CN1273110C - Systems for the treatment of mucosal surfaces - Google Patents

Abstract

A system for treating a condition associated with a mucosal surface, the system comprising an Immune Response Modifier (IRM) compound and an applicator for applying the IRM compound to the mucosal surface. The IRM compound is selected from the group consisting of imidazoquinoline amines, imidazopyridine amines, 6, 7-fused cycloalkylimidazopyridine amines, imidazo 1, 5-naphthyridine amines, * oxazoloquinoline amines, thiazoloquinoline amines, 1, 2-bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. The system of IRM compound and applicator is useful for treating mucosal surface related disorders such as cervical dysplasia and cervical intraepithelial neoplasia.

Description

Systems for the treatment of mucosal surfaces

This application is a continuation-in-part (CIP) of co-pending Serial No. 09/676,339, filed September 29,2000. No.09/676,339 is the continuation of No.09/479,578 (now US Patent No.6,245,776), No.09/479,578 was filed on January 7, 2000, and the application was filed on January 8, 1999 No. 60/115,253 has priority. This application also claims priority to Provisional Application No. 60/213,420, filed June 22,2000. Additionally, the contents of each of the above-mentioned applications are incorporated herein by reference.

Description of the invention

field of invention

The present invention relates to systems and methods for treating disorders associated with mucosal surfaces such as the vaginal portion of the cervix. In particular, the systems and methods may include an immune response modifier (IRM) compound selected from the group consisting of imidazoquinolineamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, imidazo1,5- Naphthyridine, oxazoloquinolineamine, thiazoloquinolineamine, 1,2-bridged imidazoquinolineamine and pharmaceutically acceptable salts thereof. In an optional embodiment, the system and method has unique advantages.

The invention also relates to drug delivery devices and methods of use. Aspects of the invention relate to the delivery of drugs to a designated place with only a small amount of drug delivery around it. In some optional embodiments, the present invention has unique advantages for localized drug delivery to the cervix.

Background of the invention

Many imidazoquinolineamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, 1,2-bridged imidazoquinolineamines, thiazoloquinolineamines, oxazoloquinolineamines , thiazolopyridinamine, oxazolopyridinamine, imidazolo-1,5-naphthyridine and tetrahydroimidazo-1,5-naphthyridine compounds have shown potent immunostimulatory, antiviral and anti- Tumor (including anti-malignant tumor) activity has also been shown to be used as a vaccine adjuvant to enhance the body's preventive immune system response to vaccines. These compounds are sometimes collectively referred to hereinafter as "IRM" (immune response modifier) compounds of the invention. The IRM compound may be selected from the group consisting of imidazoquinolineamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, imidazo1,5-naphthyridineamines, oxazoloquinolineamines, thiazoles quinolinamine, 1,2-bridged imidazoquinolineamine and pharmaceutically acceptable salts thereof. Methods of preparing these immune response modifiers and pharmaceutical compositions containing them are disclosed, for example, in U.S. Patent Nos. 4,689,338; 5,389,640; 5,268,376; 4,929,624; 5,525,612; 5,175,296; 5,693,811; 5,741,908; 5,939,090; 6,110,929; 4,988,815; 5,376,076; Each of these patents and patent applications is incorporated herein by reference in its entirety.

The immunostimulatory, antiviral, and antitumor activities of these compounds have been discussed in detail, and they have been identified for the treatment of certain specific diseases, including basal cell carcinoma, eczema, essential thrombocythemia, hepatitis B, multiple sclerosis, Neoplastic disease, psoriasis, rheumatoid arthritis, herpes simplex type I, herpes simplex type II, and warts. Imiquimod, one of these immune response modifier compounds, has been commercialized in a topical formulation under the trademark Aldara( ^TM ) for the treatment of anal and genital warts associated with human papillomavirus.

The mechanism of action of the antiviral and antitumor activity of these immune response modifier compounds is thought to be largely due to an enhanced immune response due to the induction of several important cytokines (interferon, interleukin, tumor necrosis factor wait). These compounds can stimulate the rapid release of certain cytokines from monocytes or macrophages, and can also stimulate B cells to secrete antibodies that play an important role in the antiviral and antitumor activities of these immune response modifier compounds. One of the major immunostimulatory responses to these compounds is the induction of alpha-interferon (IFN) production, which is believed to be important in the known acute antiviral and antitumor activities. In addition, upregulation of cytokines such as tumor necrosis factor (TNF), interleukin 1 and interleukin 6 also has potentially useful activity, which is thought to contribute to the antiviral and antitumor activity of these compounds.

While some beneficial effects of immune response modifier compounds are known, the ability to provide this therapeutic benefit by topical application of immune response modifiers to treat specific diseases at specific sites has been hampered by problems with the topical use of these compounds, namely Irritation, rapid clearance of formulation, poor transdermal properties, and undesired systemic delivery. Accordingly, new methods, formulations and systems are needed to maximize the efficacy of these compounds.

Topical administration on tissue surfaces can provide local therapeutic effects without concomitant systemic effects. However, localized drug delivery is often difficult and impossible due to the anatomical location of the tissue. In some cases, administration at a general anatomical site including or surrounding the target tissue may be chosen instead of direct topical administration. However, if the drug is irritating, this option comes with the disadvantage of potentially irritating the tissue surrounding the target tissue. In addition, even if the drug is not irritating, regional administration generally requires the use of higher drug doses or concentrations to achieve the same efficacy as direct target tissue administration.

The cervix is an example of a target tissue that is difficult to administer topical drugs. Relative to the erect position, the cervix is generally located in the uppermost part of the vaginal canal. However, although the cervix is located in the uppermost part of the vaginal canal, age, stage of the estrous cycle, pregnancy, and other factors cause the position of the cervix to vary between women and within women at different ages.

Certain cervical disorders can advantageously be treated by topical administration. Cervical dysplasia is one such example of a treatment that can be administered topically. This condition can be effectively treated by delivering drugs directly to the surface of the cervix, where abnormal cells are typically found. Unfortunately, currently available applicators for vaginal administration are not capable of applying the drug to the surface of the cervix. Also, because cervical dysplasia can lead to cervical cancer, choosing an applicator that is less than optimal is unacceptable.

Currently, most vaginal applicators available are generally intended for administration to the vaginal cavity, not directly to the cervix. Often, the length and configuration of the applicator does not ensure drug delivery to the highest part of the vaginal canal. Delivering the drug to the middle or lower part of the vagina does not ensure that the drug reaches the cervical tissue in the upper part of the vagina. Also, except in certain positions, gravity will force the drug out of the cervix. Normal menstrual and nonmenstrual discharge and fluid flow can also expel the drug from the cervix. Therefore, any applicator that fails to repeatedly deliver the appropriate amount of drug to the uppermost end of the vaginal cavity runs the risk of suboptimal efficacy.

Excessive volume or concentration administered to overcome the imprecision of current vaginal applicators may be unacceptable when used for cervical administration due to the risk of adverse effects on surrounding tissue. However, reducing the volume or concentration administered in order to avoid irritation of surrounding tissues runs the risk of serious therapeutic ineffectiveness.

Accordingly, there is a continuing need for improved delivery systems and methods for topical medications.

Summary of the invention

One aspect of the invention includes systems for treating diseases associated with mucosal surfaces. The system includes an immune response modifier (IRM) compound selected from the group consisting of imidazoquinoline amines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, 1,2-bridged imidazoquinoline Amines and their pharmaceutically acceptable salts. The system also includes an applicator for applying the immune response modifier compound to the mucosal surface. In this system, the IRM compound is contained in a container separate from the applicator. Also included in the system are measurement indicia on the applicator to assist the user in determining the amount of IRM compound in the applicator. In the system described above, the applicator includes a hollow tube having distal and proximal administration ends and a piston slidably received in the hollow tube; the system also includes a component configured to move the piston distally. In the system described above, the applicator is configured to limit the proximal retraction movement of the member when the piston is positioned adjacent the distal end, the member being longer than the proximal end and the proximal end when the piston is positioned farthest from the proximal end. The distance between the pistons is short. In a system having the above applicator, the piston includes a portion extending from the distal end when the piston is in a position furthest from the proximal end.

Another aspect of the invention includes a system comprising an immune response modifier (IRM) compound. The immune response modifier compound is selected from the group consisting of imidazoquinoline amine, imidazopyridine amine, 6,7-fused cycloalkyl imidazopyridine amine, imidazolo-1,5-naphthyridine, oxazoloquinoline Amines, thiazoloquinoline amines, 1,2-bridged imidazoquinoline amines, and pharmaceutically acceptable salts thereof. The system also includes an applicator for applying the immune response modifier compound to the mucosal surface.

For example, the immune response modifier compound may be, 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine, or 4-amino-α,α-di Methyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol, or 2-propyl[1,3]thiazolo[4,5-c]quinoline -4-amine.

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

In an exemplary embodiment, the applicator may include a hollow tube and a piston slidably received within the hollow tube.

Yet another aspect of the invention includes methods of treating diseases associated with mucosal surfaces. The method comprises providing an immune response modifier (IRM) selected from the group consisting of imidazoquinoline amines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, imidazo1,5-di Azanaphthylamine, oxazoloquinolineamine, thiazoloquinolineamine, 1,2-bridged imidazoquinolineamine and pharmaceutically acceptable salts thereof. The method also includes providing an applicator for applying the immunomodulatory compound to the mucosal surface. Among other things, the method includes applying the immunomodulatory compound to the mucosal surface with an applicator.

The method may include inserting the applicator into the vagina, then placing the distal end of the applicator near the vaginal site of the cervix, and applying the immunomodulator compound to the vaginal site of the cervix.

At least some embodiments disclosed herein provide drug delivery systems and methods suitable for local delivery to target tissues. The system and method are advantageous for intravaginal delivery of pharmaceutical formulations. For example, some embodiments provide for the effective topical application of a drug to the cervix for the treatment and prevention of conditions such as cervical dysplasia.

Other aspects will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. It should be understood that in several places throughout the specification, teaching is provided by way of example. In each case, the stated list is only a representative example; it is not meant to be exhaustive.

It is to be understood that both the foregoing general description and the following detailed description are illustrative and explanatory only and are not restrictive.

