RELATED APPLICATION/S

This application claims the benefit of priority of U.S. Provisional Patent Application No. 62/664,300 filed on April 30, 2018, the contents of which are incorporated herein by reference in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to a device for delivering an agent to a body cavity or tissues adjacent thereto. Embodiments of the present invention relate to an intrauterine device for delivering an agent to the uterus and/or surrounding tissues such as the vaginal canal.

Drugs have long been used to treat diseases and extend lives. Drugs can be delivered locally or systemically with the efficacy of the drug being directly related to the way its formulated and delivered.

Systemic delivery methods such as oral, intravenous, intramuscular, and transdermal are effective but can produce undesirable side effects due to systemic exposure and may result in a less than optimal quantity of a drug at the desired treatment site.

Local drug delivery via, for example a local injection, addresses this limitation of systemic delivery but can be difficult to carry out especially in cases where the targeted tissue is deep within the body and/or the treatment regimen requires more than a single administration.

Various drug delivery devices have been developed in order to address these limitations of systemic and local delivery. Such devices are implanted in the body or positioned within body cavities to deliver a drug locally over a period of days or months.

Although such devices can be used for local drug delivery, long term use thereof can lead to discomfort and result in poor compliance.

SUMMARY OF THE INVENTION

According to one aspect of the present invention there is provided a device for delivering an agent into a body cavity comprising a strand capable of self-forming a three dimensional anchor having a first loop approximately perpendicular to, and positioned through, a second loop; and a delivery conduit attached to, or forming a part of, the strand, the delivery conduit being for delivering the agent into the body cavity from outside the body when the three dimensional anchor is in the body cavity. According to an embodiment of the present invention the body cavity is the uterus and the strand is selected such that the three dimensional anchor is capable of elastically compressing in response to contraction of the uterus.

According to an embodiment of the present invention the strand is composed of Nitinol wire having a diameter of 0.3-0.5 mm.

According to an embodiment of the present invention a distal end portion of the delivery tube is positioned over at least a portion of the strand.

According to an embodiment of the present invention a distal end portion of the delivery tube is molded over at least a portion of the strand.

According to an embodiment of the present invention a distal end portion of the delivery tube includes at least one opening for delivering the agent.

According to an embodiment of the present invention the strand is at least partially hollow and the delivery conduit forms a part of the strand.

According to an embodiment of the present invention n the strand is composed of an elastic polymer.

According to an embodiment of the present invention the at least one opening is positioned within or adjacent to the three dimensional anchor.

According to an embodiment of the present invention the device further comprises a reservoir filled with the agent in fluid communication with the delivery conduit.

According to an embodiment of the present invention n the agent is selected from the group consisting of at least one hormone, an antineoplastic, an analgesic, an antibiotic, a stimulant, an ablative agent and a contraceptive.

According to an embodiment of the present invention the at least one hormone is selected from the group consisting of estrogen, progesterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH), Human chorionic gonadotropin (HCG).

According to an embodiment of the present invention the strand is formed from Nitinol and the delivery tube is formed from a polymer.

According to an embodiment of the present invention a proximal portion of the strand is positioned outside the body cavity when the three dimensional anchor is in the body cavity.

According to an embodiment of the present invention the proximal portion of the strand is attached to an outer surface of the delivery tube.

According to an embodiment of the present invention the three dimensional anchor is 12- 20 mm in diameter. According to another aspect of the present invention there is provided a device for delivering an agent to a tissue region adjacent a body cavity comprising a strand capable of self forming a three dimensional anchor having a first loop approximately perpendicular to, and positioned through, a second loop; and a delivery element attached to, or forming a part of, the strand, the delivery element including the agent and being in contact with the tissue region when the three dimensional anchor is in the body cavity.

According to an embodiment of the present invention the body cavity is the uterus and the adjacent tissue region is the cervix or vaginal canal.

According to an embodiment of the present invention the agent is selected from the group consisting of a chemotherapeutic agent, at least one hormone, an analgesic and an antibiotic.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

In the drawings:

FIG. 1 illustrates an embodiment of the present device having a delivery tube covering the entire length of the strand.

