WO2009073782A2

WO2009073782A2 - Apparatus and methods for treatment of pathologic proliferative conditions of uterine tissue

Info

Publication number: WO2009073782A2
Application number: PCT/US2008/085530
Authority: WO
Inventors: Thomas Q. Dinh
Original assignee: Ams Research Corporation
Priority date: 2007-12-04
Filing date: 2008-12-04
Publication date: 2009-06-11
Also published as: WO2009073782A3

Abstract

A pelvic treatment device for localized delivery of one or more anti-proliferative agents to prevent further growth and development of female or male pelvic proliferative cells. With the benefit of localized delivery of the anti-proliferative agents, the anti-proliferative agents can be introduced to pelvic proliferative cells at dosage levels less than would be expected for conventional system delivery mechanisms so as to reduce or eliminated common side effects or toxic conditions. Generally, the one or more anti-proliferative drugs can be introduced in conjunction with or integral to a physical element that retains the anti-proliferative agents for localized release.

Description

APPARATUS AND METHODS FOR TREATMENT OF PATHOLOGIC PROLIFERATIVE CONDITIONS OF UTERINE TISSUE

Priority Claim The present application claims priority to United States Provisional Application Serial

No. 60/992,211, filed December 4, 2007 and entitled, "APPARATUS AND METHODS FOR TREATMENT OF PATHOLOGIC PROLIFERATIVE CONDITIONS OF UTERINE TISSUE", as well as to United States Provisional Application Serial No. 61/075,633, filed June 25, 2008 and entitled, "APPARATUS AND METHODS FOR TREATMENT OF PATHOLOGIC RROLIFERATIVE CONDITIONS OF UTERINE TISSUE", both of which are herein incorporated by reference in their entirety.

Field of the Disclosure

The present disclosure relates generally to treatment of uterine conditions resulting from cellular proliferation. More specifically, the present disclosure relates to a device for localized delivery of an anti-pro liferative drug for treatment of uterine fibroids so as to maintain systemic levels of the anti-pro liferative drug below levels commonly associated with side effects include irnmuno suppression.

Background of the Disclosure

A variety of pathological conditions of the uterus are the result of cellular proliferation or abnormal cell division and growth of the myometrium or endometrium. Representative uterine conditions can include fibroids, abnormal uterine bleeding, pelvic adhesions, endometriosis and the like. Uterine leiomyomas or fibroids are the most common tumor of the female reproductive tract affecting 20 - 25% of all women during their reproductive years. While uterine fibroids are generally non-cancerous, their presence can lead to a variety of problems including excessive uterine bleeding, pain and even infertility. Because of these possible issues, a variety of treatment options have been developed to address the presence of uterine fibroids. One common method, and the most drastic one at that, for eliminating uterine fibroids is the surgical removal of the uterus or hysterectomy. Generally, hysterectomies are performed on women who are beyond their child bearing years or have made the decision to forego bearing children. A hysterectomy is an invasive surgical procedure in which the uterus must be sufficiently exposed such that the attached vascular network, fallopian tubes and ligaments can be severed. In addition to eliminating a woman's ability to bear children, a hysterectomy as a truly invasive surgery has the potential for a variety of surgical consequences including complications such as, for example, blood loss, pain and discomfort, extended convalescence and potentially increased costs due to extended and further hospital care. Uterine fibroids can form in a variety of locations along the uterus with each location providing a unique set of symptoms and effecting surrounding tissue in different ways. Regardless of location, uterine fibroids rely on the highly vascularized nature of the female reproductive system to grow and develop. As such, a variety of alternative treatment methods have been proposed in which the blood vessels connected to said uterine fibroids are accessed to provide treatment. For example, U.S. Patent No. 6,059,766 proposes accessing vessels of the fibroid mass such that a minimally invasive catheter or probe can administer an embolyzing material. Another alternative treatment method has proposed temporary clamping of the vessels supplying a fibroid mass for a period long enough to cause fibroid cell death without permanently reducing blood flow to the myometrium and ovaries while also avoiding ischemia injury.

Finally, a variety of treatment protocols have been proposed in which the physical structure of the uterine fibroid is attacked so as result in tissue ablation and in some instances, physical removal of only the fibroid mass. For example, it has been proposed that appropriate medical imaging technologies can be utilized to deliver focused ultrasound energy into the fibroid mass to ablate the tissue wherein the fibroid can be resorbed within the body. In other instances, it has been proposed to introduce a cryogenic instrument capable of freezing, and thereby, killing the fibroid ceils. Finally, a variety of minimally invasive instruments have been proposed to core or debulk fibroid masses wherein the material can then be removed by a suction device. While a variety of procedures have been contemplated for treatment of uterine fibroids, there remains a need for new minimally invasive procedures that delivery effective treatment options while reducing the potential for negative treatment outcomes.

Summary of the Disclosure The present application describes a uterine fibroid treatment device that provides for localized delivery of one or more anti -proliferative agents to treat uterine conditions including, for example, uterine fibroids, abnormal uterine bleeding, pelvic adhesions and endometriosis. Generally, the uterine treatment device comprises a physical positioning element that can be inserted, positioned and maintained in close proximity to the uterine tissue to be treated. Depending upon tissue location and the desired treatment regimen, the physical element can take on a variety of physical configuration including, for example, an occluding stent, a vaginal ring, an inflation balloon, a constricting band, clamp or suture, microspheres, gel, IUD, spring or pipe cleaner-like configurations, sponges, discs, silicone plugs/members, slings, prolapse mesh and the like. Generally, the one or more antiproliferative agents are introduced to the treatment location by absorbing, encapsulating or integrating the one or more antiproliferative agents with the physical element. Representative anti-proliferative agents can include, for example, rapamycin, rapamycin analogs, podophyllotoxin, podophyllotoxin analogs, curcumin, halofuginone and 2-methoxyestradiol. By delivering the one or more anti-proliferative drugs locally as opposed to systemically such as by, for example, intravenous or oral administration, dosage levels of the anti-proliferative agent can be delivered at lower levels so as to avoid or at least minimize common side effects such as, for example, immunodeficiency issues and potential toxic consequences. In some embodiments, the physical element can serve the dual purpose of delivering the anti-proliferative agent while simultaneously cutting off blood flow to a mature fibroid to initiate hypoxic/ischemic conditions within the mature fibroid. In this dual capacity, the physical element and anti-proliferative agent can prevent the revival of mature proliferative cells and prevent further growth and development of non-mature proliferative cells. After a period time, the lack of oxygen kills mature cells and can induce proliferation within non-mature cells. At this point, the one or more anti-proliferative drugs prevent non-mature cells from maturing.