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

Brief description of the drawings

Figure 1A is a top view of a therapeutic system comprising an applicator and a container containing a packaged immune response modifier compound;

Figure 1B, is a top view of a therapeutic system, wherein the therapeutic system includes several sleeves pre-loaded with immunomodulator compounds;

Fig. 2 is an exploded perspective view of vaginal applicator components;

Figure 3 is a proximal point view of an exemplary vaginal applicator;

Figure 4, is a longitudinal cross-sectional view of an exemplary vaginal applicator taken through line 4-4, wherein the advancing member is retracted at the proximal end;

Figure 5, is a longitudinal cross-sectional view of an exemplary vaginal applicator, wherein the advancing member is advanced to the distal end;

Fig. 6 is a close-up view of the proximal end of the vaginal applicator shown in Fig. 5;

Fig. 7 is a close-up view of the distal end of the vaginal applicator shown in Fig. 5;

Figure 8, is an exploded perspective view of parts of a vaginal applicator in accordance with an alternative embodiment of the present invention;

Fig. 9 is a longitudinal sectional view of the vaginal applicator in Fig. 8, wherein the advancing member is retracted at the proximal end;

Figure 10 is a longitudinal sectional view of the vaginal applicator in Figure 8 with the advancing member advanced to the distal end;

Fig. 11 is a close-up view of the distal end of the vaginal applicator shown in Fig. 10;

Fig. 12 is a close-up view of the proximal end of the vaginal applicator shown in Fig. 10;

Figure 13 is a perspective view of an alternative proximal end of a vaginal applicator;

Figure 14 is a perspective view of another alternative proximal end of the vaginal applicator;

Figure 15 is a longitudinal sectional view of an exemplary pre-filled vaginal applicator;

Fig. 16 is a comparative diagram of imiquimod hairless mice transdermal transport of 3 pharmaceutical preparations each containing 5% imiquimod;

Figure 17 is a comparative diagram of the transdermal transport of imiquimod hairless mice with 4 pharmaceutical preparations containing different concentrations of imiquimod and isostearic acid;

Figure 18 is a comparison chart of the average serum concentration of imiquimod in rats after vaginal single dose administration of preparation A or preparation B; and

Fig. 19A and Fig. 19B are bar charts comparing the pharmacokinetics of imiquimod in rats after vaginal administration of preparation A or preparation B to rats.

Description of implementation

Some exemplary embodiments of the invention are described in detail below, some examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.

The present invention may relate in part to applicators and methods of how to deliver medication to a designated site. In some alternative embodiments, the dispenser is particularly suitable for vaginal administration. In an optional embodiment, the disclosed dispenser can be used for topical administration at designated sites of the vagina, such as the cervix, to treat diseases including, for example, cervical dysplasia. Typically, an applicator is used to deliver the drug at the frequency and dosage necessary to achieve the desired therapeutic effect.

Throughout the specification, the listed examples may serve as a guide. In each instance, the enumerated list is representative only, however, this is not to say that the list is exclusive.

As used herein, the term "medicament" includes any agent or combination of agents used to diagnose, treat, treat, ameliorate, prevent or otherwise manage a disease in a patient. The term "disease" refers to any infectious, non-infectious, pathological, physiological, biochemical, or other condition of a patient's body that may be treated in accordance with the present invention.

Throughout the specification, unless otherwise stated, the terms "proximal" and "distal" are relative. The term "proximal" refers to the location closest to the user (eg, the user's hand with which to operate the applicator), while the term "distal" refers to the location farthest from the user. Therefore, in an exemplary embodiment, the proximal end of the applicator is the location closest to the user or where the user grasps it, and the distal end is the location closest to the tissue site to be administered.

As used herein, "mucosal-associated disease" refers to inflammation, infection, neoplasia, or other disease involving or in close proximity to a mucosal surface to the extent that it would be affected by a therapeutic or prophylactic agent applied topically to the mucosal surface.

Unless otherwise stated, the term "treatment" as used herein generally refers to the application of a drug to a patient for any reason, and does not distinguish between prophylactic, therapeutic, diagnostic, palliative, or other procedures. The term "therapeutically effective amount" refers to an amount administered to achieve a desired therapeutic effect, such as induction of cytokine, antiviral or antitumor activity. A "therapeutically effective dose" includes a single dose that achieves a good therapeutic effect over a period of treatment.

In some optional embodiments, the devices and methods of the present invention are advantageous in treating (ie, preventing, diagnosing, ameliorating, etc.) cervical disorders by vaginally delivering drugs to the cervix. In certain optional embodiments, the applicators of the present invention may be particularly advantageous for delivering immune response modifiers (IRMs) to the cervix for the treatment of cervical disorders. Examples of immune response modifiers suitable for the present invention include those disclosed in, for example, U.S. Patent Nos. 4,689,338; 5,389,640; 5,268,376; 4,929,624; 5,175,296; 5,693,811; 5,741,908; 5,939,090; 6,110,929; 4,988,815; 5,376,076; and PCT publications WO 99/29693; WO 00/76505; WO 00/76518; Each of these patents and patent applications is incorporated herein by reference in its entirety. Some optional immune response modifiers suitable for the present invention include 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine (imiquimod) and Those compounds and formulations are disclosed in co-pending US Patent Application Serial No. 09/479,578 and PCT Publication WO 00/06577. Each of these patents and patent applications is incorporated herein by reference in its entirety.

Typically, "users" of the disclosed dispensers (also referred to herein as applicators) include healthcare providers who administer medication to patients or patients themselves who administer medication to themselves.

In some optional embodiments, the dispenser is capable of delivering a precise, predetermined dose to a selected site while reducing the possibility of inadvertent administration to surrounding tissue. In general, the predetermined dose will be an effective dose for single administration. Precise administration at the selected site advantageously reduces the dose necessary to achieve a therapeutic effect and minimizes the potential for irritation of tissues adjacent to the selected site of administration.

In the case of intravaginal medication, the dispenser can reduce unwanted side effects from the medication. For example, when it is desired to deliver a drug only to the cervix, such as to treat cervical disease, delivering the drug to a site other than the upper vaginal canal may unnecessarily expose the lower vaginal canal and other surrounding tissues to the drug. This not only exposes the non-target tissue to the drug, but also exposes the non-target tissue to potential tissue irritation from the drug or the agent or other components of the drug formulation.

An intravaginal dosing dispenser can selectively deliver precise volumes of a drug (or formulation thereof) that are smaller than typical dosing volumes for other vaginal medications. In some optional embodiments, the intravaginal dosing dispenser may provide a dosing volume in the range of about .01-10 ml, in other optional embodiments about 0.5-4 ml, typically about 1.0 ml.

The dispenser can be preloaded with a therapeutically effective dose of a particular drug, or it can be loaded when the user administers the drug. In the latter case, the dispenser is constructed so that the drug can be obtained from a drug source (eg, aluminum tube, plastic tube, etc.) which is mountable to the dispenser for charging. Some optional dispensers generally provide a fixed maximum dose. Alternatively or additionally, the dispenser may have incremental charge scales smaller than the dispenser's maximum volume.

In an optional embodiment, the dispenser is preloaded with medication to avoid the possibility of inaccurate dose loading. In an optional embodiment, the dispenser can be prefilled with a formulation comprising a single administration amount of an immune response modifier (IRM) compound. Whether the dispenser is pre-filled or not, the dispenser may be wrapped in an outer wrap, such as a foil wrap, which maintains the dispenser in a sterile state and also protects against moisture.

The dispenser can be made by known methods, such as injection molding, which is a plastic applicator made of a polymeric material such as high density polyethylene, low density polyethylene, linear low density polyethylene or polypropylene.

FIG. 1A shows a therapeutic system 400 comprising an applicator 10 and a container 401 of preparations housed together in a package 402 . By placing the applicator 10 in fluid communication with the container 401, it can be designed to be filled with the formulation contained in the container 401.

FIG. 1B shows a treatment system 400 in which formulations have been pre-filled with cannulae 401a-401d, which can be loaded into dispenser 10 one at a time.

Fig. 2 and Fig. 4 are schematic diagrams of alternative embodiments of the vaginal applicator 10 of the present invention. As shown, the applicator 10 includes a distal end 1, a proximal end 2, and a longitudinal axis X-X passing therethrough. Figure 2 is an exploded perspective view of the components of the applicator 10, including the elongated tube 3 with the drug delivery end 4 and the operative end 5 and the lumen 6 therethrough. The operating end 5 includes a control handle 7, such as opposing wings 8a and 8b, which can be used to hold the applicator 10 when it is in use. In some embodiments, the length dimension of the elongated tube 3 is about 6 cm to 24 cm, typically about 10 cm to 18 cm.

The advancing member 11 is slidably accommodated in the lumen 6 of the elongated tube 3 and includes a advancing end 12 and a driving end 13 . The pushing end 12 includes a support plate 14 for placing the user's thumb or other fingers to push the pushing member 11 distally in the official cavity 6 . A piston 15 may be mounted on the drive end 13 of the advancing member 11, which may have a distal tip 16 opposite a distal end 17. End cap 18 is removably attached to distal end 4 of applicator 10 using known structures such as screws or a friction fit.

FIG. 3 is a distal view of the applicator 10 . FIG. 4 is a longitudinal cross-sectional view of applicator 10 through line 4-4 in FIG. 3 . In Fig. 4, the piston 15 is mounted on the drive end 13 of the advancing member 11 in a first position with the applicator chamber 20 filled or containing a predetermined dose of medicament.

In some optional embodiments, the applicator chamber 20 can provide a drug dose of about 5ml to 0.1ml, typically about 2ml to 0.5ml, preferably about 1.0ml. In a preferred embodiment, the drive end 13 of the propulsion member 11 is removably nestable into the bore 19 of the piston 15 . Therefore, in this preferred embodiment, if the pusher part 11 is retracted proximally, the driving end 13 of the pusher part 11 can be freely pulled out from the hole 19, and the piston 15 will not retract with the pusher part 11 to the proximal end. back. This preferred structure can prevent re-inhalation of the drug after the drug is ejected from the applicator cavity 20, and it can also prevent the release end 4 of the tube 3 from sucking the tissue when the pushing member 11 is retracted proximally.

Additionally, in some preferred embodiments, the lumen 6 may include a detent 40, such as a protrusion 41, that may protrude into the lumen 6 to prevent the proximal retraction of the piston 15. Whether the applicator 10 is preloaded or is filled by the user during use, the stopper 40 is positioned such that the applicator chamber 20 has a fixed maximum volume to accommodate a predetermined amount of medication. This stop conveniently prevents the user from administering more than the established dose if the user loads the applicator 10 with medication prior to use.

An end cap 18 fits over the delivery end 4 of the applicator 10 . The end cap 18 may be a friction fit with the outer layer 35 of the applicator delivery end 4 . Alternatively, or in addition, the end cap 18 may comprise a stem 18a which is a friction fit with the distal end 1 of the lumen 6 . The distal end 1 of the lumen 6 may alternatively be provided with a female thread (not shown) which can be screwed onto a male thread (not shown) which may be present on the outer surface of the handle 18a. The end cap 18 may also have tabs 18b to make it easier to grip the end cap 18 when it is removed from the tube 3 .

