WO2022029780A1

WO2022029780A1 - Intrauterine device for controlled drug release

Info

Publication number: WO2022029780A1
Application number: PCT/IL2021/050950
Authority: WO
Inventors: Efrat SCHURR; Uzi Dan; Shlomo Lewkowicz
Original assignee: Bless Medical Ltd.
Priority date: 2020-08-06
Filing date: 2021-08-04
Publication date: 2022-02-10

Abstract

The present invention provides an intrauterine device and methods of use thereof, the device comprising at least one support member and at least one foldable sheet coupled thereto comprising a drug releasing matrix comprising at least one pharmaceutical active agent, wherein following delivery, the device is configured to transition between a compressed configuration to an expanded configuration, and wherein during the expanded configuration the device is configured to enable the controlled or sustained release of the pharmaceutical active agent therefrom.

Description

INTRAUTERINE DEVICE FOR CONTROLLED DRUG RELEASE

Field of the Invention

[0001] Provided herein are intrauterine devices (IUDs) and methods for controlled and/or sustained drug release therefrom within a uterine cavity.

Background of the Invention

[0002] Abnormal uterine bleeding can be caused by several factors, such as structural abnormalities in the reproductive tract, anovulation, bleeding disorders, hormone issues or cancer of the reproductive tract. Bleeding disorders are one of the most frequent gynecological problems. There are about 1.2 billion human females in the world today in their fertile age, and approximately one third of them (about 400-500 million females) report that they suffer from bleeding disorders such as heavy menstrual bleeding. Menstrual bleeding disorders can include excessive and prolonged bleeding, which can affect both their health and quality of life, since excessive bleeding can lead to anemia which presents as fatigue, shortness of breath, and weakness.

[0003] Tranexamic acid (TA) is a small molecule drug typically used for treating or preventing excessive blood loss resulting from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and menstruation.

[0005] Tranexamic acid (TA)

[0006] A standard medical treatment for various menstrual bleeding disorders includes oral administration of tranexamic acid (in a dosage form of up to 1000 mg, 4 times a day) during menstruation. This treatment route utilizes a high dosage of tranexamic acid, which is associated with various side effects such as nausea, vomiting, diarrhea and muscle pain. Additionally, oral administration depends on patient compliance and responsibility.

[0007] An alternative oral administration route includes hormonal treatment, such as contraceptive pills containing progesterone or estrogen-progesterone combinations, which can be administered on a daily, weekly, or monthly basis. Said hormonal treatment associated with various side effects such as weight gain, nausea, decrease in libido, headaches, and ovary cysts.

[0008] An additional possible treatment utilizes the use of intrauterine devices (IUDs) which are configured to be inserted to the uterine cavity, and are typically adapted for releasing progesterone thereto during prolonged durations of about 3-5 years.

[0009] US Pat. No. 9,999,592 discloses a method for contraception and for reducing menstrual problems and inducing amenorrhea, wherein an intrauterine device is used for the controlled release of a combination of progestogen or a drug having a progestogenic activity and at least one therapeutically active substance capable of preventing or suppressing abnormal and/or irregular endometrial bleeding over a prolonged period of time.

[0010] U.S. Pub. No. 2014/0328884 discloses a polymeric matrix for controlled release comprising at least one material selected from the group consisting of an ethylene copolymer, an ethyl cellulose, a thermoplastic polyurethane, or any partially crosslinked polymer thereof.

[0011] U.S. Pub. No. 2015/0306230 discloses a drug delivery vehicle (e.g., a patch, a pill, an intravaginal ring, and an implant) which may include a polymer matrix comprising a plasticizer and at least one material selected from the group consisting of: a cellulose ester, a cellulose ether, a starch ester, a starch ether, and a combination thereof.

[0012] There remains an unmet need for simple, effective, and cost-efficient intrauterine devices and methods of use, adapted to release TA for reducing or treating menstrual bleeding disorders, resulting in effective treatment and/or reduced side effects associated with other administration routes thereof (e.g., oral administration). of the Invention

[0013] The present invention provides intrauterine devices and methods for reducing or managing menstrual bleeding in female subjects in their fertile age, wherein the intrauterine devices comprises at least one pharmaceutical active agent (such as for example, tranexamic acid) and are configured for the controlled and/or sustained release thereof, optionally over prolonged durations of time. Furthermore, the intrauterine devices of the present invention may be used for treating or suppressing gynecological -related diseases or disorders in female subjects. Moreover, the intrauterine devices of the present invention may be used for preventing pregnancy (contraception). In addition, the intrauterine devices of the present invention may contain analgesics such as NSAIDS, corticosteroids and other drugs, in order to relieve menstrual cramps, premenstrual pains, as well as pains resulting from the insertion of the device.

[0014] Thus, according to a certain aspect, there is provided an intrauterine device (IUD) configured to be inserted into a uterine cavity of a user, the device comprising (a) at least one support member, comprising a first arm and a second arm joined at a junction, wherein the first arm is extending between a first end thereof and the junction, and wherein the second arm is extending between the junction and a second end thereof; and (b) and at least one foldable sheet comprising a drug releasing matrix comprising a polymer and at least one pharmaceutical active agent, wherein the sheet is coupled to at least a portion of the support member.