In one aspect of the present disclosure, a device for the treatment of pelvic proliferative conditions comprises a physical member for local delivery of anti-proliferative agents. In one embodiment, the device provides for the treatment of uterine proliferative conditions by utilizing the physical member to locally deliver one or more anti-proliferative agents to uterine proliferative cells including, for example, uterine fibroids. Alternatively, male pelvic tissue including prostate or testes tissue having proliferative conditions can be similarly treated with the device. Representative physical members are generally configured to maintain their position proximate tissue to be treated and can include, for example, an occluding stent, a vaginal ring, an inflation balloon, a constricting band, clamp or suture, microspheres, gel, IUD, spring or pipe cleaner-like configurations, sponges, discs, silicone plugs/members, slings, prolapse mesh and the like. The anti-proliferative agent is delivered with the physical member by coating the physical member, encapsulating the anti-proliferative agent within the physical member or otherwise integrating the anti-proliferative agent into the physical member. Representative antiproliferative agents can include, for example, rapamycin, rapamycin analogs, podophyllotoxin, podophyllotoxin analogs, curcumin, halofliginone and 2-methoxyestradiol. As the antiproliferative agents are delivered locally, the anti-pro liferative agents can be delivered at dosage levels lower than typically necessary for treatment of mature proliferative cells such that immunodeficiency issues and potential toxic consequences often associated with anti- proliferative agents can be at least minimized if not eliminated entirely. In some embodiments, the physical member can perform the additional function of blocking the flow of blood and consequently oxygen to mature proliferative cells to initiate hypoxic and ischemic conditions within the uterine fibroids and to further assist in eliminating and/or preventing growth of uterine fibroids. In some embodiments, the device can further include additional therapeutic agents such as, for example, pain relieving medication, so as to alleviate discomfort associated with treatment of the proliferative condition.

In another aspect of the present disclosure, a minimally invasive device can be delivered intravaginally to deliver one or more anti-proliferative agents for the treatment of uterine proliferative conditions. The minimally invasive device can comprise a physical structure impregnated with, molded with, coated with or otherwise retaining the one or more antiproliferative agents. The minimally invasive device generally comprises a physical device capable of maintaining its position proximate tissue to be treated, In some embodiments, the minimally invasive device can comprise a vaginal ring for placement and retention within the uterus. In some embodiments, the minimally invasive device can comprise a rod-like device having a pointed end to promote insertion into the vaginal wall. In some embodiments, the minimally invasive device can comprise a plurality of microspheres for injection directly into a uterine fibroid or proximate the supply side vascular network of the uterine fibroid. The one or more anti-proliferative agents can include rapamycin, rapamycin analogs, podophyllotoxin, podophyllotoxin analogs, curcumin, halofuginone and 2-methoxyestradiol. Generally, the one or more anti-proliferative drugs are delivered at dosage levels lower than required for the treatment and/or elimination of mature proliferative cells such that potentially damaging or toxic side effects associated with anti-proliferative drugs can be reduced/eliminated. The minimally invasive device can be configured for delivery utilizing minimally invasive introductory devices including, for example, balloon catheters or high-pressure fluid injectors. In some embodiments, the minimally invasive device can restrict blood flow to mature proliferative cells such as fibroids so as to induce hypoxic/ischemic conditions within the mature proliferative cells.

In another aspect of the present disclosure, a device can be delivered transperineally to deliver one or more anti-proliferative agents for the treatment of male proliferative conditions. The minimally invasive device can comprise a physical structure impregnated with, molded with, coated with or otherwise retaining the one or more anti-proliferative agents. The minimally invasive device generally comprises a physical device capable of maintaining its position proximate tissue to be treated.

In another aspect of the present disclosure, a uterine treatment system can comprise an occlusion device including an anti-proliferative agent for positioning in a lumen proximate uterine tissue to be treated or alternatively, within a vascular network supplying proliferative cells. The occlusion device can comprise an occluding stent that is delivered into a suitable lumen such as, for example, a patient's fallopian tubes or uterine artery utilizing a conventional balloon catheter. The occluding stent can be crimped in place over the balloon catheter such that upon inflation of the balloon, the occluding stent is expanded so as to be retained in place within the lumen. The occluding stent can be coated and/or molded with one or more anti-proliferative agents. Representative anti-proliferative agents can include rapamycin, rapamycin analogs, podophyllotoxin, podophyllotoxin analogs, curcumin, halofuginone and 2-methoxyestradiol. Through local delivery of the anti-proliferative agent to the uterine tissue to be treated, the dosage levels of the anti-proliferative agent can be reduced as compared to conventional systemic delivery vehicles such that potential damaging and/or toxic side-effects associated with the use of anti-proliferative agents can be reduced if not eliminated entirely. In some embodiments, the occluding stent can further induce hypoxic/ischemic conditions within proliferative cells to further assist in treating uterine tissue. In another aspect of the present disclosure, a method for treating uterine proliferative conditions can comprise administering locally one or more anti-proliferative agents to treat uterine fibroids. Generally, local administration of the anti-proliferative agent includes positioning a physical member proximate the uterine tissue to be treated. The administration of the one or more anti-proliferative agents can be accomplished by incorporating the one or more anti-proliferative agents into the physical device. Suitable methods can be utilized to incorporate the anti-proliferative agent into the physical device including, for example, coating, encapsulating or otherwise integrating the anti-proliferative agent into the physical device. In some embodiments, the physical member can comprise an occlusive member introduced directly into a lumen proximate the uterine fibroids. In some other embodiments, the physical member can comprise a vaginally introduced member. In some preferred embodiments, administering the anti-proliferative agent can comprise administering reduced dosage levels of the antiproliferative agent than would be typically necessary for systemic delivery, including oral or intravenous delivery of the anti-proliferative agent. In some embodiments, the method can further comprise inducing ischemic/hypoxic conditions within mature proliferative cells by blocking blood and consequently oxygen flow to the proliferative cells with the physical member.

The above summary of the invention is not intended to describe each illustrated embodiment or every implementation of the present invention. The figures and the detailed description that follow more particularly exemplify these embodiments.

Brief Description of the Figures

These as well as other objects and advantages of this invention, will be more completely understood and appreciated by referring to the following more detailed description of the presently preferred exemplary embodiments of the invention in conjunction with the accompanying drawings of which:

Figure 1 is an illustration of a female reproductive system.

Figure 2 is an illustration of a female reproductive system including a plurality of uterine fibroids. Figure 3 is a plan view of an expandable occlusion stent positioned crimped over an inflation balloon of an inflation catheter.

Figure 4 is a plan view of the expandable occlusion stent of Figure 3 inflated to an expanded state through inflation of the inflation balloon.

Figure 5 is a plan view of the expandable occlusion stent of Figure 3 in a cone-like disposition following deflation of the inflation balloon.

Figure 6 is as section view of the expandable occlusion stent of Figure 3 taken at line 6-6 of Figure 5.