The end cap 18 may optionally have some texture, such as embossing, ridges, etc., to facilitate removal. Some markings, such as raised arrows, can optionally be attached to the end cap 18 to show the direction of screwing out when removing, so as to facilitate the use of the applicator.

In FIG. 5 , the advancing member 11 has been pushed distally to a position where the drug is ejected from the applicator cavity 20 . In the illustrated optional embodiment, the distal tip 16 of the piston 15 protrudes outside the distal end 4 of the elongated tube 3 when the pushing member 11 is pushed distally. In addition, the tip 16 of the distal end can be made into a convex shape or an outward hemispherical shape to further ensure that the medicine can be sprayed out from the applicator cavity 20 completely.

Figure 6 is a close-up view of an optional embodiment of the proximal end 2 of the applicator 10. In the illustrated embodiment, the supporting plate 14 of the pushing member 11 forms a shoulder 25 at the position where it connects with the pushing end 12 of the pushing member 11 . When the advancing member 11 is advanced distally in the lumen 6, the shoulder 25 ensures a stop by pressing against the operating end 5 of the elongated tube 3, which may indicate complete ejection of the drug from the applicator lumen 20.

Figure 7 is a close-up view of an optional embodiment of the distal end 1 of the applicator 10. As shown, the distal end of applicator lumen 20 of lumen 6 has a converging taper 30 . The outer surface 31 of the piston 15 may also have a converging taper 32 extending to the distal tip 16 . When the propulsion member 11 is advanced distally, the corresponding converging cones 30 and 32 allow the drug in the applicator cavity 20 to be ejected completely and conveniently. The piston 15 can also have a sealing ring 33, such as a circumferential flange 34, which can be tightly attached to the lumen 6 to ensure that most of the medicine, preferably all the medicine, is ejected from the lumen 6 when the piston 15 is pushed to the far end. Therefore, the lumen 6 has at least two different diameters, the lumen diameter _LD and the drug delivery end diameter _DD . A typical lumen diameter _LD is about 5 to 15 mm, while a typical delivery tip diameter _DD is about 2 to 10 mm. In an example of an applicator 10 with a maximum lumen 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 3 may also have a converging taper 36 for facilitating the insertion of the distal end 1 of the applicator 10 into the vagina. Converging cone 36 also ensures that all sprayed medicament remains at the delivery site after medicament is ejected from applicator chamber 20 . For example, when delivering a drug to the cervix, the vaginal walls surrounding the distal end 1 tightly encase the distal end 1, and the pointed end is more pronounced compared to a square end (i.e., straight cylindrical) or a square end with rounded corners. Any medication left on it can be wiped off by it.

During use, the user can place the thumb and the middle finger on the wings 8a and 8b near the control handle 7 to grasp the selected part of the applicator 10; Pushing the propulsion member 11 distally makes the distal tip 16 of the piston 15 eject the drug from the applicator cavity 20 and deliver the drug to a certain part of the vagina, such as the mucosal surface of the cervix.

Figure 8, is an exploded perspective view of the components of another optional embodiment vaginal applicator 100. As shown, the applicator 100 includes a proximal end 101, a distal end 102 and a longitudinal axis X-X passing therethrough. The elongated tube 103 may have a drug delivery end 104, an operating end 105 and a lumen 106 therethrough. The end cap 108 can be slid or screwed onto the distal end 102 of the vaginal applicator 100, just like the end cap 18 of the vaginal applicator 10 described above.

The manipulating end 105 of the elongated tube 103 includes a handle 107 with a side 118 for grasping the vaginal applicator 100 during use. In the illustrated optional embodiment, the edge 118 may extend continuously around the operative end 105 . It should be understood, however, that the sides 118 need not be continuous, and in other embodiments, the sides 118 may be omitted.

Advancing member 111 is slidably received within lumen 106 and may include an advancing end 113 and a driving end 114 with a shaft 115 extending therebetween. The propulsion end 113 includes a support plate 116 on which a user's thumb or other fingers can be placed to push the propulsion member 111 distally during use. The pad 116 may have a concave surface 117 to better fit the end of the user's finger or thumb. Piston 120 may be fixed to drive end 114 of propulsion member 111 , or drive end 114 may be removably inserted into bore 122a at tip 122 . The piston 120 has a distal tip 121 . In some embodiments, the distal tip 121 may protrude distally or be dome-shaped outward to further ensure that the drug is completely ejected.

9 is a longitudinal cross-sectional view of the vaginal applicator 100 showing the applicator cavity 130 containing or containing a predetermined dose of medication when the advancing member 111 is retracted proximally within the lumen 106 of the elongated tube 103 . FIG. 10 shows that the distal tip 121 of the piston 120 can protrude outside the distal end 102 of the elongated tube 103 when the advancing member 111 is advanced distally.

11 , is a close-up view of the distal end 102 of the vaginal applicator 100 showing the applicator lumen 130 having a converging taper 131 at the distal end 102 of the lumen 106 . The converging taper 131 of the optional applicator lumen 130 can be made to mate with the corresponding converging taper 132 of the distal portion of the plunger 120 . The converging surfaces 131 and 132 allow the drug in the applicator chamber 130 to be ejected completely and conveniently.

The piston 120 can also have a sealing ring 133, such as a circumferential flange 134, which can be tightly attached to the lumen 106 to ensure that when the piston 120 is pushed to the far end, all the medicine can be sprayed out from the lumen 6. The outer surface 135 of the distal end 102 of the elongated tube 103 may form a converging taper 136 for the same reasons discussed above.

As with vaginal applicator 10, in some optional embodiments, lumen 106 can have a detent 140, such as protrusion 141, that can protrude into lumen 106 to prevent proximal retraction of plunger 120. Whether the applicator 100 is pre-loaded or filled by the user during use, the stopper 140 is positioned such that the applicator chamber 130 has a fixed maximum volume to accommodate a predetermined amount of medication.

FIG. 12 is a close-up view of a preferred embodiment of the proximal end 101 of the vaginal applicator 100 shown in FIG. The operating end 105 of long pipe 103 is inside. In the event that the advancing member 111 is inadvertently retracted proximally after the drug has been expelled, this feature reduces the possibility of sucking some or all of the drug ejected from the applicator chamber 130 back into the applicator after administration. Possibility of medicine chamber 130.

Likewise, in some preferred embodiments, the operating end 105 of the elongated tube 103 and the advancing end 113 of the advancing member 111 can be configured to provide audible and/or tactile feedback to the user after the drug has been completely expelled. According to the preferred embodiment, the operative end 105 of the lumen 106 has a protruding surface 145, such as a ridge 146, positioned close to the paddle 116 when the advancing member 111 is fully pushed distally. The paddle 116 can be sized such that when the paddle 116 is pushed distally over the ridge 146, an audible click is heard; the sound produced by the action over the ridge 146 informs the user that the drug has been completely expelled. Ridge 146 may also serve to "lock" advancement member 111 advanced to the distal portion so that proximal retraction of advancement member 111 may be prevented.

It should be understood that in addition to the lumen diameter _LD and the delivery end diameter _DD , the lumen 106 also has a diameter _PO at the operative end 105. Lumen 106 may therefore have a taper 150 extending between diameters _PO and _LD . In an example of an applicator 100 having a maximum lumen volume of about 1 ml, the length of the elongated tube 103 is about 15-17 cm, the _LD is about 11-15 mm, and the D _D is about 7-12 mm.

In another optional embodiment, the region of the elongated tube 103 shown with parallel sides extending from the proximal end to the distal end (see, e.g., FIG. 9 ) may also have a converging cone extending from the proximal end to the distal end. shape. This facilitates loading of the drug into the applicator from the proximal rather than the distal end of the elongated tube. That is, without the tapering as described, the charge would be trapped in the air between the piston's seal and the lumen wall when the charge was filled and attempted to push the piston distally along the non-tapered lumen hinder. By tapering the elongated lumen as described, a gap is created between the piston and the lumen wall, allowing air to escape as the piston is pushed distally. Such a taper may be formed gradually along the length of the elongated tube, or abruptly near the distal end of the elongated tube where a plunger is placed to set a predetermined volume.

Fig. 13 shows another optional embodiment of the operating end of the elongated tube suitable for the vaginal applicator 10, 100 of the present invention. According to this embodiment, the operative end 201 of the elongated tube 200 may contain a structure for providing an indicator 203 of the orientation of the elongated tube 200 about the longitudinal axis X-X. Therefore, in the embodiment of FIG. 13, the opposing sides 204 and 205 are linear, so that the operating end has an elliptical cross-sectional structure. In this embodiment, the rim 206 may extend around the circumference of the operating end 201 . However, it should be understood that this rim may be absent at all or be discontinuous around the circumference.

Fig. 14 shows another preferred embodiment of the operating end of the elongated tube 300 suitable for the vaginal applicator of the present invention. In this embodiment, the operative end 301 of the elongated tube 300 may also contain structure for providing an indicator 303 of the orientation of the elongated tube 300 about the longitudinal axis XX. The operating end 301 may have ribs 304a-304d. Walls 305a-305d between ribs 304a-304d at operative end 301 form a converging taper varying from operative end diameter _PO to lumen diameter _LD . In the illustrated embodiment, the proximal surface of each of the walls 305a-305d may have a cavity 306a-306d extending distally into the surface of the walls 305a-305d, respectively. Additionally, the plate 350 of the advancing member (not seen here) may have a distal concave surface 351 and four ribs 352a-352d that mate with the ribs 304a-304d of the walls 305a-305d. A lip or flange (not shown in this embodiment) may or may not be present around the proximal edge of the operative end 301 as described for the vaginal applicators 10 and 110 .

The vaginal applicator provides precise, smaller doses than other conventional vaginal medications. Many vaginal applicators are designed to give about 5ml of drug, generally they cannot be administered topically but can deliver drug generally to the vagina.

In an optional embodiment, such as that shown in Figure 15, an applicator 10 pre-filled with medication P can eliminate the possibility of misfilling the applicator. However, if the applicator is charged at the time of use, structures such as detents on the applicator can set a maximum volume to help eliminate the possibility of exceeding the intended dose.