FIG. 2 illustrates an embodiment of the present device having a delivery tube covering a three dimensional anchor portion of the strand. FIG. 3 illustrates another embodiment of the present device having a delivery tube covering a linear portion (tail) of the strand.

FIG. 4 illustrates an embodiment of the present device connected to an automated drug pump.

FIG. 5 illustrates an embodiment of the present device connected to a syringe.

FIG. 6 illustrates an embodiment of the present device having drug release openings in a single loop of the three dimensional anchor.

FIG. 7 illustrates an embodiment of the present device having drug release openings along the entire three dimensional anchor.

FIGs. 8A-D illustrate delivery of an embodiment of the present device into a uterus.

FIG. 9 illustrates an embodiment of the present device having a drug release reservoir portion connected to an anchor portion.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention is of a device for delivering an active agent to a body cavity to or to tissues adjacent the body cavity. Specifically, the present invention can be used to deliver an active agent such as a hormone or an anti-neoplastic drug to the uterus or adjacent tissues.

The principles and operation of embodiments of the present invention may be better understood with reference to the drawings and accompanying descriptions.

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

Localized delivery of drugs can be effected via a local injection or via implanted drug depots. The latter approach is advantageous in that it enables sustained delivery of a drug in a localized manner thereby traversing the need for repeated injections while minimizing side effects typically associated with systemic delivery.

The present inventors have devised a drug delivery device that enables localized delivery of an active agent such as a drug in a sustained or pulsatile manner. Such a device is particularly advantageous when configured for pulsatile delivery of gonadotropins to the uterus for the purpose of inducing ovulation for IVF treatment.

IVF treatment is typically effected using one of three main approaches: (i) Luteal suppression (or long luteal or simply just long) - involves suppression of the ovaries using a GnRH analog such as Lupron™) during the luteal phase of the menstrual cycle preceding the planned IVF treatment cycle. Once the ovaries are suppressed, ovarian stimulation is accomplished with daily sub cutaneous or intra muscular injections of gonadotropins (e.g., Gonal-F™, Follistim™). Lupron is usually continued until the day of the HCG trigger shot (to trigger ovulation). A common variation of this protocol is to stop Lupron at the time of starting stimulation with the gonadotropins.

(ii) Flare stimulation in which no medications are taken until the second day of the menstrual cycle. At that time, a micro-dose (most commonly) of Lupron is used to stimulate the pituitary gland and induce it to release its store of FSH and LH. Simultaneously, gonadotropins are administered producing an accumulated effect of ovarian stimulation.

(iii) GnRH-antagonist stimulation in which GnRH antagonists are added later in the stimulation cycle in order to prevent premature ovulation. In this approach, the gonadotropins are started on cycle day 2 of a normal menstrual period. Once the follicles have reached a specific size (usually 12 to 14 mm), the woman begins the GnRH-antagonist medication, which almost instantaneously prevents the pituitary gland from generating an LH surge.

Common to all of the above mentioned approaches is daily subcutaneous (SC) or intra muscular (IM) injections of gonadotropins (Doses are measured by IU and are generally few ten’s IU per daily injection) for about 7-12 days (depending on ovarian reaction) during which the patient performs a daily (or every other day) ultrasound (US) examination to asses her ovarian reaction. After each US examination, instructions with respect to gonadotropin dosages for that day are provided to the patient. Once there are enough developed follicles the patient is instructed to inject HCG (Chorigon™) and invited the day after for ovum pickup under general anesthesia. The ova are fertilized and injected back to the uterus 3-5 days later.

Thus, according to one aspect of the present invention there is provided a device for delivering an agent into a body cavity.

As used herein, the phrase "body cavity" refers to any hollow tissue structure. Examples of body cavities include, but are not limited to, the anal canal, the rectum, the GI tract, the urinary tract, the uterus, the vaginal canal, the nasal tract and the respiratory tract.

Embodiments of the device of the present invention include a strand capable of self forming a three dimensional anchor having a first loop about perpendicular to a second loop. The first loop can be positioned the second loop (intersecting a plane thereof), or it can be positioned outside the second loop. As used herein, the term "strand" denotes an elongated member having two free ends. The strand can be a wire (e.g. single filament, multi-filament or braided metal or polymer wire), a string, a strip or a tube. The strand can be solid or hollow.