Figure 7 is an illustration of an embodiment of a physical device for treatment of uterine proliferative conditions. Figure 8 is an illustration of an embodiment of a physical device for treatment of uterine proliferative conditions.

Figure 9 is a plan view of a clip for treatment of uterine proliferative conditions.

Figure 10 is a section view of the clip of Figure 9 taken at line 10-10 of Figure 9.

Figure 11 is an illustration of embodiments of a physical device for treatment of uterine proliferative conditions.

Figure 12 is an illustration of a female reproductive system including a vaginally introduced device for treatment of uterine proliferative conditions.

Figure 13 is a plan view of a vaginal ring for treatment of uterine proliferative conditions. Figure 14 is a section view of the vaginal ring of Figure 13 taken at line 14-14 of Figure 13 according to an embodiment of the invention.

Figure 15 is a section view of the vaginal ring of Figure 13 taken at line 15-15 of Figure 13 according to an embodiment of the invention. Figure 16 is a chart illustrating effectiveness of an implanted vaginal ring having rapamycin on fibroid tumor growth results for Group I control and test group mice previously implanted with Eker rat leiomyoma (ELT3) cell line cells.

Figure 17 is a chart illustrating effectiveness of an implanted vaginal ring having rapamycin on fibroid tumor growth results for Group II control and test group mice previously implanted with Eker rat leiomyoma (ELT3) cell line cells.

Figure 18 is a chart illustrating effectiveness of an implanted vaginal ring having rapamycin on fibroid tumor growth results for Group III control and test group mice previously implanted with Eker rat leiomyoma (ELT3) cell line cells.

Figure 19 is a photograph visually depicting fibroid tumor size for a non-treated control mouse previously implanted with Eker rat leiomyoma (ELT3) cell line cells.

Figure 20 is a photograph visually depicting fibroid tumor size for a non-treated control mouse previously implanted with Eker iat leiomyoma (ELT3) cell line cells.

Figure 21 is a photograph visually depicting fibroid tumor size for a non-treated control mouse previously implanted with Eker rat leiomyoma (ELT3) cell line cells. Figure 22 is a photograph visually depicting fibroid tumor size for a non- treated control mouse previously implanted with Eker rat leiomyoma (ELT3) cell line cells.

Figure 23 is a photograph visually depicting fibroid tumor size for a locally administered, rapamycin treated test mouse previously implanted with Eker rat leiomyoma (ELT3) cell line cells. Figure 24 is a photograph visually depicting fibroid tumor size for a locally administered, rapamycin treated test mouse previously implanted with Eker rat leiomyoma (ELT3) cell line cells.

Figure 25 is a photograph visually depicting fibroid tumor size for a locally administered, rapamycin treated test mouse previously implanted with Eker rat leiomyoma (ELT3) cell line cells.

Figure 26 is a photograph visually depicting fibroid tumor size for a locally administered, rapamycin treated test mouse previously implanted with Eker rat leiomyoma (ELT3) cell line cells. Figure 27 is a plan view of a vaginally introduced inflation balloon for treatment of uterine proliferative conditions in an insertion disposition.

Figure 28 is a plan view of the vaginally introduced inflation balloon of Figure 27 for treatment of uterine proliferative conditions in an inflated disposition. Figure 29 is an illustration of a female reproductive system including a vaginally introduced device for treatment of proliferative cellular conditions.

Figure 30 is an illustration of a female reproductive system including a vaginally introduced device for treatment of proliferative cellular conditions.

Figure 31 is an illustration of a high pressure fluid injection system. Figure 32 is an illustration of a female reproductive system including a vaginally introduced device for treatment of proliferative cellular conditions.

Figure 33 is a plan view of an insertion rod for treatment of uterine fibroids.

Figure 34 is a section view of the insertion rod of Figure 33 taken at line 34-34 of Figure 33 according to an embodiment of the invention. Figure 35 is a section view of the insertion rod of Figure 33 taken at line 35-35 of Figure

33 according to an embodiment of the invention.

Figure 36 is a chart illustrating fibroid drug screening results for uterine smooth muscle cells (UtSMC) with Rapamycin, Podophyllotoxin, Etoposide, Troglitazone and Rosilitazone at various concentration levels. Figure 37 is a chart illustrating fibroid drug screening results for Eker rat leiomyoma

(ELT3) cell line cells with Rapamycin, Podophyllotoxin, Etoposide, Troglitazone and Rosilitazone at various concentration levels.

Figure 38 is a chart illustrating fibroid drug screening results for uterine smooth muscle cells (UtSMC) with Curcumin, Tranilast, Halofuginone, 2-methoxyestradiol and Sulfasalazine at various concentration levels.

Figure 39 is a chart illustrating fibroid drug screening results for Eker rat leiomyoma (ELT3) cell line cells with Curcumin, Tranilast, Halofuginone, 2-methoxyestradiol and Sulfasalazine at various concentration levels.

Figure 40 is a chart illustrating Day 1 cellular viability results for uterine smooth muscle cells (UtSMC) and human leiomyoma (GMl 096) cell line cells treated with Wortmannin, Tyrphostin, Rapamycin and Reveromycin A.

Figure 41 is a chart illustrating Day 4 cellular viability results for uterine smooth muscle cells (UtSMC) and human leiomyoma (GMl 096) cell line cells treated with Wortmannin, Tyrphostin, Rapamycin and Reveromycin A. Figυre 42 is a chart illustrating Day 7 cellular viability results for uterine smooth muscle cells (UtSMC) and human leiomyoma (GMl 096) cell line cells treated with Wortmannin, Tyrphostin, Rapamycin and Reveromycin A.

Figure 43 is a chart illustrating Day 14 cellular viability results for uterine smooth muscle cells (UtSMC) and human leiomyoma (GM1096) cell line cells treated with Wortmannin, Tyrphostin, Rapamycin and Reveromycin A.

Figure 44 is a graph illustrating Rapamycin release data for an embodiment of a Drug Eluting Intravaginal Ring.

Figure 45 is a graph illustrating Rapamycin release kinetics for an embodiment of a Drug Eluting Intravaginal Ring.

Figure 46 is a graph illustrating Rapamycin release data for an embodiment of a Drug Eluting Intravaginal Ring.

Figure 47 is a graph illustrating Rapamycin release kinetics for an embodiment of a Drug Eluting Intravaginal Ring. Figure 48 is a chart illustrating synergistic effects of combinations of two antiproliferative agents at lower concentration levels than the normal effective doses for the Eker rat leiomyoma (ELT3) cell line cells.

Detailed Description of the Disclosure The present disclosure is directed to a device for the treatment of pelvic proliferative conditions. As described throughout the following detailed description, the device can provide for treatment of female pelvic proliferative conditions including, for example, uterine fibroids, abnormal uterine bleeding, pelvic adhesions, endometriosis and the like. It is to be understood that various described embodiments will find similar application with male pelvic proliferative conditions including, for example, proliferative cells located within prostate or testes tissue.