[0015] The IUD is configured to be delivered into a uterine cavity in a compressed configuration. Following delivery, the support member is configured to transition between a folded configuration to a spread configuration which facilitates transition of the IUD from the compressed configuration to an expanded configuration. During the transition between the folded configuration to the spread configuration, the first end and the second end of the support member are configured to expand or extend in opposite directions relative to each other. The foldable sheet is coupled to the first and second arms such that when the support member transitions to the spread configuration the sheet spreads therewith, thus enabling the release of the pharmaceutical active agent therefrom.

[0016] According to some embodiments, the first arm and the second arm are integrally formed and are joined in the junction, or wherein the first arm and the second arm are separate components attached to each other directly or indirectly via intermediate components.

[0017] According to some embodiments, during the expanded configuration the first arm, the second arm, and the foldable sheet substantially reside in the same plane.

[0018] According to some embodiments, during the compressed configuration the first end of the support member is in the vicinity of the second end thereof. [0019] According to some embodiments, the foldable sheet extends between at least two sides, wherein a first side of the foldable sheet is coupled to the first arm of the support member, and wherein a second side of the foldable sheet is coupled to the second arm of the support member.

[0020] According to some embodiments, during the folded configuration, the support member is configured to maintain the foldable sheet in a curled or folded configuration, such that the first side of the foldable sheet is in the vicinity of the second side thereof.

[0021] According to some embodiments, during the spread configuration of the support member, the first side and the second side of the foldable sheet are configured to planarly expand in opposite directions relative to each other, due to the expansion of the first and second arms.

[0022] According to some embodiments, during the transition to the spread configuration of the support member, the first and second arms are expanding in opposite directions relative to each other, so that an angle a is formed at the junction therebetween. In further embodiments, the angle a is selected from the range of about 5° - 90°.

[0023] According to some embodiments, the first and the second arms have a non-linear shape in the spread configuration thereof, such that each arm defines a curvilinear shape. In further embodiments, the first and second arms are bent such that a first and second bending points are formed, respectively, defining two first arm sections between the junction and the first and second bending points, wherein in the spread configuration of the support member, both first arm sections are substantially parallel to each other defining together with the junction a U-shaped configuration. In still further embodiments, both first arm sections extend into an elongated member and are coupled thereto, wherein the member is configured to accommodate therein electrical elements comprising at least one electromagnetic force generator, configured to induce a magnetic or an electric field or current.

[0024] According to some embodiments, the IUD further comprises at least one elongated member, wherein said at least one elongated member is coupled to the first and/or second arm of the support member, wherein the elongated member is configured to accommodate therein various electrical elements comprising at least one electromagnetic force generator, configured to induce a magnetic or an electric field or current. [0025] According to some embodiments, the IUD further comprises at least one elongated member, wherein said at least one elongated member is coupled to at least one of the first arm, the second arm, the junction, or to a combination thereof, and wherein the elongated member is configured to accommodate therein various electrical elements comprising at least one electromagnetic force generator, configured to induce a magnetic or an electric field or current.

[0026] According to some embodiments, the IUD further comprises an elongated member, wherein the first arm and the second arm are separate components attached to each other indirectly via the elongated member, and wherein the at least one foldable sheet comprises at least two separate sheet sections, such that a first sheet section extends between the first arm and a portion of an external surface of the elongated member, and a second sheet section extends between the second arm and a portion of the external surface of the elongated member. In some embodiments, the first and second sheet sections are coupled to substantially opposite portions of the external surface of the elongated member. In some embodiments, during the folded configuration, the first and the second ends of the arms are in the vicinity of each other and the elongated member, and wherein during the folded configuration the first and second arms are configured to maintain the first and second sheet sections, respectively, in a curled or folded configuration. In some embodiments, during the transition from the folded configuration to the spread configuration, the first arm and the second arm are configured to expand in opposite directions relative to each other, resulting in the expansion of the first and second sheet sections in opposite directions, respectively.

[0027] According to some embodiments, the at least one support member comprises at least one shape memory material, configured to enable the transition thereof from the folded configuration to the spread configuration. In further embodiments, the shape memory material is selected from a nickel titanium alloy, a copper-aluminum-nickel alloy, a zinc- copper-aluminum alloy, a zinc-copper-gold-iron alloy, an iron-manganese-silicon alloy, and a combination thereof. In still further embodiments, the shape memory material comprises a nickel titanium (nitinol) alloy.

[0028] According to some embodiments, the weight of the pharmaceutical active agent is in the range of about 1-50% w/w based on the total weight of the drug releasing matrix. In further embodiments, the weight percent of the pharmaceutical active agent is in the range of about 1-30% w/w based on the total weight of the drug releasing matrix. [0029] According to some embodiments, the polymer of the drug releasing matrix is a crosslinked copolymer comprising at least one first region and at least one second region, wherein the at least one pharmaceutical active agent is at least partially either dispersed or retained within the copolymer. The at least one first region and the at least one second region within the copolymer each comprise at least 2 repeating units. The repeating units of the at least one first region are selected from the group consisting of: propylene glycol, ethylene glycol, vinyl alcohol, glycerol, pentaerythritol, sorbitol, and combinations thereof. The repeating units of the at least one second region are represented by the formula: (-CO-X-(CH- R)_n-Y-), wherein X is O, NH or absent and Y is O or NH, wherein n is an integer selected from 1 to 10, and R is selected from H, alkyl, aryl, hydroxyl and amine. According to some embodiments, the at least one first region comprises polypropylene glycol (PPG), polyethylene glycol (PEG), or both. In some embodiments, the repeating units of the at least one second region are represented by the formula: (-CO-(CH2)_n-O-), wherein n is an integer selected from 2 to 8. In some embodiments, the crosslinked copolymer is an elastomer.