Embodiments of the present device further include a delivery conduit attached to, or forming a part of, the strand. The delivery conduit can be configured for delivering the agent into the body cavity from outside the body when the three dimensional anchor is in the body cavity. The delivery tube includes two openings fluidly connected via a conduit (the lumen of the delivery tube). A first (proximal) opening is positionable outside the body and a second (distal) opening is positionable within the cavity. The first opening can be connected to a reservoir/source (e.g. syringe) of an active agent provided in liquid/gel form.

The delivery tube can be 100-2000 mm in length with an inner lumen/s diameter/s of 0.3- 6 mm and a wall thickness of 0.1-1 mm. The delivery tube can be made from a polymer such as silicone, polyethylene and the like. The proximal opening of the delivery tube can be fitted with a port (e.g. a Luer lock port or a sterilizable injection port) for connecting to a source of the delivered agent.

As is further described hereinunder, the delivery conduit can be a tube attached to the strand by gluing or welding a wall portion of the delivery tube to a wall of the strand or by molding the delivery tube over a (proximal) portion of the strand. The delivery tube and strand can also be a unitary structure, e.g., the strand and tube can be fabricated from a single elastic hollow tube (metallic or polymeric).

As is mentioned hereinabove, the strand portion of embodiments of the present device is capable of forming an elastically deformable three dimensional anchor.

The strand can be composed of an elastic material selected capable of being pre-shaped into the three dimensional anchor and being linearized by a pulling force on the ends of the strand. Such a transition between three dimensional and linear configurations can be effected repeatedly due to the elastic nature of the material and its ability to maintain the three dimensional shape in the absence of any pulling force on the ends of the wire (e.g. shape memory).

Examples of materials suitable for such purposes include alloys such as stainless steel, nickel-titanium, copper- aluminum-nickel and other copper containing alloys or polymers such as polyurethanes, polyols, polyethylene terephthalates and acrylates.

The strand can be 50-200 mm long with the portion forming the three dimensional anchor being 50-100% of the overall length (50-80 mm). The three dimensional anchor of embodiments of the present device is formed by two or more contiguous loops of the strand which are angled with respect to each other. The loops can be 10-20 mm in diameter and can be arranged (in a two loop configuration) such that one loop is positioned within the plane of the second loop and is angled 60-120, preferably 80-100 degrees with respect thereto (the angle is measured at the wire portion interconnecting the loops). Thus, the loops form a loop-in-loop structure that 'traps' a roughly spherical volume of 0.5-4.2 cm ³ (1.15-3.0 cm ³ preferred) with a surface area of 3.1-12.6 cm ² (5.3-10.2 cm ² preferred). Further description of the three dimensional anchor and formation of the loops from the linear/linearized wire is provided hereinbelow.

As is described hereinabove, the present device was designed in order to enable localized delivery of an active agent such as a drug with the three dimensional anchor configured for anchoring an opening of a delivery tube within the cavity in which delivery of the drug is desired.

In the case of delivery into a uterus, the three dimensional anchor must provide stable anchoring of the delivery tube throughout the delivery regimen and must resist migration during uterine contractions and possible unintentional pull out forces applied to the proximal end of the delivery tube.

In order to provide the requisite stability, the present inventors have uncovered that a wire diameter of 0.5 mm combined with a device overall diameter of 20 mm result in elastic resistance to wall forces of a relaxed uterus with a slight device shape change under contractile forces. Thus, embodiments of the present device apply a counter force to both the relaxed and contracted states of the uterus. Such a counterforce ensures that the three dimensional anchor portion of embodiments of the present device does not substantially migrate within the uterus and more importantly, is not accidentally pulled out from the uterus.

The agent deliverable through embodiments of the present device can be a hormone (e.g., a gonadotropin), an antineoplastic (e.g., paclitaxel), an analgesic (e.g., ibuprofen), an antibiotic (e.g., doxycycline), a stimulant (e.g., methylphenidate), an anesthetic (e.g., lidocaine), an immunotherapy agent (e.g., bevacizumab), an antidepressant agent (e.g., sertraline), an ablative agent (e.g., silver nitrate) or a contraceptive (e.g., levonorgestrel).