As illustrated generally in Figure 1, a female reproductive tract 100 generally comprises uterus 102, fallopian tubes 104a, 104b, ovaries 106a, 106b, cervix 108 and vagina 110. The uterus 102 defines a uterine cavity 112 connecting the vagina 110 with fallopian tubes 104a, 104b, thus allowing for the passage and fertilization of female reproductive cells. The uterus 102 is generally defined by a uterine wall 1 14 having an outer membrane or myometrium 116 and an inner membrane or endometrium 118.

Referring to Figure 2, female reproductive tract 100 is again illustrated with the further inclusion of mature proliferative cells, herein depicted as a plurality of uterine fibroids 120. Generally uterine fibroids 120 are distinguished relative to their positioning with respect to the uterine wall 1 14. For example, uterine fibroid 120a is generally referred to an intramural uterine fibroid and is positioned within the myometrium 116 which can distort the contour of uterine cavity 112. Uterine fibroid 120b is referred to as a subserosal uterine fibroid and is positioned just under the uterine serosa and may be attached to the corpus. Uterine fibroid 120c is referred to as a submucosal uterine fibroid and is located within the myometrium 1 16 and proximate the endometrium 118 thereby causing the endometrium 118 to bulge into uterine cavity 112. Uterine fibroids 12Od and 12Oe are referred to as pedunculated uterine fibroids with uterine fibroid 12Od extending into the uterine cavity 1 12 while uterine fibroid 12Oe extends into available space outside the myometrium 116. Uterine fibroids 120 generally comprise well circumscribed, solid and typically benign fibroid masses composed of smooth muscle cells and collagen. Uterine fibroids 120 receive nourishment through a discrete vascular network 124 including veins and arteries that extends from myometrium 116.

According to the present invention, treatment of mature proliferative cells, i.e., uterine fibroids 120, is accomplished through local delivery of one or more antiproliferative agents to prevent further growth and even shrink the size of uterine fibroids 120 as opposed to physical removal of uterine fibroids 120. In order to deliver the antiproliferative agents locally, a physical device is fabricated capable of remaining positioned proximate the uterine fibroids 120 that are to be targeted. The physical device includes the antiproliferative agent for administration over an extended period of time so as to prevent further growth and shrink the uterine fibroids 120. Generally, the anti -proliferative agent is coated, encapsulated or otherwise integrated with the physical device. By targeting uterine fibroids 120 with localized delivery of the antiproliferative agent, dosage levels conventionally associated with systemic delivery methods such as, for example, oral or intravenous introduction, can be substantially reduced to reduce or otherwise eliminate potential side effects and toxic consequences commonly experienced with the use of antiproliferative agents. In some embodiments, the physical device can provide the dual function of targeting and limiting blood supply and consequently, oxygen to uterine fibroids 120 so as to induce hypoxic/ischemic conditions within the uterine fibroids 120. By reducing or eliminating oxygen to the uterine fibroids 120, the mature proliferative cells are effectively killed and recurrence of uterine fibroids 120 is prevented. In one representative embodiment, the anti-proliferative agent comprises one or more of rapamycin or rapamycin analogs. Additionally, representative anti-proliferative agents can include, for purposes of example, podophyllotoxin, podophyllotoxin analogs, curcumin, halofuginone and 2-methoxyestradiol. Used individually or in combination, these antiproliferative agents generally function to prevent the proliferation of smooth muscle cells and can shrink mature fibroids by killing mature smooth muscle cells. In addition to preventing proliferation of smooth muscle cells, these anti-proliferative agents can provide additional beneficial mechanisms such as, for example, acting in an anti-inflammatory or anti-angio genie capacity. In addition, anti-fibrosis agents such as Tranilast and halofuginone can be used in combination with other anti-proliferative agents since uterine fibroids also consist of collagen.

In some embodiments of the present invention, the physical device can be deployed to be in direct contact with the vascular network 124 supplying the proliferative cells. In this manner, the physical device releases anti-proliferative agents directly into the vascular network 124 for delivery to the proliferative cells. As will be described in detail below, the physical device can comprise a variety of configurations including a stent for placement into the vascular network 124 and an external restricting member such as, for example, a clamp, a suture and a constricting band or clip. Depending upon the configuration of the physical device, the physical device not only delivers the anti-proliferative agents but also interacts directly with the vascular network 124 to limit blood flow, and consequently, oxygen flow to the proliferative cells to initiate hypoxic/ischemic conditions within the proliferative cells.

As illustrated in Figure 3, a representative physical device can include an occluding stent 200. Occluding stent 200 generally comprises an expandable body 202 defining a lumen 204. Expandable body 202 can comprise suitable materials including, for example, stainless steel, tantalum, MP35, iridium-titanium alloys and similar. Occluding stent can also be fabricated from biodegradable polymers. Examples of biodegradable polymers include polylactide (PLA), polylactide-co-glicolide (PLGA)₅ polycaprolactone (PCL), polyarylates, polybutyrate. Occluding stent 200 can be crimped in place over a conventional balloon catheter 206 such that occluding stent 200 assumes a crimped state 207 having approximately 2/3 of the length of expandable body 202 residing over an inflatable balloon 208. In crimped state 207, occluding stent 200 can be steerably directed to a desired location in vascular network 124. Confirmation of the placement of occluding stent 200 can be accomplished utilizing a suitable medical imaging technology including, for example, computer axial tomography (CAT), magnetic resonance imaging (MRI), or transrectal ultrasound (TRUS). Alternatively, occluding stent 200 can comprise designs and methods as taught in U.S. Patent No. 7,073,504 and U.S. Patent Publication No. 2005/0045183Al, both of which are commonly owned by the assignee of the present application, American Medical Systems of Minnetonka, MN, and both of which are herein incorporated by reference in their entirety.

Once occluding stent 200 is positioned, inflatable balloon 208 is inflated such that the portion of the expandable body 202 residing over inflatable balloon 208 is expanded such that occluding stent 200 assumes an expanded state 210 as shown in Figure 4. As inflatable balloon 208 is subsequently deflated, occluding stent 200 assumes a deployed state 212 in which, the portion of expandable body 202 residing over the inflatable balloon 208 contracts slightly from expanded state 210 as shown in Figure 5. Following deflation of inflation balloon 208, balloon catheter 206 can be withdrawn which leaving occluding stent 200 retained in place within the vascular network 124.

