17 PH 5.1 Viscosity (cps) 6.4 x 10 ⁵

Example 3 Preparation of Pharmaceutical Formulations C-F

Pharmaceutical Formulations C-F were prepared with the ingredients cited in Table 3 below. The method of preparation of Formulations C-F was the same as described for the preparation of Formulation B in the Example 2.

9 · 9 •

9 ·

Table 3

Folders Preparation C % w / w Preparation D % w / w Preparation E % w / w Preparation F % w / w Imiquimod 1.0 1.0 3.0 3.0 Acid isostearová 5.6 28.0 16.8 28.0 Pluronic F68 1, 79 1, 79 1.79 1.79 Purified water 69.05 48,30 56.25 46.75 Carbopol 974P 2.8 2.10 2.5 1, 80 At ₂ EDTA 0.05 0.05 0.05 0.05 Propylene glycol 15.0 15.0 15.0 15, 0 Acid sorbová 0.15 0, 15 0.15 0.15 Metylparaben 0.15 0.15 0.15 0.15 Sleep 85 1,21 1,21 1,21 1,21 5N NaOH 3.2 2.26 3.1 2.1 PH 5.1 5.2 5.2 5.3 Viscosity (cps) 5.8 X 10 ⁵ 8.8 X 10 ⁵ 10.0 x 10 ⁵ 10.0 x 10 ⁵

Example 4 Transport of imiquimod through the skin of a hairless mouse from two formulations A and B containing 5% w / w imiquimod.

Figure 16 is a graph of the results of imiquimod penetration studies with Formulations A and B of Examples 1 and 2 using fur-free 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, hairless mouse skin was removed from 5 to 7 week old female hairless mice (available from Charles River). The skin was maintained by this to this to this. ·· · «·· on ice until use. Mouse skin was attached to the type of diffusion cell disclosed in US Patent No. 5,238,944.

Part of the cell under the attached skin was completely filled with 0.1 N HCl receptor fluid so that the receptor fluid was in contact with the skin. The receptor fluid was mixed using a magnetic stirrer and magnetic stirrer.

Approximately 100 ± 5 mg of the formulation to be tested was applied to the epidermal (upper) layer of the skin to cover a homogeneous layer of only the skin area that would be in contact with the receptor fluid when the skin was attached to the diffuse cell. The preparations were applied to the skin before the time of addition of the receptor fluid to the cell under the skin.

The cell was then placed in a constant temperature chamber (31 ° C). To maintain a constant temperature, the chamber used a heat exchanger coupled to a constant temperature bath with a fan to circulate air. The receptor fluid was agitated through a magnetic stirrer during the experiment to ensure sample uniformity and reduce the diffusion barrier layer on the dermal side of the skin. At the specified time intervals (1, 2, 4, 6, 8, 12 and 24 hours), the entire volume of receptor fluid was collected and immediately replaced with fresh receptor fluid. The collected receptor fluid was analyzed for imiquimod content by conventional high pressure chromatography under the following conditions:

Detector: UV at 258 nm; Mobile phase: 25/75 acetonitrile / water containing 1% triethylamine, 0.2% 1-acetate sulfonate adjusted to pH 2.0 with H ₃ PO ₄ ; Stationary phase: C8 Zorbax RX ··· «a ···· a · ·· · f · 4

4 '* * * · ϊ ϊ 4 «9 9 9 9 9

C8 5 u; Flow rate: 2 ml / min; Chromatography time: approximately 10 minutes.

Cumulative amounts of penetration were plotted against time to obtain a steady state.

Example 5 Transport of imiquimod through the skin of nude mice from C-F formulations containing 1% w / w and 3% w / w imiquimod with different concentrations of isostearic acid (ISA).

Table 4 below provides the concentrations of imiquimod, isostearic acid, viscosity, pH and steady state (µg / hour) of C-F formulations through the skin of nude mice.

The results are shown in the graph of FIG. 17. The procedure used to study skin penetration was the same as that described in the Example 4.

Table 4

Preparation Concentration IRM (% w / w) Concentration ISA% w / w Viscosity (x 10 ⁵ cps) Steady state (ug / hour) C 1% 5.6% 5.8 18.1 D 1% 28% 8.8 26.1 E 3% 16.8% 11 39.9 F 3% 28% 10 71.5

Example 6 Comparison of imiquimod pharmacokinetics in rats after vaginal administration of a single dose of Formulation A and Formulation B

Serum imiquimod versus time profiles were compared in ovariectomized rats following a single intravaginal dose of Formulation A or Formulation B. Two 5% w / w formulations were administered at a dose of 35 mg / kg. . After administration of the preparation, a collar was clipped on each rat to prevent removal of the preparation by licking. After approximately six hours, vagina was lavaged and the collars were removed. Blood samples were taken before · «· *» ·

4499 by dosing and at 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 better than Formulation A.