Referring now to the drawings, Figures 1-8D illustrates embodiments of the present device configured for uterine drug delivery and referred to herein as device 10.

As is shown in Figure 1, device 10 includes a strand 12 forming a three dimensional anchor 14 having a first loop 16 contiguous with a second loop 18. The distal end of strand 12 (indicated by E) is turned inward in the direction of the volume defined by loops 16 and 18 of device 10 and can include a protective thickening or bead 15. Proximal end E can be pulled into a delivery sleeve 100 for strand 12 linearization.

Loops 16 and 18 are connected via a contiguous segment 20 which forms an angle Ά' between loops 16 and 18; angle Ά' can be 60-100 degrees.

Three dimensional anchor 14 is attached to or contiguous with proximal portion 38 (also referred to herein as tail 38) of strand 12.

The overall diameter of three dimensional anchor 14 (D) can be 15-20 mm. Loops 16 and 18 are substantially of equal diameter (d) of 15-20 mm. The diameter of strand 12 can be 0.2 - 0.6 mm.

As is mentioned hereinabove, three dimensional anchor 14 is configured to partially compress under the forces applied by the walls of a relaxed uterine cavity.

Lor example, a three dimensional anchor 14 having an overall diameter of 20 mm constructed from a Nitinol wire (0.2 mm in diameter) formed into two contiguous loops (each 20 mm in diameter) angled at 90 degrees with respect to each other would partially compress under a gram force (grL) of 25-190 grams per cm ² . Near flattening of this configuration of device 10 would require about 120-380 grams per cm ² . Device 10 can be compressed between the loops with (25-120 grL - partial to near flat), or through a loop (190-380 grL - partial to near flat).

When partially compressed, three dimensional anchor 14 applies an elastic counterforce to the walls of the uterine cavity thus firmly securing three dimensional anchor 14 in position.

Compression of three dimensional anchor 14 under such forces is influenced by two separate or combined mechanisms, change in angle A (elastic bending at segment 20) and shape change (round to oval) in each of loops 16 and 18 (elastic bending of the loops).

Compression along one axis of three dimensional anchor 14 is primarily mediated by segment 20 which can bend under relatively lower forces (exerted by relaxed uterine walls). Such compression of device enables three dimensional anchor 14 to assume the oval-shaped configuration described above. Collapse along the other axis requires a larger force (uterine contractions) since it necessitates a shape-change (round to oval) in loops 16 and 18 (as well as further bending of segment 20). Collapse through a combination of axis is also possible and will depend on the orientation of three dimensional anchor 14 in the uterine cavity and type of contractions.

Device 10 further includes a delivery tube 30 attached to (co-axially), or forming a part of strand 12. Delivery tube includes proximal opening 32 and at least one distal opening 34 (Ligures 2, 3, 6 and 7) fluidly connected via lumen 36. Figure 1 illustrates a configuration of device 10 in which delivery tube 30 covers the entire length of strand 12 (anchor 14 and tail 38). Figures 2 and 3 illustrate configurations of device 10 in which delivery tube 30 is attached to a proximal portion 38 (tail) of strand 12. Such attachment can be effected by gluing, welding or otherwise mechanically securing a distal portion 40 of delivery tube 30 to proximal portion 38 of strand 12 (e.g., outer wall to outer wall). Alternatively, and as is shown in Figures 2-3, distal portion 40 of delivery tube 30 can be positioned over (joined to) a proximal portion 38 of strand 12 in a manner which enables delivery of an agent from opening 34. For example, distal portion 40 can be molded over proximal portion 38 of strand 12 or it can simply be threaded over strand 12. In such configurations, opening(s) 34 of delivery tube can be positioned proximally to the region of joining or opening 34 can be formed between delivery tube 30 and strand 14 (as is shown in Figures 2 and 3).

Figures 2 and 3 illustrate two slightly different configuration of device 10. While both configurations include two loops roughly perpendicular to each other, differences in segment 20 connecting loops 16 and 18 and region of intersection between the loops result in a slightly different overall shape of three dimensional anchor 14.