Any of the applicators mentioned above are of sufficient length so that the distal end of the applicator is at or very close to the cervix, and the proximal end of the applicator is outside the vagina when a portion of the applicator passes through the vagina. The length of the applicator can be made to ensure that the immune response modifier is delivered to the uppermost end of the vaginal canal while the proximal end of the applicator remains outside the vagina. For example, the length of the applicator may be sufficient to accommodate variations in the anatomy of a woman's vagina, thus not compromising the treatment of women with long vaginas.

When in use, grasp the proximal end of the vaginal applicator between the thumb and the middle finger, press down (that is to say, advance toward the far end) the supporting plate of the advancing part with the index finger to eject the medicine.

In an optional embodiment, a propulsion member is pre-positioned in the chamber of the elongate tube ready for use. If the applicator is filled before use, the distal end of the elongated tube can have a female thread that mates with the male thread of the drug-filled container (such as an aluminum tube), so that the drug is transferred from the drug-filled container to the applicator cavity. Can provide thread seal when chambered.

The applicator may be enclosed in an overwrap that maintains sterility and moisture resistance. The outer pouch can be made of any material suitable for protecting the drug, such as foil or composite laminated foil (eg, metal and plastic layers). In some embodiments, the outer packaging bag can protect the drug from water loss or oxidation of the drug.

The applicator may be part of an assembly used in a system or method involving additional components or components. In an optional embodiment, the systems and methods include immune response modifier (IRM) compounds for the treatment or prevention of diseases associated with mucosal surfaces. For example, formulations containing immune response modifier compounds can be administered to the mucosal surface of the cervix to treat cervical disorders, including cervical dysplasia, such as cervical intraepithelial neoplasia.

In some optional embodiments, certain formulations may be used to apply immune response modifiers to mucosal surfaces. In some optional embodiments, the formulation enhances the therapeutic effect of the immune response modifier by increasing mucosal permeability or prolonging the duration of contact of the immune response modifier with the mucosal surface. Pharmaceutical formulations may contain a preservative system to make the drug suitable for packaging in multiple-use containers.

Immune Response Modulator Compounds

As mentioned above, many of the imidazoquinolineamines, imidazopyridinamines, 6,7-fused cycloalkylimidazopyridinamines, 1,2-bridged imidazoquinolineamines, thiazolo Quinolinamine, oxazoloquinolineamine, thiazolopyridinamine, oxazolopyridinamine, imidazolo-1,5-naphthyridine, tetrahydroimidazo-1,5-naphthyridine immune response Modulator compounds have shown potent immunomodulatory activity. Some optional immune response modifiers of the invention include 1H-imidazo[4,5-c]quinolin-4-amine, as defined in one of Formulas I-V below:

in

R ₁₁ is selected from alkyl groups containing 1 to 10 carbon atoms, hydroxyalkyl groups containing 1 to 6 carbon atoms, acyloxyalkyl groups (wherein the acyloxy moiety is alkanoyloxy group containing 2 to 4 carbon atoms) or benzoyloxy, the alkyl moiety contains 1 to 6 carbon atoms), benzyl, (phenyl)ethyl and phenyl, substitutions of the above-mentioned benzyl, (phenyl)ethyl and phenyl is any substitution on the benzene ring by 1 or 2 moieties independently selected from alkyl groups with 1 to 4 carbon atoms, alkoxy groups with 1 to 4 carbon atoms and halogens. The proviso is that if the above-mentioned benzene ring is substituted by the above-mentioned two moieties, the number of carbon atoms contained in the above-mentioned moieties does not exceed 6 in total.

R _is selected from hydrogen, alkyl containing 1 to 8 carbon atoms, benzyl, (phenyl) ethyl and phenyl, and the benzyl, (phenyl) ethyl or phenyl substituents are optionally Substituted on the benzene ring by 1 or 2 moieties independently selected from alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms and halogen, with the proviso that if the benzene ring is substituted by 2 of the above moieties, the said moieties together contain no more than 6 carbon atoms; and

Each R _is independently selected from alkoxy containing 1 to 4 carbon atoms, halogen and alkyl containing 1 to 4 carbon atoms, n is an integer from 0 to 2, with the proviso that if n is 2, Then the above-mentioned R ₁ groups contain a total of no more than 6 carbon atoms;

in

_R is selected from linear or branched alkenyl groups containing 2 to 10 carbon atoms and substituted linear or branched alkenyl groups containing 2 to 10 carbon atoms, wherein the substituents are selected from the group consisting of 1 to 4 straight-chain or branched-chain alkyl groups of carbon atoms and cycloalkyl groups of 3 to 6 carbon atoms; and straight-chain or branched-chain alkyl groups of 1 to 4 carbon atoms Cycloalkyl; and

_R is selected from hydrogen, straight or branched chain alkyl containing 1 to 8 carbon atoms, benzyl, (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl or benzene The base substituent is optionally substituted on the benzene ring by 1 or 2 moieties independently selected from straight or branched chain alkyl groups containing 1 to 4 carbon atoms, straight chain alkyl groups containing 1 to 4 carbon atoms or branched alkoxy and halogen, provided that, if the benzene ring is substituted by 2 such moieties, the said moieties together contain not more than 6 carbon atoms; and

Each R _is independently selected from linear or branched alkoxy containing 1 to 4 carbon atoms, halogen and linear or branched alkyl containing 1 to 4 carbon atoms, n is from 0 to 2 Integers, with the proviso that, if n is 2, the total number of carbon atoms contained in the aforementioned _R2 groups does not exceed 6;

in

_R23 is selected from hydrogen, straight chain or branched chain alkyl containing 1 to 8 carbon atoms, benzyl, (phenyl) ethyl and phenyl, said benzyl, (phenyl) ethyl or benzene The base substituent is optionally substituted on the benzene ring by 1 or 2 moieties independently selected from straight chain or branched chain alkyl groups containing 1 to 4 carbon atoms, straight chain alkyl groups containing 1 to 4 carbon atoms or branched alkoxy and halogen, provided that, if the benzene ring is substituted by 2 such moieties, the said moieties together contain not more than 6 carbon atoms; and

Each R _{is independently} selected from linear or branched alkoxy containing 1 to 4 carbon atoms, halogen and linear or branched alkyl containing 1 to 4 carbon atoms, n is from 0 to 2 Integers, with the proviso that, if n is 2, the total number of carbon atoms contained in the aforementioned _R3 groups does not exceed 6;

in

R ₁₄ is -CHR _x R _y , where R _y is hydrogen or a carbon-carbon bond, with the proviso that, if R _y is hydrogen, then R _x is an alkoxy group containing 1 to 4 carbon atoms, containing 1 to 4 Hydroxyalkoxy with carbon atoms, 1-alkynyl with 2 to 10 carbon atoms, tetrahydropyranyl, with 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the alkyl part Alkoxyalkyl, 2-, 3-, or 4-pyridyl, with the further proviso that if R _y is a carbon-carbon bond, then R _y and R _x taken together are optionally substituted by 1 or 2 substituents The tetrahydrofuryl group, said substituents are independently selected from hydroxyl and hydroxyalkyl containing 1 to 4 carbon atoms;

_R24 is selected from hydrogen, alkyl containing 1 to 4 carbon atoms, phenyl, and substituted benzyl, the substituents in the substituted benzyl group are selected from alkyl containing 1 to 4 carbon atoms, containing Alkoxy and halogen of 1 to 4 carbon atoms; and

R is selected from hydrogen, straight chain or branched chain alkoxy containing 1 _to 4 carbon atoms, halogen and straight chain or branched chain alkyl containing 1 to 4 carbon atoms;

in

R ₁₅ is selected from: hydrogen; straight chain or branched chain alkyl containing 1 to 10 carbon atoms and substituted straight chain or branched chain alkyl containing 1 to 10 carbon atoms, wherein the substituents are selected from the group consisting of 3 to 6 Cycloalkyl groups of 3 to 6 carbon atoms and cycloalkyl groups of 3 to 6 carbon atoms substituted by linear or branched chain alkyl groups of 1 to 4 carbon atoms; straight or branched chains of 2 to 10 carbon atoms Alkenyl and substituted linear or branched alkenyl groups containing 2 to 10 carbon atoms, wherein the substituents are selected from cycloalkyl groups containing 3 to 6 carbon atoms and cycloalkyl groups containing 1 to 4 carbon atoms Cycloalkyl groups of 3 to 6 carbon atoms substituted by linear or branched chain alkyl groups; hydroxyalkyl groups of 1 to 6 carbon atoms; alkoxyalkyl groups, wherein the alkoxy moiety contains 1 to 4 carbon atoms Atoms, the alkyl part contains 1 to 6 carbon atoms; acyloxyalkyl, wherein the acyloxy part is an alkanoyloxy or benzoyloxy group containing 2 to 4 carbon atoms, and the alkyl part has 1 to 6 carbon atoms 6 carbon atoms; benzyl; (phenyl)ethyl; and phenyl; the aforementioned benzyl, (phenyl)ethyl or phenyl substituents are optionally substituted by 1 or 2 moieties on the benzene ring , said moieties are independently selected from alkyl groups containing 1 to 4 carbon atoms, alkoxy groups containing 1 to 4 carbon atoms, and halogen, provided that if the above benzene ring is substituted by the above two moieties, then the above Parts of which contain a total of not more than 6 carbon atoms;

R ₂₅ is

in

R _S and R _T are independently selected from hydrogen, alkyl containing 1 to 4 carbon atoms, phenyl, and substituted phenyl, wherein the substituents are selected from alkyl containing 1 to 4 carbon atoms, alkyl containing 1 to 4 alkoxy and halogen of carbon atoms;

X is selected from alkoxy groups containing 1 to 4 carbon atoms, alkoxyalkyl groups having 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the alkyl part, containing 1 to 4 carbon atoms Atoms of hydroxyalkyl, haloalkyl containing 1 to 4 carbon atoms, alkylamido having 1 to 4 carbon atoms in the alkyl part, amino, substituents are alkyl containing 1 to 4 carbon atoms or hydroxy Alkyl substituted amino, azido, chlorine, hydroxy, 1-morpholino, 1-pyrrolidino, alkylthio having 1 to 4 carbon atoms; and

R _is selected from hydrogen, a straight chain or branched chain alkoxy group containing 1 to 4 carbon atoms, halogen, and a straight chain or branched chain alkyl group containing 1 to 4 carbon atoms;

Or a pharmaceutically acceptable salt of any of the above compounds.