The serum was analyzed for imiquimod by HPLC. The mean serum concentrations of imiquimod versus time are shown in Figs. 18. Time to reach maximum serum concentrations of imiquimod

(T _max ) was similar ( 1 hour) for both preparations. imiquimod concentration (C _max ) for Preparation (B) approximately 1.6 times taller than for Preparation And a area below curve versus time (AUC) was 3.3 times

19A and 19B). Based on these imiquimod, the greater of Formulation B than the data was the range of Formulation A.

absorption

Example 7 Preparation of a pharmaceutical composition G

The weight percentages (w / w) of the components for Formulation G are shown in Table 5. The oil phase was prepared as follows. Imiquimod (20.0 g) was added slowly to isostearic acid (3000 g) with stirring. The mixture was stirred and heated as necessary to 55 ° C to facilitate dissolution of imiquimod. Upon dissolution, heating was turned off. Was

Sorbitan trioleate (200 g) was added ^and thoroughly mixed. Carbomer 974 was added slowly with stirring. Stirring was continued until the carbomer was homogeneously dispersed in the oil phase. The oil phase was then cooled to less than 30 ° C.

The aqueous phase was prepared as follows. Sorbic acid (30.0 g) and methyl paraben (40.0 g) were added to the propylene glycol (1000 g) with stirring. The resulting mixture was stirred and gently heated (below 45 ° C) until a solution was obtained. Heat source removed. Polaxamer 188 (500 g) was added to the solution. The resulting mixture was agitated until the polaxamer was stirred. · Moisture is sufficiently damp. · · · · · · · · · · · · · · · · · · · · · · · The resulting product was then added to a solution of sodium edetate (10.0 g) in purified water (13950 g). The resulting mixture was stirred until a clear solution was obtained.

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

The oil phase was added to the aqueous phase and then sodium hydroxide solution was added. The resulting mixture was stirred for a minimum of 30 minutes until a fine and clear cream was obtained. The pH was determined and adjusted, if necessary, to pH 5.6-5.8 with sodium hydroxide solution.

Example 8 Preparation of Pharmaceutical Formulations H-J

Pharmaceutical formulations C-F were prepared using the method of Example 7. The weight percentages (w / w) of the ingredients in the formulations are shown in Table 5 below.

····

Table 5

Folders G (% w / w) H (% w / w) I (% w / w) J (% w / w) Acid isostearová 15.0 15.0 15.0 18.0 Imiquimod 0.1 0.5 1.5 3.0 Sorbitan Trioleate 1.0 1.0 1.0 1.0 Propylene glycol 5.0 5.0 5.0 5.0 Acid sorbová 0.15 0.15 0.15 0.15 Metylparaben 0.20 0.20 0.20 0.20 Purified water 75,00 74.60 73.60 69.1 Sodium edetate 0.05 0.05 0.05 0.05 Polaxamer 188 2.50 2.50 2.50 2.50 Karbomer 974 1, 00 1.00 1, 00 1, 00 Hydroxide sodium qs qs QS qs Total% (w / w) 100 ALIGN! 100 ALIGN! 100 ALIGN! 100 ALIGN!

Therefore, it will be appreciated from the foregoing discussion that imidazoquinoline amines, imidazopyridine amines, 6.7 fused cycloalkylimidazopyridine amines and 1,2 bridge-linked imidazoquinoline amines may be useful for treating mucosal-associated diseases including cervical dysplasia. Moreover, said pharmaceutical preparations may be particularly advantageous for topical administration of an IRM compound to the mucosal surface.

From the foregoing detailed description and examples, it will be appreciated that modifications and variations may be made to the compounds, compositions, devices, systems and methods disclosed herein. Other forms of the invention will be apparent to those skilled in the art. It is intended that the specifications and exemplary embodiments of the invention are to be considered as illustrative only.