Regardless of the configuration, the loops of device 10 are oriented such that when the device is pulled out of the cavity by linearizing anchor 14, loops 16 18 freely slide with respect to each other without entangling.

Strand 12 can alternatively be formed from a hollow polymeric or metallic wire with a first portion capable of self forming three dimensional anchor 14 and a second and contiguous portion forming delivery tube 30. One or more openings 34 can be positioned along strand 12 at the first and/or second portions.

Figures 6 and 7 illustrate a device 10 configuration in which delivery tube 30 includes openings 34 along a portion of a single loop (Figure 6) or the entire three dimensional anchor (Figure 7). Such openings can be 0.1-0.5 mm in diameter and can be shaped as simple cylindrical holes or, for example, as outward cones for aerosolizing a delivered fluid.

Figures 4 and 5 illustrate the present device connected to an automated drug delivery pump 70 (Figure 4) or a syringe 80 (Figure 5). A proximal opening 32 of delivery tube 30 can include a fitting (e.g. Luer lock) to enable connection to pump 70 or syringe 80.

Device 10 of the present invention can be used to deliver an agent such as a hormone, an antineoplastic, an analgesic, an antibiotic, a stimulant, an ablative agent or a contraceptive to the walls of the uterus and/or fallopian tube openings in a pulsatile or continuous manner over a period of hours, days, weeks or months. Figures 8A-D illustrate delivery of device 10 into the uterus (U) of an IVF patient. Device 10 is first linearized within a delivery sleeve 70 by pulling the distal end of strand 12 into a lumen of delivery sleeve 100 until the region of strand 12 forming three dimensional anchor 14 is completely linearized with delivery tube 30 positioned outside delivery sleeve 100 (Figure 8A). A distal opening of delivery sleeve 100 is then positioned inside the uterus and three dimensional anchor 14 is deployed therein (Figure 8B) by pulling on an end of delivery tube 30 while holding delivery sleeve 100 in position. Once three dimensional anchor 14 is deployed (Figure 8C), and delivery sleeve 100 is removed (Figure 8D), a proximal opening 32 of delivery tube 30 is connected to a pump 70/syringe 80 containing gonadotropins at IVF concentrations and a delivery dose suitable for IVF treatment (as described hereinabove) is provided to the patient in a bolus or pulsatile manner.

Since the present device allows a more localized delivery and thus a more efficacious uptake of gonadotropins, lower doses can be used in IVF treatment. For example, the present device can enable a dose regimen including half or less of the gonadotropin dose typically administered in IVF treatment. The device also enables to abrade (scratch) the endometrium (Pippelle) prior to its removal by producing suction in the delivery tube via a syringe. Such abrasion can increase the embryo implantation success rate.

Once the regimen is completed, device 10 is pulled out of the uterus by simply pulling on the proximal end of delivery tube 30.

As is mentioned hereinabove, embodiments of the present device can also be configured for delivery of an agent to tissues adjacent the body cavity.

One configuration of such a device is illustrated in Figure 9 and is referred to herein as device 200.

Device 200 includes strand 202 (which is similar to strand 12 described above) capable of self forming a three dimensional anchor 204 and a reservoir 206 attached thereto. The reservoir can take the form of a strip, tube and the like and includes (or can be filled with) and agent in liquid, gel or solid form. The agent can be configured for bulk or continuous release. An example of reservoir 206 can be a strip or a perforated tube that can include an antineoplastic (e.g., paclitaxel), an analgesic (e.g., ibuprofen) or an antibiotic (e.g., doxycycline) in liquid/gel or dry form.

Device 200 can be used by positioning three dimensional anchor 204 within cavity (as is described above for device 10) such that attached reservoir 206 is positioned adjacent to, and optionally in contact with, the walls of the cervix (C) and/or vagina to enable delivery of an agent contained therein to these tissues. Device 200 can be used to treat cervical cancer by delivering chemotherapy to cervical tissues.

As used herein the term“about” refers to ± 10 %.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims. All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention.

In addition, any priority document(s) of this application is/are hereby incorporated herein by reference in its/their entirety.