A preferred 6,7-fused cycloalkylimidazopyridinamine immune response modifier compound can be represented by the following formula VI:

where m is 1, 2, or 3;

R ₁₆ is selected from hydrogen; cycloalkyl containing 3, 4, or 5 carbon atoms; straight chain or branched chain alkyl containing 1 to 10 carbon atoms and substituted straight chain containing 1 to 10 carbon atoms or branched chain alkyl, wherein the substituents are selected from cycloalkyl groups containing 3 to 6 carbon atoms and rings containing 3 to 6 carbon atoms substituted by linear or branched chain alkyl groups containing 1 to 4 carbon atoms Alkyl; fluorine- or chloroalkyl containing 1 to 10 carbon atoms and 1 or more fluorine or chlorine atoms; straight-chain or branched alkenyl and substituted containing Straight-chain or branched alkenyl groups of 2 to 10 carbon atoms, wherein the substituents are selected from cycloalkyl groups of 3 to 6 carbon atoms and substituted by straight-chain or branched chain alkyl groups of 1 to 4 carbon atoms Cycloalkyl groups containing 3 to 6 carbon atoms; hydroxyalkyl groups containing 1 to 6 carbon atoms; alkoxyalkyl groups, wherein the alkoxy part has 1 to 4 carbon atoms and the alkyl part has 1 to 6 6 carbon atoms; acyloxyalkyl, wherein the acyloxy moiety is alkanoyloxy or benzoyloxy having 2 to 4 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, provided that, Any of said alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl or acyloxyalkyl does not have an all-carbon carbon atom directly attached to the nitrogen atom); Benzyl; (phenyl) ethyl; and phenyl; said benzyl, (phenyl) ethyl or phenyl substituents are optionally substituted by 1 or 2 moieties on the benzene ring, said moieties independently selected from alkyl groups containing 1 to 4 carbon atoms, alkoxy groups containing 1 to 4 carbon atoms, and halogen, with the proviso that if the above-mentioned benzene ring is substituted by the above-mentioned 2 moieties, the above-mentioned moieties together Contains not more than 6 carbon atoms;

and -CHR _x R _y

in

R _y is hydrogen or a carbon-carbon bond, with the proviso that if R _y is hydrogen, then R _x is alkoxy of 1 to 4 carbon atoms, hydroxyalkoxy of 1 to 4 carbon atoms, 2 1-alkynyl with up to 10 carbon atoms, tetrahydropyranyl, alkoxyalkyl with 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, 2-, 3 -, or 4-pyridyl, with the further proviso that if R _y is a carbon-carbon bond, then R _y and R _x together form tetrahydrofuranyl optionally substituted by 1 or more substituents independently selected from hydroxyl and hydroxyalkyl groups containing 1 to 4 carbon atoms,

R is selected from _hydrogen , straight chain or branched chain alkyl containing 1 to 8 carbon atoms, straight chain or branched chain hydroxyalkyl containing 1 to 6 carbon atoms, morpholinoalkyl, benzyl, ( phenyl)ethyl, and phenyl, wherein the benzyl, (phenyl)ethyl or phenyl substituents are optionally substituted on the benzene ring with moieties selected from methyl, methoxy and halogen; and

-C(R _S )(RT)(X), wherein R _S and _{R T are} independently selected from hydrogen, alkyl containing 1 to 4 carbon atoms, phenyl, and substituted phenyl, in substituted phenyl The substituents are selected from alkyl groups containing 1 to 4 carbon atoms, alkoxy groups containing 1 to 4 carbon atoms, and halogen;

X is selected from alkoxy groups containing 1 to 4 carbon atoms, alkoxyalkyl groups having 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the alkyl part, containing 1 to 4 carbon atoms Atom haloalkyl, alkylamido with 1 to 4 carbon atoms in the alkyl moiety, amino, substituted amino with alkyl or hydroxyalkyl with 1 to 4 carbon atoms, azido, containing 1 Alkylthio to 4 carbon atoms, and morpholinoalkyl having 1 to 4 carbon atoms in the alkyl moiety, and

_R is selected from hydrogen, fluorine, chlorine, straight chain or branched chain alkyl containing 1 to 4 carbon atoms, and straight chain or branched chain fluorine containing 1 to 4 carbon atoms and at least 1 fluorine or chlorine atom- or chloroalkyl;

and pharmaceutically acceptable salts thereof.

Preferred imidazopyridine amine immune response modifier compounds can be represented by the following formula VII:

in

R ₁₇ is selected from hydrogen; -CH ₂ R _W , wherein R _W is selected from straight chain, branched chain or cycloalkyl containing 1 to 10 carbon atoms, straight chain or branched alkenes containing 2 to 10 carbon atoms A straight-chain or branched hydroxyalkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 1 to 4 carbon atoms in the alkoxy part and 1 to 6 carbon atoms in the alkyl part, and phenethyl); and -CH=CR _Z R _Z , wherein each R _Z is an independent linear, branched or cyclic alkyl group containing 1 to 6 carbon atoms;

_R27 is selected from hydrogen, straight chain or branched chain alkyl containing 1 to 8 carbon atoms, straight chain or branched chain hydroxyalkyl containing 1 to 6 carbon atoms, and the alkoxy moiety has 1 to 4 carbons Alkoxyalkyl, benzyl, (phenyl)ethyl, and phenyl having 1 to 6 carbon atoms in the atom and alkyl moiety, said benzyl, (phenyl)ethyl or phenyl The substituent is optionally substituted on the benzene ring by a moiety selected from methyl, methoxy and halogen; and morpholinoalkyl, wherein the alkyl moiety has 1 to 4 carbon atoms;

_R67 and _R77 are independently selected from hydrogen and alkyl groups containing 1 to 5 carbon atoms, with the proviso that _R67 and _R77 together contain no more than 6 carbon atoms, and with the further proviso that when _R77 is When hydrogen, R ₆₇ is not hydrogen, R ₂₇ is not hydrogen or morpholinoalkyl, and the further condition is that when R ₆₇ is hydrogen, R ₇₇ and R ₂₇ are not hydrogen;

and pharmaceutically acceptable salts thereof.

A preferred 1,2-bridged imidazoquinoline amine immune response modifier compound is represented by the following formula VIII:

in

Z selected from:

-(CH ₂ ) _p -, wherein p is 1 to 4;

-(CH ₂ ) _a -C( _RD R _E )(CH ₂ ) _b -, where a and b are integers, a+b is 0 to 3, R _D is hydrogen or an alkane containing 1 to 4 carbon atoms group, and _RE is selected from alkyl containing 1 to 4 carbon atoms, hydroxyl, -OR _F (where R _F is alkyl containing 1 to 4 carbon atoms), and -NR _{G R'G} (where R _G and _R'G are independently hydrogen or alkyl containing 1 to 4 carbon atoms); and

-(CH ₂ ) _a -(Y)-(CH ₂ ) _b -, where a and b are integers, a+b is 0 to 3, Y is O, S, or -NR _J -, where R _J is hydrogen or an alkyl group containing 1 to 4 carbon atoms;

and wherein q is 0 or 1, R _is selected from alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, and halogen,

and pharmaceutically acceptable salts thereof.

Suitable thiazoloquinolineamines, oxazoloquinolineamines, thiazolopyridinamines and oxazolopyridinamines include compounds of formula IX:

in

R ₁₉ is selected from oxygen, sulfur and selenium;

R ₂₉ selected from

- Hydroxy;

-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;

-halogen;

- haloalkyl;

-N(R ₅₉ ) ₂ ;

or when _R39 and _R49 are taken together, form a fused aromatic ring, heteroaromatic ring, cycloalkane ring or heterocyclic ring;

X is selected from -O-, -S-, _-NR59- , -C(O)-, -C(O)O-, -OC(O)-, and a bond; and

Each R ₅₉ is independently hydrogen or C _1-8 alkyl.

Suitable imidazo-1,5-naphthyridine and tetrahydroimidazo-1,5-naphthyridine immune response modifier compounds are those represented by formulas X and XI below:

in

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

=CR-CR=CR-N=;

R ₁₁₀ is selected from:

-hydrogen;

-C _1-20 alkyl or C _2-20 alkenyl substituted or unsubstituted by 1 or more substituents selected from:

-Aryl;

- heteroaryl;

- heterocyclyl;

-OC _1-20 alkyl,

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

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

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

-C _1-20 alkoxycarbonyl;

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

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

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

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

-N(R ₃₁₀ ) ₂ ;

-N ₃ ;

oxo;

-halogen;

_-NO2 ;

-OH; and

-SH; and

-C _1-20 alkyl-NR ₃₁₀ -QXR ₄₁₀ or -C _2-20 alkenyl-NR ₃₁₀ -QXR ₄₁₀ , wherein Q is -CO- or -SO ₂ -; X is a bond, -O- or - NR ₃₁₀ -; and R ₄₁₀ are aryl; heteroaryl; heterocyclyl; or -C _1-20 alkyl or C _2-20 alkenyl substituted or unsubstituted by 1 or more substituents, all The substituents are selected from:

-Aryl;

- heteroaryl;

- heterocyclyl;

-OC _1-20 alkyl;

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

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

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

-C _1-20 alkoxycarbonyl;

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

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

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

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

-N(R ₃₁₀ ) ₂ ;

-NR ₃₁₀ -CO-OC _1-20 alkyl;

-N ₃ ;

oxo;

-halogen;

_-NO2 ;

-OH; and

-SH; or R ₄₁₀ is

Among them, Y is -N- or -CR-;

R ₂₁₀ is selected from:

-hydrogen;

-C _1-10 alkyl;

-C _2-10 alkenyl;

-Aryl;

-C _1-10 alkyl-OC _1-10 -alkyl;

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

-C _1-10 alkyl or C _2-10 alkenyl substituted by 1 or more substituents selected from:

-OH;

-halogen;

-N(R ₃₁₀ ) ₂ ;

-CO-N(R ₃₁₀ ) ₂ ;

-CO-C _1-10 alkyl;

-N ₃ ;

-Aryl;

- heteroaryl;

- heterocyclyl;

-CO-aryl; and

-CO-heteroaryl;

each R ₃₁₀ is independently selected from hydrogen and C _1-10 alkyl; and

Each R is independently selected from hydrogen, C _1-10 alkyl, C _1-10 alkoxy, halogen and trifluoromethyl, or a pharmaceutically acceptable salt thereof.

in

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

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

R ₁₁₁ is selected from:

-hydrogen;

-C _1-20 alkyl or C _2-20 alkenyl substituted or unsubstituted by 1 or more substituents selected from:

-Aryl;

- heteroaryl;

- heterocyclyl;

-OC _1-20 alkyl;

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

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

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

-C _1-20 alkoxycarbonyl;

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

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

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

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

-N(R ₃₁₁ ) ₂ ;

-N ₃ ;

oxo;

-halogen;

_-NO2 ;