[0030] According to some embodiments, the at least one pharmaceutical active agent is selected from the group consisting of tranexamic acid (TA), a hormone, an analgesic, a chemotherapeutic drug, and combinations thereof. In further embodiments, the pharmaceutical active agent is tranexamic acid (TA). In further embodiments, the pharmaceutical active agent is a hormone selected from progestogen, progestin, estrogen, and combinations thereof.

[0031] According to some embodiments, the foldable sheet further comprises an inner support layer, wherein the drug releasing matrix envelopes or surrounds at least a portion of the inner support layer, and wherein the support layer is extending between the first arm and the second arm of the support member and is coupled thereto. In further embodiments, the inner support layer comprises at least one polymer selected from the group consisting of polypropylene, polyester, polyamide, polyacrylate, polymethacrylate, and copolymers thereof. In still further embodiments, the inner support layer is in the form of a mesh structure.

[0032] According to some embodiments, the foldable sheet further comprises an outer layer, wherein said outer layer envelopes or surrounds at least a portion of the drug releasing matrix, and wherein the outer layer comprises an electrically or magnetically responsive porous membrane having an adjustable permeability, configured to enable the controlled release of the pharmaceutical active agent from the drug releasing matrix therethrough. In further embodiments, said electrically or magnetically responsive porous membrane is configured to be reversibly actuated from a closed or semi closed state to an open state due to the influence of an electric or magnetic field or current, wherein in the open state the pores of the membrane are open, thereby enabling diffusion and drug release therethrough, and wherein in the closed or semi closed state the pores of the membrane are fully closed or semi closed, thereby preventing or substantially preventing drug release therethrough.

[0033] According to some embodiments, the IUD further comprises at least one elongated member, wherein said at least one elongated member is coupled to at least one of the first arm, the second arm, the junction, or to a combination thereof, wherein at least a portion of the elongated member is hollow and accommodates therein various electrical elements comprising at least one of a power source, a communication module, a controller, an electromagnetic field generator, and combinations thereof.

[0034] According to some embodiments, the elongated member comprises the electromagnetic force generator comprising an induction coil, configured to generate an inner magnetic or electric field or current, wherein said field or current is configured to affect the permeability of the electromagnetically responsive porous membrane, and thus to control the release rate and duration of the pharmaceutical active agent from the drug releasing matrix therethrough.

[0035] According to some embodiments, the electromagnetic force generator is configured to automatically generate the inner magnetic or electric field in response to an external magnetic field, generated externally to the uterine cavity.

[0036] According to some embodiments, the elongated member further comprises the power source and the controller, wherein the electromagnetic force generator is configured to generate the inner magnetic or electric field in response to receiving power from the power source, upon receiving commands from the controller.

[0037] According to some embodiments, the elongated member further comprises an optic detection module and at least one optic member, wherein said optic detection module is electrically and/or functionally connected to the optic member, wherein the optic detection module is configured to communicate with the controller and enable the operation of the optic member, and wherein the optic member comprises at least one optic sensor and at least one LED light. In further embodiments, the optic member is configured to enable the at least one LED light and the at least one optic sensor to transfer and to detect light therethrough, respectively, in order to detect the presence of red blood cells (RBC) in the vicinity thereof within the uterine cavity, and/or to measure an increase in a concentration thereof relative to a threshold value, and to transfer optic data indicative thereof to the controller, via the optic detection module.

[0038] According to some embodiments, the controller is configured to automatically activate the electromagnetic force generator, thereby inducing the inner magnetic or electric field or current, upon receiving the optic data indicating the presence of RBC and/or the increase in the concentration thereof relative to the threshold value, or based on a predetermined monthly timetable.

[0039] According to some embodiments, the elongated member further comprises the communication module, wherein the controller is configured to activate the electromagnetic force generator upon user demand, thereby generating the inner magnetic field, wherein the user operates the controller via wireless communication using a remote device.

[0040] According to some embodiments, the IUD further comprises at least two electrodes configured to measure impedance levels residing therebetween indicative of the RBC concentration or amount in the vicinity thereof, wherein the controller is configured to detect an increase in the concentration or amount of RBC and to automatically activate the electromagnetic force generator, or to issue a notification indicating the user thereto via wireless communication using a remote device.

[0041] According to some embodiments, the IUD further comprises at least one sensor configured to measure the levels of a physiological or biological indicator in the vicinity thereof within the uterine cavity, and to transfer data indicative thereof to the controller, and wherein the controller is configured to detect a change in the levels of the physiological or biological indicator and to automatically activate the electromagnetic force generator, or to issue a notification indicating the user thereto via wireless communication using a remote device.

[0042] According to some embodiments, the IUD as disclosed herein above is for use in reducing or managing menstrual bleeding in a subject in need thereof. [0043] According to some embodiments, the IUD as disclosed herein above is for use in the treatment of a gynecological disease or a disorder in a subject in need thereof. According to further embodiments, the gynecological disease or a disorder is selected from the group consisting of a menstrual bleeding disorder, cervical cancer, vaginal cancer, endometrial cancer, uterus cancer, and a combination thereof. According to still further embodiments, the gynecological disease or a disorder is a menstrual bleeding disorder.