Claims (39)

PATENT CLAIMS A system for treating diseases associated with the mucosal surface, the system comprising: an immune response modifying compound (IRM) selected from imidazoquinoline amines, imidazopyridine amines, 6.7 fused cycloalkylimidazopyridine amines, 1.2 bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof, and delivery devices for applying the IRM compound to the mucosal surface. The system of claim 1, wherein the IRM compound is 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine. 3. The system of claim 1, wherein the IRM compound is 4-amino-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol The system of claim 1, wherein the system further comprises a pharmaceutical composition comprising: An IRM compound; a fatty acid; and a preservative system comprising propylene glycol. The system of claim 1, wherein the applicator device is 'pre-filled' with a therapeutically effective amount of an IRM compound. The system of claim 1, wherein the IRM compound is contained in a container separate from the device. The system of claim 1, further comprising markings on the applicator device to assist the user in determining the amount of IRM compound in the applicator device. The system of claim 1, wherein the disease associated with the mucosal surface is cervical dysplasia. The system of claim 1, wherein the mucosal surface is the cervix. • ·· · 10, Art The system of claim 9, wherein the mucosal surface is on the vaginal portion of the cervix. System according to claim associated with the mucosal surface of cervical neoplasia. A system according to claim device comprising: a hollow tube with a distal transport end and a proximal end; and a piston displaceable in the tube. The system of claim 12, further comprising an element configured to cause the piston to move toward the distal end. The system of claim 13, wherein the device is to limit the retraction movement of the element towards the plunger when the plunger is located near where the disease is intraepithelial 1, wherein the applicator configured to the proximal end, the distal end. The system of claim 13 removably coupled to the element. The system of claim 13, displaceably disposed within the hollow tube. The system of claim 12 further comprising a stop limiting the retraction movement of the piston towards the proximal where the piston is the end element. The system of claim 12, wherein the plunger includes a portion extending from the distal end when the plunger is positioned at a distance from the proximal end. The system of claim 12, wherein the distal end is tapered on its outer surface. The system of claim 13, wherein the element has a length shorter than the distance between the proximal end and the plunger when the plunger is located furthest from the proximal end. A system for treating diseases associated with the mucosal surface, the system comprising: ···· immune response modifying compound (IRM) selected from imidazoquinoline amines, imidazopyridine amines, 6.7 fused cycloalkylimidazopyridine amines, oxazoquinoline amines, 1,2 linked bridges and their pharmaceutically imidazonaphthyridine amines, thiazoloquinazoline amines, imiazazoquinoline amines, imiazazoquinoline amines, imiazazoline pyridines an apparatus for applying an IRM compound to the mucosal surface. The system of claim 21, wherein the IRM compound is 1- (2-methylpropyl) -1H-imidazo [4,5-c] quinolin-4-amine. The system of claim 21, wherein the IRM compound is 4-amino-α, α-dimethyl-2-ethoxymethyl-1H-imidazo [4,5-c] quinoline-1-ethanol. The system of claim 21, wherein the IRM compound is 2-propyl [1,3]] thiazolo [4,5-c] quinolin-4-amine. The system of claim 21, wherein the system further comprises a pharmaceutical composition comprising: -IRM compound; at least one fatty acid; and - a preservative system containing propylene glycol. The system of claim 21, wherein the applicator device ¹ is prefilled with a therapeutically effective amount of an IRM compound. The system of claim 21, wherein the IRM compound is contained in a container separate from the device. The system of claim 21, further comprising tags on the applicator device to assist the user in determining the amount of IRM compound in the applicator device. where throat dysplasia disease where mucosal 29. System according to patent claim 21, associated se mucous membrane surface Yippee uterine. 30. System according to patent claim 21 the surface is the cervix. ·· ·· * · The system of claim 30, wherein the mucosal surface is on the vaginal portion of the cervix. The system of claim 31, wherein the intraepithelial surface disease is wherein the applicators associated with mucosal neoplasia of the cervix. The system of claim 21, the apparatus comprising: a hollow tube with a distal transport end and a proximal end; and a piston retractable in the tube. The system of claim 12, further comprising an element configured to cause the piston to move toward the distal end. The system of claim 34, wherein the device is configured to restrict the retraction movement of the member toward the proximal end when the piston is positioned near the distal end. The system of claim 34, wherein the piston is removably coupled to the member. The system of claim 34, wherein the member is displaceably disposed within the hollow tube. The system of claim 33, further comprising a piston-limiting retraction-movement stop toward the proximal end. The system of claim 33, wherein the plunger includes a portion extending from the distal end when the plunger is positioned at a distance from the proximal end. The system of claim 33, wherein the distal end is tapered on its outer surface. The system of claim 34, wherein the element has a length shorter than the distance between the proximal end and the plunger when the plunger is located furthest from the proximal end.