-OH; and

-SH; and

-C _1-20 alkyl-NR ₃₁₁ -QXR ₄₁₁ or -C _2-20 alkenyl-NR ₃₁₁ -QXR ₄₁₁ , wherein Q is -CO- or -SO ₂ -; X is a bond, -O- or - NR ₃₁₁ -; and R ₄₁₁ are aryl; heteroaryl; heterocyclyl; or -C _1-20 alkyl or C _2-20 alkenyl substituted or unsubstituted by one or more substituents, said Substituents are selected from:

-Aryl;

- heteroaryl;

- heterocyclyl;

-OC _1-20 alkyl;

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

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

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

-C _1-20 alkoxycarbonyl;

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

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

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

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

-N(R ₃₁₁ ) ₂ ;

-NR ₃₁₁ -CO-OC _1-20 alkyl;

-N ₃ ;

oxo;

-halogen;

_-NO2 ;

-OH; and

-SH; or R ₄₁₁ is

Among them, Y is -N- or -CR-;

R ₂₁₀ is selected from:

-hydrogen;

-C _1-10 alkyl;

-C _2-10 alkenyl;

-Aryl;

-C _1-10 alkyl-OC _1-10 alkyl;

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

-C _1-10 alkyl or C _2-10 alkenyl substituted by one or more substituents selected from:

-OH;

-halogen;

-N(R ₃₁₁ ) ₂ ;

-CO-N(R ₃₁₁ ) ₂ ;

-CO-C _1-10 alkyl;

-N ₃ ;

-Aryl;

- heteroaryl;

- heterocyclyl;

-CO-aryl; and

-CO-heteroaryl;

each _R is independently selected from hydrogen and C _1-10 alkyl; and

Each R is independently selected from hydrogen, C _1-10 alkyl, C _1-10 alkoxy, halogen and trifluoromethyl, and pharmaceutically acceptable salts thereof.

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

The above substituents R ₁₁ -R ₁₁₁ are collectively referred to herein as "1-substituent". Preferred 1-substituents are alkyl having 1 to 6 carbon atoms and hydroxyalkyl having 1 to 6 carbon atoms. The optional 1-substituent is 2-methylpropyl or 2-hydroxy-2-methylpropyl.

The above substituents R ₂₁ -R ₂₁₁ are collectively referred to herein as "2-substituents". The optional 2-substituents are hydrogen, alkyl having 1 to 6 carbon atoms, alkoxyalkyl having 1 to 4 carbon atoms in the alkoxy moiety and alkoxyalkyl having 1 to 4 carbon atoms in the alkyl moiety, and hydroxyalkyl groups of 1 to 4 carbon atoms. Optional 2-substituents are hydrogen, methyl, butyl, propylhydroxymethyl, ethoxymethyl or methoxyethyl.

In the example where n can be 0, 1 or 2, n is preferably 0 or 1.

Immune Response Modulator Pharmaceutical Preparations

The therapeutically effective dosage of an immune response modifier compound in a particular instance will depend upon such factors as the activity of the particular compound, the mode of administration, the particular formulation and the disease being treated. Again, it is not practical to ascertain a specific amount to be administered herein; however, one of skill in the art will be able to determine an appropriate effective therapeutic dose based on the guidance provided herein, the usage information pertaining to these compounds and routine testing.

The pharmaceutical formulations described below are useful for topical administration of immune response modifiers. Many of the formulations provided herein are particularly advantageous for topical administration to mucosal surfaces. In some embodiments, the formulation is capable of affecting the pharmacokinetics of the immune response modifier such that a reduced concentration of the immune response modifier provides a similar pharmacodynamic effect as a greater concentration of the immune response modifier in other formulations.

In general, pharmaceutical formulations of the present invention include immune response modifiers, fatty acids, preservative systems and optionally viscosity increasing agents such as carbomers. Methods employed to prepare immune response modifiers are described in the patents cited in the Background of the Invention section above and in US Patent Nos. 4,988,815; 5,367,076; 5,175,296; 5,395,937; All percentages are by weight based on the total weight of all components unless otherwise stated.

The amount of immune response modifier present in the pharmaceutical formulations of the invention is an amount effective to treat the indicated disease, prevent recurrence of the disease, or increase immunity to the disease. The preferred amount of immune response modifier is approximately from about 0.1% to about 9% by weight of the total formulation. For mucosal administration, the optional amount of immune response modifier is up to about 5% by weight, most preferably from about 0.1% to about 3% by weight.

The pharmaceutical formulations of the invention are generally oil-in-water emulsions. The oil component of the formulation includes an immune response modifier and a fatty acid. The amount of fatty acid in the formulation is sufficient to solubilize the immune response modifier. The amount used is usually about 2% to about 45%, generally about 10% to about 30%, preferably about 15% to about 18%, based on the total weight of the preparation. Fatty acids such as isostearic acid are well suited for pharmaceutical formulations. In addition, the immune response modifier can also be dissolved in a linear carboxylic acid of 6-8 carbon atoms.

The pharmaceutical formulations of the invention can also include emulsifying agents such as nonionic surfactants. Suitable surfactants include, for example, polysorbate 60, sorbitan monostearate, polyglyceryl-4 oleate, polyoxyethylene (4) lauryl ether, and the like. For some preparations, it is preferred to use alone or in combination such as Poloxamers (for example, Pluronic F68, available from BASF Corporation, Ludwigschafen, Germany) and sorbitan trioleate (for example, Span 85, available from Sigma Chemical Co., St. .Louis, MO) surfactant. The amount of nonionic surfactant is generally about 0.5%-10% of the total weight of the preparation. In a preferred embodiment, the total amount of emulsifier is no more than about 5% by weight of the formulation, preferably about 3.5% by weight of the formulation.

The formulations of the invention can also include a viscosifying agent such as carbomer, preferably having mucoadhesive properties. The amount of carbomer may be about 0.1%-8%, preferably about 0.5%-4%, more preferably about 0.5-3%, and the optimal amount is about 1.0%, relative to the total weight of the preparation. Suitable carbomers include polyacrylic acids such as Carbopol 934P, Carbopol 971P, Carbopol 940 and Carbopol 974P available from the B.F. Goodrich Company. A preferred carbomer is Carbopol 974P.

In some optional embodiments, the formulation can also include a chelating agent. The role of chelating agents is to form chelates with metal ions. If present, unchelated metal ions can inhibit gel formation by inhibiting ionization, which can promote gel formation in formulations containing carbomer. An optional chelating agent is ethylenediaminetetraacetic acid (EDTA) disodium salt at a concentration of about .0001-0.5%, typically about .0005-0.1% of the total weight of the formulation.

Preservatives such as methyl paraben, sorbic acid and propylene glycol can be added to the preparation. In an optional embodiment, the concentration of methyl paraben and sorbic acid is about 0.05-0.3% of the total weight of the formulation, the preferred dosage is about 0.15% of the total weight of the formulation; the concentration of propylene glycol is up to about 30%, preferably around 5%. It is found that the combined use of preservatives helps to meet the following standards, i.e. Preservation Effectiveness Test (PET), European Pharmacopoeia (1997 edition), check 5.1.3 antibacterial and antiseptic efficacy-local drug preparation-standard (Test 5.1. 3Efficacy Antimicrobial Preservation-Topical Preparations-A Criteria). This makes the formulation suitable for multi-dose dispensers without adversely affecting the stability of the formulation. Methylparaben and sorbic acid can be dissolved in propylene glycol prior to addition to the formulation.

The remainder of the drug formulation may consist of water to allow the drug formulation to be flushed from the mucosal surface via normal physiological clearance mechanisms.

In addition to imparting mucoadhesive properties to the formulation, carbomers can also increase viscosity by forming a stable gel. Many factors, such as the amount of oily phase, the amount of drug used, and the amount of carbomer used, will affect the pH at which gelation is formed. In some formulations, the presence of metal ions and surfactants increases the pH at which carbomer gels. Therefore, in the absence of chelating agents, or when the level of surfactants increases, the pH at which carbomer forms a gel increases. Therefore, it is necessary to add organic and inorganic bases or other substances that are conducive to gel formation. Suitable inorganic bases include, for example, KOH, NaOH, and the like. The pH value of the pharmaceutical preparation in the present invention is generally about pH 3.0-pH 7.0, and the preferred pH value is about pH 4.0-pH 6.0.

mucosal application

According to the invention, said composition can be applied topically, and is particularly suitable for non-keratinized epithelial surfaces such as mucosal surfaces. Mucosa surfaces include mucous membranes such as oral, gingival, nasal, tracheal, bronchial, gastrointestinal, rectal, urethral, ureteral, vaginal, cervical, and uterine mucous membranes. Because of the concentration of the immune response modifier, the composition of the formulation, and the mucosal surface, the efficacy of the immune response modifier may only extend to the superficial and submucosal tissues.

In one embodiment, the disclosed immune response modifiers may be administered topically in the vagina or supravaginal region of the cervix to treat dysplastic disorders, such as cervical intraepithelial neoplasia. In some embodiments, the formulations described above are particularly advantageous for cervical administration of an immune response modifier for a period of time sufficient to achieve the desired therapeutic effect without undesired systemic absorption of the immune response modifier.

Cervical Intraepithelial Neoplasia (CIN)

Despite widespread screening for women to detect precursor cell changes, approximately 16,000 new cases of invasive cervical cancer are diagnosed each year in the United States. In the United States alone, approximately 3,000 people die from cervical cancer, often due to failure to detect early cancer lesions in time.

The Papanicolaou test (Pap stain), used since the 1950s, is a screening test to detect abnormal cells in the cervix, such as cervical inflammation and cervical dysplasia, including cervical cancer. This screening test is widely used in industrialized countries, and it has a profound impact on cervical cancer-related mortality. Abnormal Pap staining prompts the conclusion of observation of the disease process and possible therapeutic intervention such as destruction or resection of cancerous or precancerous tissue. These resection treatments are costly, uncomfortable, and have a failure rate of 2-23%, which has been reported to be higher for advanced tumors. Recently it has been demonstrated that the failure rate with laser therapy approaches 10%.

The cause of cervical cancer was initially thought to be a herpes virus. However, attention gradually shifted to the human papillomavirus (HPV) when it was observed that its cytopathic effects in experimental systems closely approximated its effects on human disease. . Based on past experimental methods, new and improved experimental methods can assess the entire HPV subtype spectrum, and the conclusion is that high-risk HPV types (eg, HPV16, 18, and less common 31, 33, 35, 45) are very likely to be The sole initiating factor (that is, carcinogenic factor) of cervical dysplasia and secondary neoplasia. The mechanism by which HPV converts normal cells into dysplastic cells is related to the HPV-encoded oncoproteins (E6 and E7) from high-risk genotypes that combine the tumor suppressor gene products p53 and Rb, resulting in disruption of the cell cycle regulation mechanism, p53 and Rb play an important role in the mechanism of cell cycle regulation. In addition, the application of these molecular methods has led to the epidemiological observation that nearly 93% of cervical tumors can be isolated from HPV, which further strengthens the generally accepted conclusion that HPV infection is the most important initiating factor of cervical cancer.