[0044] According to some embodiments, the IUD as disclosed herein above is for use in birth control.

[0045] According to another aspect, there is provided a method for reducing or managing menstrual bleeding in a subject in need thereof, the method comprising delivering the IUD as disclosed herein above into the uterine cavity of the subject, and inducing the controlled release of TA therefrom.

[0046] According to another aspect, there is provided a method for the treatment of a gynecological-related disease or a disorder, the method comprising delivering the IUD as disclosed herein above into the uterine cavity of a subject in need thereof, and inducing the controlled release of TA therefrom.

[0047] Certain embodiments of the present invention may include some, all, or none of the above advantages. Further advantages may be readily apparent to those skilled in the art from the figures, descriptions, and claims included herein. Aspects and embodiments of the invention are further described in the specification herein below and in the appended claims.

[0048] 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 pertains. In case of conflict, the patent specification, including definitions, governs. As used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more" unless the context clearly dictates otherwise.

[0049] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative, but not limiting in scope. In various embodiments, one or more of the abovedescribed problems have been reduced or eliminated, while other embodiments are directed to other advantages or improvements. of the Fi:

[0050] Some embodiments of the invention are described herein with reference to the accompanying figures. The description, together with the figures, makes apparent to a person having ordinary skill in the art how some embodiments may be practiced. The figures are for the purpose of illustrative description and no attempt is made to show structural details of an embodiment in more detail than is necessary for a fundamental understanding of the invention. For the sake of clarity, some objects depicted in the figures are not to scale.

[0051] In the Figures:

[0052] Figs. 1A-B illustrates views in perspective of an intrauterine device (IUD) 100, in compressed configurations, according to some embodiments.

[0053] Figs. 2A-B illustrate a view in perspective and a cross sectional top view, respectively, of the IUD 100 of Figs. 1A-B, in an expanded configuration, according to some embodiments.

[0054] Fig. 3 illustrates the IUD 100 of Fig. 2A in the expanded configuration disposed within a uterine cavity 150, according to some embodiments.

[0055] Fig. 4A illustrates a view in perspective of an IUD 200 in an expanded configuration, according to some embodiments.

[0056] Figs. 4B-C illustrates cross sectional top views of the IUD 200 of Fig. 4A, in the expanded configuration, according to some embodiments.

[0057] Figs. 5A-B illustrates a view in perspective and a cross sectional top view, accordingly, of an IUD 300 in an expanded configuration, according to some embodiments.

[0058] Fig. 6A illustrates an IUD 400 in an expanded configuration disposed within a uterine cavity 150, according to some embodiments.

[0059] Fig. 6B illustrates an enlargement of a portion of the IUD 400, according to some embodiments. [0060] Figs. 7A-B illustrate views in perspective of an IUD 500, in a compressed configuration and in an expanded configuration, accordingly, according to some embodiments.

[0061] Figs. 8A-D illustrate views in perspective of an IUD 600, in different compressed configurations, according to some embodiments.

[0062] Fig. 9 illustrates a view in perspective of the IUD 600 of Figs. 8B-C, in an expanded configuration, according to some embodiments.

[0063] Figs. 10A-B illustrates cross sectional top views of the IUD 600, in the expanded configuration, according to some embodiments.

[0064] Figs. 11A-C illustrates functional block diagrams of an elongated member 660 of the IUD 600, according to some embodiments.

[0065] Fig. 12 illustrates a general formula of the copolymer synthesized in Example 1, prior to the addition of TA, according to some embodiments.

[0066] Fig. 13 shows Differential scanning calorimetry (DSC) results for samples 1, 3 and 5 of Table 1. The lines in the graph from left to right relate to samples 1, 3 and 5, accordingly.

[0067] Figs. 14A-B shows Fourier transform infrared spectroscopy (FTIR) results for sample 3 of Table 1 : the polymer without TA (Fig. 14A); and the polymer with TA, the polymer without TA, and TA (Fig. 14B). FTIR measurements ware performed under atmospheric conditions.

[0068] Fig. 15 shows a calibration graph for TA, produced via high pressure liquid chromatography.

[0069] Figs. 16A-B shows a concentration vs. time graph representing the daily release rate of TA for two samples from Table 1 : sample 1.4 (Fig. 16A), and sample 1.1 (Fig. 16B).

[0070] Fig. 17 shows a concentration vs. time graph representing the daily release rate of TA for sample 2.1 from Table 2. [0071] Fig. 18 shows a concentration vs. time graph representing the daily release rate of TA for the samples: 3.1 from Example 3, and 4.1 from Example 4.

Detailed

[0072] The present invention provides intrauterine devices (IUDs) and methods for reducing and managing menstrual bleeding in female subjects in their fertile age and/or treating or suppressing gynecological -related diseases or disorders, wherein the intrauterine devices are comprising at least one pharmaceutical active agent (such as for example, tranexamic acid) and are configured for controlled and/or sustained release thereof over prolonged durations of time. Furthermore, the intrauterine devices of the present invention may be used for preventing pregnancy (contraception).

[0073] In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the disclosure. In the figures, like reference numerals refer to like parts throughout.

[0074] The term “controlled drug release” as used herein, refers to the control of the release rate and/or quantity of the pharmaceutical active agent delivered by the IUDs of the present invention. The controlled release can be continuous or discontinuous, and/or linear or non-linear. The term “sustained drug release” means that the pharmaceutical active agent is released over an extended period of time.