One or more anti-proliferative agents 216 can be coated to expandable body 202 utilizing a variety of suitable processes including, for example, spraying, dipping, molding and the like. Preferably, the one or more anti-proliferative agents are coated to the occlusion stent 200 such that the one or more anti-proliferative agents can be dissolved and delivered to any non-mature proliferative cells that have commenced growth and proliferation initiated by exposure to the hypoxic/ischemic conditions induced with occlusion stent 200. Generally, the anti-proliferative agents are delivered to the non-mature proliferative cells at a substantially reduced dosage level than that necessary for treatment of mature proliferative cells. In some embodiments, the anti- proliferative agents can be administered at a dosage level of only a few hundred micrograms per day. As many of the anti-proliferative agents contemplated for use in shrinking or otherwise eliminating uterine fibroids 120 are extremely potent and in some cases, toxic, delivery of small doses over an extended period of time comprises a preferred method of administration.

In one representative embodiment, a 360° film can be formed surrounding occlusion stent 200. Occlusion stent 200 can be mounted upon a mandrel such that the occlusion stent 200 can be dipped into a polymer solution. The polymer solution can include the one or more antiproliferative agents dissolved within a solvent. Following one or more dips of the occlusion stent 200 into the polymer solution, expandable body 202 is essentially encased within a coating comprising the solvent and one or more anti-proliferative agents. The solvent can be subsequently evaporated leaving the one or more anti-proliferative agents coated to the expandable body 202.

In another representative embodiment, a similar dip-style process can be utilized in which the polymer solution includes a suitable porogen, preferably a water-soluble porogen. Following formation of a coating on the expandable body 202, the occlusion stent 202 can be dried, followed by immersion of the occlusion stent 202 in an aqueous solution to extract the porogen from the coating. Upon extraction of the porogen, occlusion stent 202 generally includes a porous film having interconnecting channels. The one or more anti-proliferative agents can be dissolved in a solvent that will not dissolve the porous film and the occlusion stent can be immersed within the solvent. The occlusion stent 202 can then be removed and the solvent evaporated so as to leave behind the one or more antiproliferative agents filling the porous film.

As illustrated in Figure 5, deployed state 212 can result in occluding stent 200 having a generally cone-shaped disposition 214 in which the portion of the expandable body 202 previously residing over inflatable body 208 has been expanded to essentially match the diameter of the vessel wall as shown in Figure 6 while the portion of the expandable body that previously extended beyond inflatable body 208 remains at the diameter of crimped state 207. Cone-shaped disposition 214 causes the diameter of lumen 204 to narrow as blood flows through the occluding stent 200. With cone-shaped disposition 214, not only are the one or more anti- proliferative agents 216 delivered to uterine fibroid 120 but also the blood flow is reduced and consequently, the oxygen supply to uterine fibroid 120 is substantially reduced and/or eliminated. Upon inflicting hypoxic/ischemic conditions within uterine fibroid 120, the mature proliferative cells comprising uterine fibroid 120 suffer cellular death such that the now dead fibroid mass can be biologically resorbed by the body. As illustrated in Figures 8, 9 and 10, a clamp 250 can be positioned and clamped over the vascular network 124, and more specifically, the uterine artery. Clamp 250 can comprise a one- piece body 252 having a hinge member 254 and a clasp member 256. Alternatively, clamp 250 can comprise a two-piece design having a pair of clasping ends for snapping the clamp 250 into position over the uterine artery. Inner surfaces 258 of clamp 250 can be coated or layered with one or more suitable antiproliferative agents 260 for diffusion through the vascular wall and into the bloodstream wherein the anti-proliferative agent is delivered to proliferative cells to prevent further growth and shrink the proliferative cells. Depending upon the design of hinge member 254, clamp 250 can further serve to limit blood flow to the fibroids 120. If hinge member 254 is of sufficient strength, clamp 250 can restrict blood flow to the fibroids 120, thereby initiating hypoxic/ischemic conditions which can further contribute to the treatment of the proliferative cells.

Referring to Figure 11, a coated suture 260 or constricting band 262 can be deployed over the vascular network 124 and more specifically, the uterine artery in a similar manner as clamp 250. Coated suture 260 can comprise a length of conventional suture material being coated with one or more suitable anti-proliferative agents while constricting band 262 can include a coating or layer on an inner surface of the constricting band. The coated suture 260 and constricting band 262 can both be tightened around the vasculature as desired to for positioning relative to the proliferative cells and to allow the one or more anti-proliferative agents to diffuse through the vascular wall and enter the blood stream. In this manner, the anti- proliferative agents are delivered directly to the proliferative cell to prevent further grown and to shrink the proliferative cells. In some embodiments, the coated suture 260 and constricting band 262 can be tightened about the vasculature to restrict blood flow to the uterine fibroids 120 so as to induce hypoxic/ischemic conditions within the mature proliferative cells. In addition to the localized delivery of anti-proliferative agents to uterine proliferative tissue by directly accessing the vascular network 124, some representative embodiments of the present invention can be positioned directly against the vaginal wall 111 such that antiproliferative agents can diffuse through the vaginal wall 111 and into the vascular network 124. Generally, the delivery mechanism can take the form of a coating or layer one or more anti- proliferative agents applied to the physical device. In some alternative embodiments, the delivery mechanism can take the form of an injection or similar dispensing mechanism whereby the one or more anti-proliferative agents can be delivered directly into the uterine proliferative tissue or alternatively, can be delivered to a region proximate the vascular network 124 for subsequent diffusion into the blood stream. In some embodiments, the physical device can be configured for vaginal deployment in a manner that applies pressure directly against the vaginal wall 11 1. In this minimally invasive manner, not only does the physical device allow for diffusion of the one or more anti-proliferative agents but also the pressure applied to the vaginal wall 111 can serve to physically occlude the vascular network 124 so as to initiate hypoxic/ischemic conditions within uterine proliferative cells. As illustrated in Figure 12, a vaginally introduced device 300 can be placed within vagina

110 or uterus 102 such that one or more anti-proliferative agents diffuses from the vaginally introduced device 300 and is absorbed through vaginal wall 111. Once the one or more antiproliferative agents have been absorbed, vascular network 124 delivers the one or more antiproliferative agents to the uterine proliferative cells so as to prevent further growth and shrink the proliferative cells.

As illustrated in Figures 13 and 14, vaginally introduced device 300 can comprise a vaginal ring 302 designed to reside against the cervix 108 and press outwardly against the vaginal wall 111. Alternatively, the vaginal ring 302 is designed to reside on top of, near and/or about the fibroid. In addition, an IUD may also be placed in the cervix having the antiproliferative agent thereon or somewhere therein. Vaginal ring 302 generally comprises a ring wall 304 having an internal ring 306 surrounded by a ring coating 308. In some embodiments, internal ring 306 can comprise a non-absorbable polymer such as, for example, Silicone Elastomer VIII available from Nusil Technology, LLC of Carpinteria, California. Alternatively, internal ring 306 can comprise a non-absorbable polymer having one or more antiproliferative agents molded there within. In some embodiments, ring coating 308 can comprise a coating material including a polymer such as, for example, MED 4820 with one or more antiproliferative agents. Alternatively, ring coating 308 can comprise a porous polymeric coating acting as a rate controlling membrane for administering one or more antiproliferative agents molded with the internal ring 106. Various representative compositions of vaginal ring 302 are described in Table 1 below.