Women are commonly exposed to HPV during sexual activity, but most women who are exposed to HPV can avoid developmental abnormalities or cancer. Infected women with persistent viral DNA were about five times more likely to develop persistent dysplasia than women who were able to clear the virus. The importance of cell-mediated immune (CMI) responses to HPV infection was demonstrated by the observation that antibody-mediated immune responses were ineffective in eradicating pre-existing infections, as it turned out that antiviral proteins in patients with invasive cervical cancer Antibody levels to E6 and E7 are usually elevated. This particular antibody response may reflect the increase in the number of tumor cells and the expansion of the antigen contact surface. In contrast to the apparent ineffectiveness of the humoral immune response, the cell-mediated immune response (Th-1 type response) is effective in controlling tumor development. Accompanying recovery from intraepithelial injury is a cellular infiltration consisting of CD4 ⁺ T cells, CD8 ⁺ T cells, natural killer (NK) cells, and macrophages. This inflammatory infiltration generally correlates with tumor regression, as illustrated by controls in women who did not develop an inflammatory response and women with progressive disease. In addition, patients with defective cell-mediated immune responses have an increased risk of cervical cancer, whereas patients with defective antibody production are not as susceptible.

In an optional embodiment, the inventors envision that immune response modifiers may be used topically for the non-invasive treatment of cervical disorders including cervical intraepithelial neoplasia (CIN).

IRM intravaginal applicator

In the treatment of cervical diseases, in order to obtain a good therapeutic effect or preventive effect, the IRM intravaginal applicator disclosed herein is preferred. The IRM is administered through a drug delivery preparation or a dispenser, and the dispenser can ensure that the IRM has sufficient contact time with the cervical mucosa to obtain the desired curative effect. Any of the dispensers (ie, applicators) described herein and/or shown in the Figures may be used for the administration of the IRM.

In addition to the applicators already described, IRMs can be formulated as suppositories and administered intravaginally via suppository applicators. Suitable suppository applicators include carton applicators known for administering medication to the vaginal canal. The formulations of the invention can also be administered via a barrel applicator, such as the applicators described herein and/or shown in the accompanying drawings. An example of a suitable barrel applicator can be found in US Patent No. 5,282,789. The content of this patent is incorporated herein by reference.

In an optional embodiment, the IRM can be administered directly to the cervical mucosa. In one embodiment, the IRM can be applied topically to the cervical mucosa via a direct cervical applicator (as previously described) or a cervical mask. Examples of suitable cervical masks can be found in US Patent No. 4,858,624. The content of this patent is incorporated herein by reference. Suitable IRM formulations for direct application to the cervix are disclosed above and will be disclosed in the Examples below. In general, an IRM formulated according to Formulations A-J in the Examples below can be placed in the recessed area of the cervical mask, and the cervical mask can then be applied directly to the cervix. These formulations can also be administered using other types of applicators, including those shown in the figures and those described herein. Optionally, a binder, such as carbomer, can be added to the IRM formulation to prolong the residence time of the IRM in the cervix.

The examples provided below further describe the IMR formulations and methods of the present invention. However, these examples are not intended to limit the formulation and methods.

Example

Example 1 Safety and pharmacokinetics of 1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine (imiquimod) applied to the cervix (PK) and pharmacodynamic (PD) evaluation

method

This is a single-dose, randomized, double-blind, placebo-controlled method to evaluate 5 studies of increasing doses of imiquimod, 50, 100, 150, 200, 250 mg of imiquimod in cream formulations Cervical application for 8 hours. The formulation components of the imiquimod cream (formulation A) used in this study are shown in Table 1 below. Each dose group consisted of 8 subjects (6 active drug and 2 placebo), 2 of whom were treated with the test dose, and the remaining 6 were treated after the test dose produced an acceptable response. treat. Safety was assessed by adverse events (AE's), laboratory tests, and documentation of colposcopic cervical photographs provided before, 24 hours and 48 hours after dosing, if necessary. Systemic distribution (PK) was determined by measuring metabolites of imiquimod and 48 hours post-dose, and PD response was determined by serum analysis of selected cytokines at the time of dosing and 48 hours after dosing. Yes: Tumor necrosis factor-α (TNF-α), interferon-α (IFN-α), interleukin-1 receptor agonist (IL-1RA), interleukin-6 (IL-6), neopterin (NPT ) and 2'5' oligoadenylate synthase (2'5'-AS). Statistical tests used to evaluate adverse reactions (AE's) and demographics, laboratory tests, vital signs and electrocardiograms (ECG's) were performed using the exact probability method (Fisher's Exact Test), Wilcoxon Rank-Sum Test (Wilcoxon Rank-SumTest) And Kruskall-Wallis non-parametric test (Kruskall-Wallis Test) for statistical analysis of experimental data. The cytokine changes among these dose groups were compared with experimental data by Wilcoxon Rank-Sum Test. Statistical analysis of the experimental data was performed using Spearman Rank Correlation for the comparison between the changes of cytokines and the baseline.

result

Thirty-nine females aged 18-50 years who were in good general health, had routine surgical sterilization, and were within 25% of their ideal body weight were included in this study. All women had normal baseline colposcopic findings, while cervical histology was normal and near nuclear abnormal. The majority (92%) of the adverse reactions reported in the 39 cases were usually mild elevated body temperature. There was no difference between the groups for one or more adverse reactions in the subject, or there was no difference between the groups for the adverse reactions that may or are likely to be drug-related. (Two cases of serious adverse reactions were complications related to ankle fracture and its surgical correction). There were statistically significant changes in some laboratory parameters and pulse rate, but these changes were not considered clinically significant. There were no differences in electrocardiograms (ECG's) or physical examinations. Pelvic and colposcopy showed some reactions, ie microvesicles or smaller ulcers on the cervix in 2 of 6 who received 250mg of the drug. These reactions disappeared within 48 hours. No quantifiable (>5 ng/ml) serum concentrations of imiquimod were detected. Significant changes from baseline in IFN and IL-6 were observed in the 250mg dose group, and significant changes in NPT, 2'5'AS and IL-1RA were observed in the 150mg, 200mg, and 250mg dose groups from baseline.

This study demonstrates that a single dose of imiquimod up to 250 mg administered to the cervix of healthy volunteers over 8 hours is safe with minimal systemic distribution. Imiquimod at doses ≥ 150 mg administered to the cervix enhances systemic concentrations of certain cytokines.

Table 1 components Formulation A (% w/w) Imiquimod Isostearate Benzyl Alcohol Cetyl Stearyl Alcohol White Petrolatum Polysorbate 60 Sorbitan Monostearate Glycerin Methylparaben Propylparaben Water Xanthan Gum pH Viscosity (cps) 5.025.02.02.23.13.03.40.62.00.20.0252.980.55.10.33×10 ⁵

The preparation of embodiment 2 pharmaceutical preparation B

This example describes a new formulation for vaginal administration, which is stable, high viscosity, good preservative properties, and can pass the European Preservative Effectiveness Test (PET) standards. The w/w% of the components of this formulation (Formulation B) is shown in Table 2 below.

Imiquimod is dissolved in isostearic acid together with Span 85. Pluronic F68, EDTA, Carbopol 974P, Propylene Glycol, Sorbic Acid, Methylparaben dissolved in water. After emulsification, an oil-in-water emulsion is formed, and sodium hydroxide is added to adjust the pH value to about 5.2. The pH of the formulation may range from about 4.8-6.0.

Table 2 components Formulation B (% w/w) Imiquimod Isostearic Acid Pluronic F68 Pure Water Carbopol 974P Disodium EDTA Propylene Glycol Sorbate Methyl Hydroxybenzoate Span 855N NaOHpH Viscosity (cps) 5282.9843.781.70.05150.150.152.021.175.16.4×10 ⁵

Example 3 Preparation of Pharmaceutical Preparations C-F

The components for preparing pharmaceutical formulations C-F are shown in Table 3 below. The preparation method of pharmaceutical preparations C-F is the same as the preparation method of pharmaceutical preparation B disclosed in Example 2.

table 3 components Formulation C (% w/w) Formulation D (% w/w) Formulation E (% w/w) Formulation F (% w/w) Imiquimod Isostearic Acid Pluronic F68 Pure Water Carbopol 974P Disodium EDTA PG ^* Methyl Sorbate Hydroxybenzoate Span 855N NaOHpH Viscosity (cps) 1.05.61.7969.052.80.0515.00.150.151.213.25.15.8×10 ⁵ 1.028.01.7948.302.100.0515.00.150.151.212.265.28.8×10 ⁵ 3.016.81.7956.252.50.0515.00.150.151.213.15.211.0×10 ⁵ 3.028.01.7946.751.800.0515.00.150.151.212.15.310.0×10 ⁵

^* PG is propylene glycol

Example 4 Transdermal Delivery of Imiquimod in Formulations A and B Both Containing 5% W/W Imiquimod in Hairless Mice

Fig. 16 is a graph showing the results of transdermal imiquimod transdermal study of formulations A and B in Examples 1 and 2. This study was carried out on the skin of hairless mice according to the operation method described in US Patent No. 5,238,944. The content of this patent is incorporated herein by reference.

Briefly, hairless mouse skin was obtained from 5-7 week old female hairless mice (purchased from Charles River). Hairless mouse skin was kept on ice until use. Mouse skin was placed on a diffusion cell of the type shown in US Patent No. 5,238,944. Fix the hairless mouse skin epidermis side up between the upper and lower parts of the diffusion cell with ball connection clips.

The part of the diffusion cell under the fixed hairless mouse skin was completely filled with 0.1N HCl receptor fluid to allow the receptor fluid to come into contact with the skin. Stir the body fluid with a magnetic stir bar and a magnetic stirrer.

When the skin is fixed in the diffusion cell, there is an area of skin in contact with the receptor fluid, and approximately 100 ± 5 mg of the formulation to be tested is applied to the epidermal side (upper side) of the hairless mouse skin to form a uniform layer on this area of skin. The formulation is applied to the skin before the receptor fluid is added to the diffusion cell under the skin.