[0075] The term “drug” as used herein, refers to the at least one pharmaceutical active agent. According to some embodiments, the at least one pharmaceutical active agent is tranexamic acid (TA).

[0076] Reference is now made to Figs. 1-3. Figs. 1A-B illustrates views in perspective of an intrauterine device (IUD) 100, in compressed configurations, according to some embodiments. Figs. 2A-B illustrates a view in perspective and a cross sectional top view, respectively, of the IUD 100 of Figs. 1A-B, in an expanded configuration, according to some embodiments. Fig. 3 illustrates the IUD 100 of Fig. 2A in the expanded configuration disposed within a uterine cavity 150, according to some embodiments.

[0077] According to a certain aspect, there is provided an intrauterine device (IUD) 100 configured for the controlled and/or sustained drug release of at least one pharmaceutical active agent therefrom within a uterine cavity. According to some embodiments, the IUD 100 comprises: at least one support member 102; and at least one foldable sheet 120 attached or coupled to at least a portion thereof, the foldable sheet 120 comprising a drug releasing matrix 130 comprising a polymer and at least one pharmaceutical active agent.

[0078] The shapes and sizes of the IUDs of the present invention, such as the IUD 100 as disclosed herein, are configured to fit within the dimensions of a uterine cavity. It is also evident that the devices disclosed herein are designed to apply to a user or a subject which is a female human, as well as to animal mammals.

[0079] According to some embodiments, the IUDs of the present invention, such as the IUD 100 as disclosed herein, are configured for the controlled and/or sustained release of the at least one pharmaceutical active agent therefrom into the uterine cavity, for various uses selected from: (i) reducing or managing menstrual bleeding in subjects in need thereof; (ii) birth control (contraception); (iii) reducing menstrual pains, premenstrual pains or any pain related to the insertion of the device ; (iv) treating or suppressing a gynecological -related disease or a disorder, and combinations thereof. Each possibility represents a different embodiment.

[0080] Some female subjects, which optionally do not suffer from a gynecological- related disease or a disorder, may wish to reduce the volume of blood loss during a typical menstruation cycle, for personal reasons. The IUDs of the present invention can enable female subjects (or users) to reduce or manage their menstrual bleeding, optionally upon user demand or according to preprogramed parameters within the IUD. According to some embodiments, the IUDs of the present invention (e.g., IUD 100), are configured for the controlled and/or sustained release of the at least one pharmaceutical active agent therefrom into the uterine cavity, for use in reducing or managing menstrual bleeding in subjects in need thereof. According to some embodiments, the IUDs of the present invention (e.g., IUD 100), are configured for the controlled and/or sustained release of the at least one pharmaceutical active agent therefrom into the uterine cavity, for use in reducing the volume of menstrual blood loss in a subject in need thereof.

[0081] As used herein, the term “reducing menstrual bleeding” refers to reducing the volume of menstrual blood loss in female subjects (in their fertile age). Additionally or alternatively, the term “reducing menstrual bleeding” may also refer to the suppression or prevention of menstrual blood loss during a menstrual cycle in female subjects.

[0082] Furthermore, in some embodiments, one or more external portions of the IUDs of the present invention (e.g., IUD 100) can comprise copper, which is known for its use in birth control. Thus, the IUDs of the present invention (e.g., IUD 100) can be used simultaneously for birth control by releasing copper ions therefrom, and for reducing or managing menstrual bleeding in subjects in need thereof by releasing the pharmaceutical active therefrom, into the uterine cavity.

[0083] According to some embodiments, IUD 100 may contain analgesics as NSAIDS, corticosteroids and other drugs, in order to relieve menstrual cramps, premenstrual pains, as well as pains resulting from the insertion of the device.

[0084] According to some embodiments, IUD 100 is configured for the controlled and/or sustained release of the at least one pharmaceutical active agent therefrom into the uterine cavity, wherein the pharmaceutical active agent comprises various hormones suitable for the treatment of various hormone-related conditions. For example, the IUD 100 can release one or more hormone(s) for use in birth control (contraception).

[0085] As used herein, the terms “birth control” and “contraception” are interchangeable, and refers to a method or material(s) used to prevent pregnancy in female subjects in their fertile age.

[0086] As used herein, the terms “treating” and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.

[0087] According to some embodiments, the gynecological -related disease or a disorder is selected from a menstrual bleeding disorder, cancer, or both. Each possibility represents a different embodiment. [0088] According to some embodiments, the IUDs of the present invention, such as the IUD 100 as disclosed herein, are configured for the controlled and/or sustained release of the at least one pharmaceutical active agent therefrom into the uterine cavity, for use in treating or suppressing cancer. According to further embodiments, the cancer is selected from cervical cancer, vaginal cancer, endometrial cancer, uterus cancer, and combinations thereof. Each possibility represents a different embodiment.

[0089] As used herein, the term “menstrual bleeding disorder” refers to excessive and/or prolonged menstrual bleeding in female subjects in their fertile age. Menstrual bleeding disorders may be caused by various factors, such as uterine fibroids or polyps (non-cancerous growths or tumors), cancer of the uterus or cervix, hormone-related issues, and the like.