Table 1 : Representative Compositions for Vaginal Ring 302

Referring to Figure 15, an alternative embodiment of vaginal ring 302 can comprise a single ring 310 lacking either a coating or internal ring but further including one or more antiproliferative agents in the form of a plurality of antiproliferative particles 312, Antiproliferative particles 312 can comprise particles of one or more of rapamycin and rapamycin analogs. Alternatively, antiproliferative particles 312 can comprise podophyllotoxin, podophyllotoxin analogs, curcumin, halofuginone and 2-methoxyestradiol. For example, single ring 310 can comprise a matrix design with 5% by weight rapamycin loading in MED4820.

To illustrate the effectiveness of the disclosed devices and methods, the vaginal ring embodiment was animal tested to test the efficacy of a localized, controlled release of antiproliferative agents to reduce the size of uterine fibroid (leiomyoma) formation in nude mice. The subject size comprised forty eight, 8-10 week-old, female mice. Each mouse was implanted with the leiomyoma-derived cell line, ELT-3, that produce tumors with a short latency when injected in nude mice. The forty eight mice were divided into three groups and cell suspensions in either medium (serum free DF8 medium) or Matrigel were prepared at the concentrations indicated in Table 2 below.

Table 2: Group Information for Anti-Proliferative Testing of Female Mice

200 μL of the indicated cell preparations were injected subcutaneously above each hip. Five to 9 days before inoculation, the mice were anesthetized and implanted with pellets of 17-β estradiol (one 1.7 mg 60-day release tablets in each mouse, Innovative Research, Sarasota, FL). The estradiol pellet was implanted subcutaneously in the interscapular area. The pellet was implanted using either a Trocar or surgically placed in a pocket formed between the skin and the muscle. Fresh pellets were implanted 8 weeks after initial implantation.

Following implantation, the mice were recovered, and observed weekly post-injection for tumor formation. Resulting tumors were measured (length x width) weekly with a calibrated caliper. Formation of tumors were observed weekly for up to 13 weeks or when the tumors grow to a diameter of approximately 0.75-1.0 cm. At that time, ring 302 was implanted into half the mice to test its ability to reduce tumor size through the controlled release of the antiproliferative agent rapamycin, with the remaining mice receiving a control consisting of the ring 302 absent the rapamycin. The ring 302 was implanted by surgical subcutaneous implantation alongside, on top of or around the tumor. Tumors were measured (length x width) weekly with a calibrated caliper for an additional 10 weeks. At 23 weeks, the mice were humanely euthanized, tumors observed, measured and removed and placed in 10% formalin for histopathology processing and the ring 302 was retrieved for determination of the remainder of drug in the device.

Under the conditions of this testing, the cell line did form unencapsulated malignant spindle cell tumors at the injection site of all the test and control mice examined microscopically. When the ring 302 was implanted onto the malignant tumors induced by the Eker Rat Leiomyoma Cell Line, there were larger amounts of ovoid/round cells, pleomorphism, anisokaryosis, bizarre nuclei, necrosis, hemorrhage, and mast cells in the control masses, and larger amounts of fibrosis and vascularization in the test masses. It is believed that the control masses had larger amounts of changes in the cells, nuclei and overall tumor elements because these masses were not treated with the rapamycin as the test masses were. An increase in the amount of fibrosis and vascularization in the test masses was likely found because these masses were treated and these reactions were secondary to the treatment with the rapamycin. No microscopic lesions were found in the uterine tissue that could be attributed to the test material. Changes found in the reproductive organs of the mice were considered secondary to the normal estrus cycle of females.

Results illustrating the effectiveness of localized, controlled release of rapamycin with ring 302 for Groups 1, 2 and 3 are contained in Figures 16, 17 and 18 respectively. As illustrated, the size of the measured tumors decreased from their initial sized in each test group following implantation of ring 302, and consequently, following the localized absorption/diffusion of rapamycin into the tumors while tumor size continued to increase for the control group. While subsequent tumor size did increase after Week 1 for the test Group 1 mice, after Week 3 for test Group 2 mice and after Week 2 for Group 3 mice, the tumors size remained less than all of the corresponding control group mice. The later increase in tumor size for the test groups can be attributed to the rapamycin being depleted faster than expected in some mice. The depletion of the rapamycin and resulting loss of efficacy can be addressed in a variety of ways including increasing the initial localized doses, fine tuning of the release duration of the ring 302 to release over a longer period of time or by providing a release system having a bolus release at a beginning stage and then a subsequent slower release above the inhibition level for an extended period of time. In addition, implantation of an additional ring 302 at a time subsequent to the original implantation can also be used to prevent later tumor growth. Overall, the results indicate that localized, controlled delivery of an anti-proliferative agent such as rapamycin is an effective treatment for uterine fibroids. For purposes of illustration, random photographs for individual mice illustrating the difference in tumor size and growth between control mice are shown in Figures 19, 20, 21 and 22 whereas test mice receiving rapamycin by way of ring 302 are shown in Figures 23, 24, 25 and 26.

As illustrated in Figures 27, 28 and 29, another alternative embodiment of vaginally introduced device 300 can comprise an inflation balloon 320 operably mounted over a catheter 322. Inflation balloon 320 generally comprises an inflatable body 324 capable of inflating from a non-deployed insertion disposition 326 to a fully deployed occlusion disposition 328 using a suitable inflation fluid. When inflation balloon 320 is in fully inflated disposition 328, inflatable body 324 presses outwards against the endometrium 118. Inflation balloon 320 further comprises an external coating 330 or layer of an antiproliferative agent such as rapamycin that diffuses through the endometrium 118 and into the vascular network 124 or alternatively, directly into uterine fibroids 120 that are in physical contact with the inflatable body 324. The anti-proliferative agent disrupts and/or eliminates any growth of the proliferative cells. In some embodiments, inflation balloon 320 in the fully inflated disposition 328 can sufficiently press against the endometrium 118 so as to at least partially occlude the vascular network 124. With vascular network 124 occluded, hypoxic/ischemic conditions can be introduced to fibroids 120 to further assist with shrinking or otherwise killing the proliferative cells.