Then, the diffusion cell was placed in an incubator (31° C.). The oven is maintained at a constant temperature by a heat exchanger connected to the oven and fans for air circulation. Throughout the experiment, the body fluid was stirred with a magnetic stir bar to ensure that the sample was homogeneous and to reduce diffusion barriers on the dermal side of the skin. At designated time intervals (1, 2, 4, 6, 8, 12, and 24 hours), the entire body fluid was removed and fresh body fluid was immediately placed. The recovered receptor fluid was tested for imiquimod content by conventional high-pressure chromatography. The conditions are as follows:

Detector: UV 258nm; mobile phase: 25/75 acetonitrile/water, containing 1% triethylamine, 0.2% 1-octane sulfonate, pH adjusted to 2.0 with phosphoric acid; stationary phase: C8Zorbax RX-C85μ; flow rate: 2ml/min; running time: nearly 10 minutes.

The steady state rate was obtained by plotting the cumulative amount transdermally versus time.

Example 5 Transdermal delivery of imiquimod in nude mice in formulations C-F containing 1% and 3% w/w imiquimod and various concentrations of isostearic acid (ISA)

Table 4 below provides the imiquimod concentration, isostearic acid concentration, viscosity, pH value and steady-state rate (μg/hour) of nude mouse transdermal delivery formulations C-F.

Figure 17 is a graph of the results of the study. The research method of transdermal transport is consistent with the method disclosed in Example 4.

Table 4 preparation IRM concentration (%w/w) Isostearic Acid Concentration (% w/w) Viscosity (×10 ^-5 cps) Steady state rate (μg/hour) CDEF 1% 1% 3% 3% 5.6% 28% 16.8% 28% 5.88.81110 18.126.139.971.5

Example 6 Comparison of the pharmacokinetics of imiquimod after single-dose vaginal administration of formulations A and B to rats

Concentration-time profiles of serum imiquimod were compared after single-dose vaginal administration of formulations A and B to ovariectomized rats. The dose administered for the two 5% w/w formulations was 35 mg/kg. After each rat was dosed, the rats were held by the neck to prevent them from licking off the formulation. After about 6 hours. Rats are vaginally irrigated and their necks are released. Blood samples were collected before dosing and at 0.5, 1, 2, 3, 4 and 24 hours after dosing. Because of the higher viscosity of formulation B, vaginal administration of formulation B to rats is easier than formulation A, and its retention time is longer than formulation A.

Serum imiquimod levels were analyzed by HPLC. See Figure 18 for mean serum imiquimod concentration-time profiles. The time to reach peak serum imiquimod concentration (T _max ) was similar (1 hour) for both formulations. However, the imiquimod peak concentration ( _Cmax ) of formulation B was nearly 1.6 times that of formulation A, and the areas under the respective plasma concentration-time curves (AUC) were compared, formulation B was 3.3 times that of formulation A (Fig. 19A and Figure 19B). Based on these data, Formulation B absorbed imiquimod at a greater rate and extent than Formulation A.

Example 7 Preparation of Pharmaceutical Preparation G

See Table 5 below for the w/w% of formulation G components.

The oil phase was prepared in the following manner. Imiquimod (20.0 g) was slowly added to isostearic acid (3000 g) with stirring. The mixture was stirred and heated, if necessary to 55°C, to induce dissolution of the imiquimod. Discontinue heating after complete dissolution. Add sorbitan trioleate (200 g) and stir well. Add Carbomer 974 slowly with stirring. Continue to stir until the carbomer is evenly dissolved in the oil phase. The oil phase was then allowed to cool below 30°C.

The aqueous phase was prepared in the following manner. Sorbic acid (30.0 g) and methylparaben (40.0 g) were added to propylene glycol (1000 g) with stirring. The resulting mixture was stirred and heated slightly (<45°C) until a solution. Stop on the heat. Polaxamer 188 (500 g) was added to the solution. Stir the resulting mixture until the Polaxamer is completely wetted. The obtained slurry was added to a solution of disodium edetate (10.0 g) dissolved in pure water (13950 g). The resulting mixture was stirred until it became a clear solution.

A sodium hydroxide solution was prepared by dissolving sodium hydroxide pellets (50.0 g) in pure water (1000 g).

The oil phase was added to the water phase followed by the sodium hydroxide solution. Blend the resulting mixture for at least 30 minutes until a smooth, shiny cream forms. Measure the pH value and, if necessary, adjust the pH value to 5.6-5.8 with sodium hydroxide solution.

Example 8 Preparation of Pharmaceutical Preparation H-J

The preparation of pharmaceutical preparations H-J adopts the method of Example 7. See Table 5 below for w/w % of formulation components.

table 5 Preparation components G(%w/w) H(%w/w) I(%w/w) J(%w/w) Isostearic Acid (874) Imiquimod Sorbitan Trioleate Propylene Glycol Sorbate Methyl Hydroxybenzoate Purified Water Disodium EDTA Polaxamer 188 Carbomer 974 Sodium Hydroxide 15.000.101.005.000.150.2075.000.052.501.00qs 15.000.501.005.000.150.2074.600.052.501.00qs 15.001.501.005.000.150.2073.600.052.501.00qs 18.003.001.005.000.150.2069.100.052.501.00Os Total content %w/w 100 100 100 100

Correspondingly, according to the foregoing discussion, it can be known that imidazoquinolineamine, imidazopyridinamine, 6,7-fused cycloalkylimidazopyridinamine and 1,2-bridged imidazoquinolineamine of the present invention are Treatment of mucosa-related disorders including cervical dysplasia is beneficial. In addition, the disclosed pharmaceutical formulations are particularly beneficial for the topical application of IRM in the treatment of diseases of the mucosal surface.

From the foregoing detailed description and examples, it will be apparent that modifications and variations can be made in the compounds, formulations, devices, systems and methods disclosed herein. Other embodiments will be apparent to those skilled in the art. The description and examples should be considered as exemplary only.

Claims (38)

1. be used for the treatment of the system with the mucosal surface relevant disease, it comprises:

Immune response modifier IRM chemical compound, it is selected from immidazoquinolinaminas, imidazopyridine amine, 6,7-fused rings alkyl imidazole and pyridine amine, 1,2-bridging immidazoquinolinaminas and officinal salt thereof; With

Applicator, it is used for the IRM chemical compound is applied to mucosal surface.

2. the system of claim 1, wherein the IRM chemical compound is 1-(2-methyl-propyl)-1H-imidazo [4,5-c]-quinoline-4-amine.

3. the system of claim 1, wherein said IRM chemical compound is included in the pharmaceutical preparation, and said preparation further comprises:

-at least a fatty acid; With

-comprise the preservative system of propylene glycol.

4. the system of claim 1, wherein applicator has been pre-installed the IRM chemical compound of dose therapeutically effective.

5. the system of claim 1, wherein the IRM chemical compound be contained in the isolated container of applicator in.

6. the system of claim 1 also comprises the measurement markers on the applicator, determines the amount of IRM chemical compound in the applicator to help user.

7. the system of claim 1, wherein relevant with mucosal surface disease is a cervical dysplasia.

8. the system of claim 1, wherein said mucosal surface is positioned at cervix uteri.

9. the system of claim 8, wherein said mucosal surface is positioned at Cervical vagina part.

10. the system of claim 9, wherein relevant with mucosal surface disease are that Cervical intraepithelial neoplasia forms.

11. the system of claim 1, wherein applicator comprises:

Blank pipe with administration far-end and near-end; With

Be contained in the slidably piston in the blank pipe.

12. the system of claim 11 also comprises being configured to make the parts of piston to distal movement.

13. the system of claim 12, wherein applicator is configured to limit the motion of described parts to proximal retraction when piston is positioned at the position of adjacent distal end.

14. the system of claim 12, wherein piston removably is connected with described parts.

15. the system of claim 12, wherein said parts are slidably received within the blank pipe.

16. the system of claim 11, it also comprises the brake of limited piston to proximal retraction.

17. the system of claim 11, wherein piston comprises when piston is positioned at apart from the near-end highest distance position part from remote extension.

18. the system of claim 11, wherein the outer surface of far-end forms taper.

19. the system of claim 12, the length of wherein said parts than when piston during at distance near-end highest distance position the distance between near-end and the piston lack.

20. be used for the treatment of the system with the mucosal surface relevant disease, it comprises:

Immune response modifier IRM chemical compound, it is selected from immidazoquinolinaminas, imidazopyridine amine, 6,7-fused rings alkyl imidazole and pyridine amine, imidazo naphthyridine An, oxazole and quinolinamine, thiazole and quinolinamine, 1,2-bridging immidazoquinolinaminas and officinal salt thereof; With

Applicator, it is used for the IRM chemical compound is applied to mucosal surface.

21. the system of claim 20, wherein the IRM chemical compound is 1-(2-methyl-propyl)-1H-imidazo [4,5-c]-quinoline-4-amine.

22. the system of claim 20, wherein said IRM chemical compound is included in the pharmaceutical preparation, and said preparation further comprises:

-at least a fatty acid; With

-comprise the preservative system of propylene glycol.

23. the system of claim 20, wherein applicator has been pre-installed the IRM chemical compound of dose therapeutically effective.

24. the system of claim 20, wherein the IRM chemical compound be contained in the isolated container of applicator in.

25. the system of claim 20 also comprises the measurement markers on the applicator, determines the amount of IRM chemical compound in the applicator to help user.

26. the system of claim 20, wherein relevant with mucosal surface disease is a cervical dysplasia.

27. the system of claim 20, wherein said mucosal surface is positioned at cervix uteri.

28. the system of claim 27, wherein said mucosal surface is positioned at Cervical vagina part.

29. being Cervical intraepithelial neoplasia, the system of claim 28, wherein relevant with mucosal surface disease form.

30. the system of claim 20, wherein applicator comprises:

Blank pipe with administration far-end and near-end; With

Be contained in the slidably piston in the blank pipe.

31. the system of claim 30 also comprises being configured to make the parts of piston to distal movement.

32. the system of claim 31, wherein applicator is configured to limit the motion of described parts to proximal retraction when piston is positioned at the position of adjacent distal end.

33. the system of claim 31, wherein piston removably is connected with described parts.

34. the system of claim 31, wherein said parts are slidably received within the blank pipe.

35. the system of claim 30, it also comprises the brake of limited piston to proximal retraction.

36. the system of claim 30, wherein piston comprises when piston is positioned at apart from the near-end highest distance position part from remote extension.

37. the system of claim 30, wherein the outer surface of far-end forms taper.

38. the system of claim 31, the length of wherein said parts than when piston during at distance near-end highest distance position the distance between near-end and the piston lack.

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