[0090] According to some embodiments, the IUDs of the present invention, such as the IUD 100 as disclosed herein, are configured for the controlled and/or sustained release of the at least one pharmaceutical active agent therefrom into the uterine cavity, for use in treating or suppressing a menstrual bleeding disorder in subjects in need thereof. According to some embodiments, the IUDs of the present invention (e.g., IUD 100), are configured for the controlled and/or sustained release of the at least one pharmaceutical active agent therefrom into the uterine cavity, for use in reducing or managing a menstrual bleeding disorder, in subjects in need thereof. In some embodiments, the IUDs of the present invention (e.g., IUD 100) can be used simultaneously for birth control by releasing copper ions therefrom, and for treating or suppressing a menstrual bleeding disorder in subjects in need thereof by releasing the pharmaceutical active therefrom, into the uterine cavity.

[0091] According to some embodiments, the menstrual bleeding disorder is heavy menstrual bleeding (HMB). As used herein, the terms “heavy menstrual bleeding” and “HMB” are interchangeable, and refers to female subjects in their fertile age experiencing greater than about 80 ml of blood loss per menstrual cycle, and/or experiencing a menstrual bleeding that lasts more than about 7 days (a typical menstrual cycle is about 28 days). According to some embodiments, the IUDs of the present invention, such as the IUD 100 as disclosed herein, are configured for the controlled and/or sustained release of the at least one pharmaceutical active agent therefrom into the uterine cavity, for use in treating or suppressing or reducing heavy menstrual bleeding (HMB) in subjects in need thereof. [0092] According to some embodiments, IUD 100 is configured to be inserted or delivered into a uterine cavity of a user, wherein the support member 102 is in a folded configuration, which facilitates a compressed configuration of the IUD 100. The IUD 100 is configured to be inserted vaginally through a cervix of the user and to be placed within a uterine cavity 150 utilizing any suitable IUD inserter known in the art.

[0093] According to some embodiments, the at least one support member 102 is extending from a first end 103 to a second end 105 and is defining a junction 107 positioned therebetween. According to some embodiments, the at least one support member 102 comprises a first arm 109 and a second arm 110 joined at a junction 107, wherein the first arm 109 is extending between the first end 103 and the junction 107, and wherein the second arm 110 is extending between the junction 107 and the second end 105 thereof.

[0094] According to some embodiments, the first arm 109 and the second arm 110 are integrally formed and joined in the junction 107 (for example, see Figs. 1A-2B). According to some embodiments, the first arm 109 and the second arm 110 are separate components attached to each other directly (not shown), or indirectly via intermediate components (for example, see Figs. 8A-D).

[0095] According to some embodiments, the first arm 109 and the second arm 110 are defining a plane 101 therebetween (see Fig 2B).

[0096] According to some embodiments, during delivery, the IUD 100 is positioned in a compressed configuration, within a desired location within the uterine cavity 150 (see Fig. 3).

[0097] According to some embodiments, following delivery, the support member 102 is configured to transition between a folded configuration to a spread configuration which facilitates transition of the IUD 100 from a compressed configuration to an expanded configuration, wherein during the expanded configuration the first arm 109, the second arm 110, and the foldable sheet 120 all substantially reside in the same plane 101. According to some embodiments, the foldable sheet 120 is coupled to at least a portion of the first arm 109 and to at least a portion of the second arm 110, such that when the support member 102 transitions between the folded configuration to the spread configuration, the sheet 120 moves/ spreads therewith. [0098] According to some embodiments, the foldable sheet 120 extends between at least two sides, wherein a first side 122 of foldable sheet 120 is connected/coupled to at least a portion of an external surface of the first arm 109 of the support member 102, and a second side 124 of foldable sheet 120 is connected to at least a portion of an external surface of the second arm 110 of the support member 102 (see Fig. 2A). According to some embodiments, the foldable sheet 120 further comprises a third side 126 which can be at least partially connected to the junction 107 of the support member 102 (not shown). According to some embodiments, the foldable sheet 120 further comprises a fourth side 128 configured to face the uterine cavity. The foldable sheet 120 can be connected/coupled to the arms as disclosed above, via the use of one or more of biocompatible adhesives, thermal radiation (e.g., melting), various attaching means (e.g., sutures), and the like.

[0099] According to some embodiments, the first side 122 of foldable sheet 120 is surrounding or enveloping an external surface of the first arm 109 of the support member 102, wherein the second side 124 of foldable sheet 120 is surrounding or enveloping an external surface of the second arm 110 of the support member 102 (see Fig. 2B).

[00100] According to some embodiments, during the spread configuration of support member 102, the third side 126 and/or the fourth side 128 of the foldable sheet 120 have a curvilinear shape. According to some embodiments, during the spread configuration of support member 102, the third side 126 and/or the fourth side 128 of the foldable sheet 120 are linear shaped. According to some embodiments, the third side 126 and the fourth side 128 of the foldable sheet 120 are parallel to each other (see Fig. 2A).

[00101] As used herein, the terms "folded configuration" and "compressed configuration" refers to states of the support member 102 and the IUD 100, respectively, during which the first end 103 of support member 102 is adjacent and/or is in the vicinity of the second end 105 thereof.