In some alternative embodiments, inflation balloon 320 and catheter 322 can be used in combination with a high-pressure fluid injection system 400 as shown in Figure 30 to deliver one or more anti-proliferative agents through the endometrium 118 for absorption into the vascular network 124 or directly into the uterine fibroid 120. A representative high-pressure fluid injection system is illustrated generally in Figure 31 and can comprise systems as described in International Publication No. 2007/079152A2 and commercially available from American Medical Systems of Minnetonka, MN. Generally, high-pressure fluid injection system 400 can comprise an injector 402 and an applicator lumen 404. Injector 402 can comprise a manually activated syringe 401 or alternatively, an automated injector 403 including a user interface 406 and a connector member 408. User interface 406 can comprise an input means for selectively delivering one or more therapeutic agents in the form of a pressurized fluid through the connector member 408. Representative input means can include foot pedal 407, switches, buttons or a touch-screen capable of receiving touch commands as well as displaying system information including a mode of operation as well as operating parameters.

Referring to Figure 31, applicator lumen 404 can comprise a non-metal, polymeric tube like device 412 having a proximal attachment end 414 and a distal treatment end 416. Non- metal, polymeric tube like device 412 has a tube length of sufficient length to allow distal treatment end 416 to be advanced past a distal tip 332 of catheter 322. Non-metal, polymeric tube like device 412 is generally formed so as to have a burst strength of at least about 2,000 psi. In a preferred embodiment, the non-metal, polymeric tube like device 412 is formed to have a burst strength ranging from about 2,000 psi to about 5,000 psi. In one representative embodiment, non-metal, polymeric tube like device 412 is formed of a single high strength polymer such as, for example, a polyimide, polyetherimide available from General Electric under the trade name Ultem® and linear aromatic polymers such as PEEK™ available from Victrex pic. Alternatively, the non-metal, polymeric tube like device 412 can be formed from a reinforced polymer that is reinforced with materials such as, for example, nano-particles, clays or glass. In another embodiment, the non-metal, polymeric tube like device 412 is reinforced with a polymeric material such as, for example, a Kevlar, carbon or other suitable high strength polymeric fiber braided within the non-metal, polymeric tube like device 412. Generally, the non-metal, polymeric tube like device 412 is extruded though other appropriate fabrication methods including molding can be utilized as well.

As illustrated in Figure 30, non-metal, polymeric tube like device 412 can be configured to deliver the one or more anti -proliferative agents to a desired location within female reproductive tract 100. Distal treatment end 416 is generally advanced through the catheter 322 and past the distal tip 332 to gain access to the uterine cavity 1 12 as desired. In positioning the non-metal polymeric tube-like device 412 at a desired treatment location, it will be understood that a medical professional frequently employs a medical imaging system such as, for example, computer axial tomography (CAT), magnetic resonance imaging (MRI), or transrectal ultrasound (TRUS) so as to achieve the desired position of an administration orifice 418. Through the use of a medical imaging system, a medical professional can verify that administration orifice 418 is arranged for injection of the one or more therapeutic fluids at the desired treatment location.

Once the distal treatment end 416, and more specifically, the administration orifice 418 is positioned with respect to the desired treatment location, the injector 402 can be actuated so as to begin delivery of the one or more antiproliferative agents. Generally, injector 402 directs the one or more anti -proliferative agents through the non-metal, polymeric tube-like device 412 at low velocities and high pressures generally between about 2,000 psi to about 5,000 psi. The high pressures supplied by the injector 402 are necessary due to the pressure losses experienced in the relatively, small diameter non-metal, polymeric tube like device 412. As the one or more antiproliferative agents reaches distal treatment end 416, the one or more antiproliferative agents are rapidly accelerated through the administration orifice 418 to form a fluid jet 420. Using fluid jet 420, the one or more antiproliferative agents can be controllably dispensed directly through the vaginal wall 111, uterine wall 114 or into uterine fibroid 120 so as to reduce the potential for exposure to other non- desired areas. As the fluid jet 420 moves away from the administration orifice 418, the velocity and pressure of fluid jet 420 rapidly decreases.

In utilizing high-pressure fluid injection system 400, the one or more anti-proliferative agents can comprise suitable liquid solutions or alternatively, the one or more anti-proliferative agents can comprise micropsheres or nanopsheres of encapsulated anti-proliferative agent 430 capable of being transported within a suitable carrier fluid. Generally, encapsulated antiproliferative agent 430 comprises one or more liquid or gel-based agents retained surrounded by a bioabsorbable shell. The bioabsorbable shell can comprise a suitable bioabsorbable material selected so as to avoid degradation and within carrier fluid. Representative bioabsorbable materials can include, for example, PLGA, PLA, PCl, polyhydroxybutyrate, polyorthoesters, polyoxyethylenes and copolymers of these.

In some alternative embodiments, inflation balloon 320 and catheter 322 can be used in combination with an insertion rod 500 to deliver one or more antiproliferative agents into the fibroid 120 or vascular network 124 as shown in Figure 32. Referring to Figure 33, insertion rod 500 can comprise a generally cylindrical body 502 having an introduction end 504 configured to have a pointed or otherwise sharpened tip 506. Cylindrical body 502 preferably comprises a molded, polymeric article. In some embodiments, cylindrical body 502 can be formed with solid biodegradable polymers such as PLGA, PLA, PCL and similar with anti-proliferative agents. In some embodiments, anti-fϊbrotic and/or therapeutic agents can be utilized in conjunction with the anti-proliferative agents and otherwise incorporated into the polymer matrix. The percent of drug incorporated can be range from 1% to 50% preferably from 5% to 30%.. In some embodiments, cylindrical body 502 can comprise a porous structure for retaining one or more therapeutic agents in the form of drug particles 508 including anti-proliferative agents as shown in Figure 34. Alternatively, cylindrical body 502 can comprise an inner body member 510 and exterior coating 512 of anti-proliferative agents as shown in Figure 35. In some embodiments, inner body member 510 can comprise a solid polymeric structure with exterior coating 512 including the one or more anti-proliferative agents. Alternatively, inner body member 510 can include one or more anti-proliferative agents with exterior coating 512 comprising a polymer barrier membrane for controlling the release rate of the one or more anti-proliferative agents. Generally, catheter 322 is slidably advanced into the uterine cavity 112 as previously described. Inflation balloon 320 is then inflated into inflated disposition 328 such that the inflation balloon is in contact with the endometrium 118. Insertion rod 500 can then be positioned with tip 506 proximate vaginal wall 111 or endometrium 118 such that a pushing or penetrating instrument can deliver the introduction end 504 through the vaginal wall 111 or endometrium 1 18 as shown in Figure 32. With insertion rod 500 positioned within the uterine wall 1 14, the one or more anti-proliferative agents as well as any additional anti-fibrotic or other therapeutic agents can be absorbed into the vasculature network 124 for delivery to uterine fibroid 120. In addition, the pressure applied against endometrium 118 by the inflation balloon 120 can cause the vascular network 124 to be at least partially occluded or otherwise restricted so as to induce hypoxic/ischemic conditions within uterine fibroid 120.