[00102] According to some embodiments, during the folded configuration, the first end 103 of support member 102 is adjacent to the second end 105 thereof (see Figs. 1A-B). According to some embodiments, during the folded configuration, the first end 103 of support member 102 is in the vicinity of the second end 105 thereof. According to some embodiments, during the folded configuration, the first arm 109 of the support member 102 is in the vicinity of the second arm 110 thereof. [00103] As used herein, the term “vicinity” refers to a distance within a radius of less than about 15 mm of a given three-dimensional (3D) space. According to some embodiments, the term “vicinity” refers to a distance within a radius of less than about 5 mm, preferably less than about 1 mm, or more preferably less than about 0.1 mm of a given 3D space. Each possibility represents a separate embodiment of the present invention.

[00104] According to some embodiments, during the folded configuration, the support member 102 is configured to maintain the foldable sheet 120 in a curled or folded configuration or state, in order to reduce the external dimensions of IUD 100, and thereby to enable effortless and safe insertion thereof thought the IUD inserter. According to some embodiments, during the folded configuration, the first side 122 of foldable sheet 120 is in the vicinity of the second side 124 thereof. According to some embodiments, during the folded configuration, the foldable sheet 120 is configured to be folded or coiled/curled between the first arm 109 and the second arm 110 of the support member 102. According to some embodiments, during the folded configuration of the support member 102, the IUD 100 is in the compressed configuration.

[00105] According to some embodiments, during the folded configuration, the foldable sheet 120 is configured to be folded in an accordion-like fold confirmation, between the first arm 109 and the second arm 110 of the support member 102 (see Fig. 1A). The accordionlike fold confirmation consists of a series of alternating folds resulting in multiple panels of a similar size forming the folded foldable sheet 120. According to alternative embodiments, during the folded configuration, the foldable sheet 120 is configured to be curled between the first arm 109 and the second arm 110 of the support member 102 (see Fig. IB).

[00106] According to some embodiments, during the transition from the folded configuration to the spread configuration of the support member 102, the first end 103 and the second end 105 of the support member 102 are configured to expand/stretch/extend in opposite directions relative to each other, within the uterine cavity, thus forming the expanded configuration of the IUD 100. According to some embodiments, during the transition from the folded configuration to the spread configuration of the support member 102, the first arm 109 and the second arm 110 are configured to planarly expand or extend along the plane 101 in opposite directions relative to each other, such that the first end 103 and the second end 105 are distanced from each other. In further embodiments, during the transition from the folded configuration to the spread configuration of the support member 102, the first arm 109 and the second arm 110 are configured to planarly expand or extend along the plane 101 in opposite directions relative to each other, such that the foldable sheet 120 spreads/expands therewith.

[00107] As used herein, the terms "spread configuration" and "expanded configuration" refers to states of the support member 102 and the IUD 100, respectively, during which the first end 103 of support member 102 is distanced from the second end 105 thereof.

[00108] According to some embodiments, during the spread configuration of the support member 102, each one of arms 109 and 110 has a substantially linear configuration so as to the define the plane 101 therebetween.

[00109] As used herein, the term “substantially” refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is “substantially” linear would mean that the object is either completely linear, or nearly completely linear and may a slight deviation (preferably less than 10°) form a linear plane. The exact allowable degree of deviation from linear completeness may in some cases depend on the specific context. However, generally speaking the nearness of a linear plane will be so as to have the same overall result as if absolute and a total linear plane were obtained.

[00110] According to some embodiments, during the transition from the compressed configuration to the expanded configuration of the IUD 100, the first side 122 and the second side 124 of the foldable sheet 120 are configured to planarly expand/spread along the plane 101 in opposite directions relative to each other, due to the expansion of the first arm 109 from the second arm 110 of the support member 102 in opposite directions relative to each other. According to some embodiments, the transition from the folded configuration to the spread configuration of the support member 102 results in the expansion of the foldable sheet 120 within the uterine cavity, and thus forms the expanded configuration of the IUD 100.

[00111] According to some embodiments, during the expanded configuration of the IUD 100, the sheet 120 is stretched and is extending between the first arm 109 and the second arm 110 of the support member 102.

[00112] According to some embodiments, during the transition to the spread configuration of the support member 102, the first end 103 and the second end 105 are expanding/moving in opposite directions relative to each other, so that an angle a is formed at the junction 107 between the first arm 109 and the second arm 110 of the support member 102, as illustrated at the bottom enlargement section of Fig. 3. In some embodiments, the angle a is selected from the range of about 5° - 120°. In further embodiments, the angle a is selected from the range of about 5° - 90°. In still further embodiments, the angle a is selected from the range of about 30° - 60°. In yet still further embodiments, the angle a is selected from the range of about 35° - 55°.

[00113] It is contemplated, in some embodiments, that the angle a between the first arm 109 and the second arm 110 of the support member 102 at the spread configuration thereof, is characteristic of the expanded configuration of the IUD 100. Thus, the angle a is designed to ensure that the expanded shape of IUD 100 will correspond to (or fit in) the anatomical shape and dimensions of the uterine cavity 150, in order to enhance the contact area or the proximity between the foldable sheet 120 (containing the drug releasing matrix 130) and the inner epithelial layer(s) within the uterine cavity 150.

[00114] According to some embodiments, the expanded configuration of the IUD 100 as disclosed herein is configured to correspond to the anatomical dimensions or shape of the uterine cavity 150, in order to optimize the contact/surface area or proximity between the drug releasing matrix 130 thereof and the inner epithelial layer(s) within the uterine cavity 150 (i.e., an endometrium layer 152), as illustrated at Fig. 3. Advantageously, by maximizing the contact surface area between the drug releasing matrix 130 and the endometrium layer 152 within the uterine cavity 150, the IUD 100 can ensure the effective and direct administration of the pharmaceutical active agent to the endometrium layer 152. For example, for treating menstrual bleeding disorders and/or for reducing the volume of menstrual blood loss in a subject in need thereof, the drug releasing matrix 130 can release tranexamic acid (TA) to the endometrium layer 152, preferably in a uniform and appropriate rate over a prolonged duration of time (or in a controllable manner).