As discussed previously, various embodiments of the physical device can be utilized in treating male pelvic proliferative conditions such as, for example, the presence of proliferative cells in the prostate or testes. In treating male patients, the proliferative cells can be accessed transperineally for local delivery of one or more anti-proliferative agents for the treatment of male proliferative conditions. The minimally invasive device can comprise a physical structure impregnated with, molded with, coated with or otherwise retaining the one or more antiproliferative agents. The minimally invasive device generally comprises a physical device capable of maintaining its position proximate tissue to be treated. The physical device can take the form of previously described devices or alternatively, meshes and slings as taught by U.S. Patent Publication Nos. 2002/0161382A1 and 2004/0039453A1 as well as U.S. Patent No. 6,911,003, all of which are commonly assigned to the assignee of the present application, American Medical Systems of Minnetonka, MN, and all of which are herein incorporated by reference in their entirety.

Referring now to Figures 36, 37, 38 and 39, laboratory drug screening results for treatment of uterine smooth muscle cells (UtSMC) and Eker rat leiomyoma (ELT3) cell line cells are illustrated. Referring to Figures 36 and 37, Day 1 and Day 5 testing results are displayed for Rapamycin, Podophyllotoxin, Etoposide, Troglitazone and Rosilitazone at various concentration levels. Figures 38 and 39 similarly display Day 1 and Day 5 testing results for Curcumin, Tranilast, Halofuginone, 2-methoxyestradiol and Sulfasalazine at various concentrations. In Figures 39-39 the effect of the various therapeutic agents on the Average OD of the cells is compared to growth of the cells alone absent the administration of the therapeutic agent.

In Figures 40, 41, 42 and 43, laboratory cell viability testing results for uterine smooth muscle cells (UtSMC) and Eker rat leiomyoma (ELT3) cell line cells are illustrated. The charts illustrate percent viability at Day 1 (Figure 40), Day 4 (Figure 41), Day 7 (Figure 42) and Day 14

(Figure 43) at various administration levels of Wortmannin, Tyrphostin, Rapamycin and

Reveromycin A in comparison to control cells absent the administration of the therapeutic agent.

In Figures 44, 45, 46 and 47, drug release properties for a drug eluting intravaginal ring are illustrated. The intravaginal ring can comprise a design similar to that previously disclosed as ring 302. The data points in Figures 44 and 45 correspond with the compositions previously disclosed with Examples 1, 2 and 3 of Table 1 above while the data points in Figures 46 and 47 correspond with the compositions previously disclosed with Examples 4, 5 and 6 of Table 1. Figure 48 illustrates the synergistic effect of combination of two anti-proliferative agents at lower concentration levels than the normal effective doses for the ELT-3 cell line. By providing for lower concentration levels of anti-proliferative agents, the combinations minimize the adverse or toxic effects resulting from higher concentrations of anti-proliferative agents associated with individual use of a single anti-proliferative agent, or through a systemic delivery of the anti-proliferative agents as opposed to localized delivery.

While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiments, it will be apparent to those of ordinary skill in the art that the invention is not to be limited to the disclosed embodiments. It will be readily apparent to those of ordinary skill in the art that many modifications and equivalent arrangements can be made thereof without departing from the spirit and scope of the present disclosure, such scope to be accorded the broadest interpretation of the appended claims so as to encompass all equivalent structures and products.

Claims

CLAIMSWhat is claimed is:

1. A method for treating pathologic proliferative conditions of uterine tissue comprising: identifying a location of uterine proliferative cells; and delivering an antiproliferative agent locally to the location of uterine proliferative cells so as to inhibit further development of the uterine proliferative cells and shrink a tumor size of the uterine proliferative cells.

2. The method of claim 1, wherein delivering the antiproliferative agent locally to the location of uterine proliferative cells comprises placing a physical device near a uterine artery supplying blood flow to the uterine proliferative cells.

3. The method of claim 2, further comprising: removing the physical device following treatment of the uterine proliferative cells.

4. The method of claim 2, wherein the physical device comprises a vaginal ring including the anti-proliferative agent in the form of rapamycin or a rapamycin analog.

5. The method of claim 1, wherein the anti-proliferative agent comprises rapamycin or a rapamycin analog.

6. The method of claim 1, wherein the anti-proliferative agent is selected from the group consisting of: podophyllotoxin, podophyllotoxin analogs, curcumin, halofuginone and 2- methoxyestradiol.

7. The method of claim 1, wherein the uterine proliferative cells are representative of a proliferative condition selected from the group consisting of: uterine fibroids, abnormal uterine bleeding, pelvic adhesions and endometriosis

8. A system for the treatment of pathologic proliferative condtions of uterine tissue comprising: an implantable device including an anti-proliferative treatment agent for introduction into uterine proliferative cells; and an introduction member for positioning the implantable device locally to the uterine proliferative cells.

9. The system of claim 8, wherein the implantable device comprises a restricting member for placement over a uterine artery, wherein the restricting member is fabricated to include the antiproliferative treatment agent such that the anti-proliferative treatment agent is readily absorbed through the uterine artery and into the bloodflow supplying the uterine proliferative cells.

10. The system of claim 8, wherein the implantable device comprises a vaginally introduced device including an exterior application of the anti-proliferative treatment agent.

11. The system of claim 10, wherein the exterior application of the anti-proliferative treatment agent provides for direct physical contact of the anti-proliferative treatment agent with the uterine proliferative cells such the anti-proliferative treatment agent is absorbed directly into the uterine proliferative cells.

12. The system of claim 10, wherein the exterior application of the anti-proliferative treatment agent provides for direct physical contact of the anti-proliferative treatment agent with the uterine or vaginal wall such that the anti-proliferative treatment agent is absorbed through the uterine or vaginal wall and into the uterine artery for transport to the uterine proliferative cells.

13. The system of claim 8, wherein the implantable device is selected from the group consisting of: an inflation balloon, an IUD and a vaginal ring.

14. The system of claim 8, wherein the anti-proliferative treatment agent is rapamycin or a rapamycin analog.

15. The system of claim 8, wherein the anti-proliferative treatment agent is selected from the group consisting of: podophyllotoxin, podophyllotoxin analogs, curcumin, halofuginone and 2- methoxyestradiol.

16. The system of claim 8, wherein the uterine proliferative cells are representative of a proliferative condition selected from the group consisting of: uterine fibroids, abnormal uterine bleeding, pelvic adhesions and endometriosis.

17. A system for the treatment of pathologic proliferative conditions involving pelvic tissue comprising: an implantable device including an anti-pro liferative treatment agent for introduction into pelvic proliferative cells; and an introduction member for positioning the implantable device locally to the pelvic proliferative cells.

18. The system of claim 17, wherein the pelvic proliferative cells include male pelvic proliferative cells.

19. The system of claim 18, wherein the male pelvic proliferative cells are located in pelvic tissue including testes tissue or prostate tissue.