[00115] According to some embodiments, during the spread configuration, the support member 102 is configured to maintain the expansion of the foldable sheet 120 within the uterine cavity. According to some embodiments, IUD 100 is configured to continuously maintain the expanded configuration for the duration of its placement within the uterine cavity 150. [00116] According to some embodiments, the IUD 100 further comprises a mechanical and/or an electrical mechanism configured to facilitate the transition from the compressed configuration to the expanded configuration thereof (not shown). The mechanical mechanism can be located at the junction 107, between the first arm 109 and the second arm 110 of the support member 102. The mechanical mechanism may comprise at least one elastic component such as but not limited to, a spring, and/or an expandable balloon or other pressure inducing or pressurized mechanism. According to some embodiments, the transition from the compressed configuration to the expanded configuration of the IUD 100 and/or the deployment of the foldable sheet 120 is done or is aided by an expandable balloon or other pressure inducing or pressurized mechanism. In further such embodiments, the balloon component is integrated as a part of the insertion mechanism or is inserted separately consequently. In some embodiments, the transition from the compressed configuration to the expanded configuration is aided or facilitated by the expansion of a pressurized balloon inside the uterine cavity.

[00117] According to some embodiments, the support member 102 is made from one or more shape memory material(s), and alternatively or additionally super-elastic materials, configured to enable the transition thereof from the folded configuration to the spread configuration, upon exposure to inner body heat residing within the uterine cavity 150, following delivery thereto. According to some embodiments, the support member 102 comprises at least one shape memory material typically, yet not limited to alloys comprising zinc, copper, gold, iron, nickel, titanium, aluminum, and oxides or composites or combinations thereof. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the support member 102 comprises at least one shape memory material in the form of at least one of an elongated wire, rod, shaft, and the like. Each possibility represents a different embodiment.

[00118] As used herein, the term “shape memory” refers to materials which are able to undergo deformation utilizing an external force under conditions of a first temperature, transition and remain in a deformed state when the external force is removed, and then recover to the original and undeformed state upon being exposed to conditions of a second temperature (i.e., wherein the second temperature is above the first temperature). In this context, the term “shape memory” may refer to and optionally include materials that present superelasticity, which is sometimes referred to as pseudoelasticity, and usually includes materials and specifically alloys showing mostly elastic (not plastic) responses to high strains in magnitudes of 10% and above.

[00119] According to some embodiments, the support member 102 comprises at least one shape memory material selected from, but not limited to, a nickel titanium (also known as 'Nitinol') alloy, an iron-cobalt-nickel-aluminum alloy, an iron-manganese-silicon alloy, a copper-aluminum-nickel alloy, a zinc-copper-aluminum alloy, a zinc-copper-gold-iron alloy, an iron-manganese-silicon alloy, and any combination thereof. Each possibility represents a different embodiment. The shape memory material may comprise an iron-based alloy, a copper-based alloy, or a combination thereof. According to some embodiments, the support member 102 comprises a nickel titanium (Nitinol) alloy.

[00120] According to a specific embodiment, the support member 102 is a nitinol wire which is bent, such that following the transition from the folded configuration to the spread configuration, an angle a in the range of about 20° - 90°, preferably about 30° - 70°, is formed between the first arm 109 and the second arm 110 thereof. Advantageously, the support member 102 is made from a shape memory material which enables the transition from the folded configuration to the spread configuration thereof, and thus enables the expansion of the foldable sheet 120, due to exposure to inner body temperature within the uterine cavity.

[00121] According to some other embodiments, the support member 102 comprises a metal or metal alloy which can enable the transition from the folded configuration to the spread configuration thereof. In some such embodiments, said metal or metal alloy is devoid of any shape memory material(s). In some embodiments, the support member 102 comprising the metal or metal alloy is formed to resiliently maintain its shape when not subjected to physical pressure (e.g., folded into a suitable IUD inserter). In some embodiments, the support member 102 can transition from the folded configuration to the spread configuration thereof, due to the resilient qualities or properties of the materials it is made from. The term “resilient”, as used herein with respect to the support member 102 of the present invention, refers to a member being resistant to permanent deformation when such external force is applied thereto (e.g., during the folded configuration), and having a tendency to return to an original state/shape thereof, when the external force is no longer applied thereto (e.g., the spread configuration). [00122] According to other embodiments, the support member 102 comprises a cobaltchromium (CoCr) metal alloy.

[00123] According to some embodiments, each one of the first end 103 and the second end 105 of the support member 102 is covered by a pad 111 (see Fig. 2A). The ends of the support member 102 may have sharp tips which can scrape or harm the inner tissues of the uterine cavity 150, following the delivery thereto. According to some embodiments, each pad 111 is configured to protect the inner tissues of the uterine cavity 150 (e.g., endometrium layer 152) from the ends of the support member 102. According to some embodiments, each pad I l l is shaped as a round disc. However, it is to be understood that each pad 111 can have the same utilization while having different shapes, such as spheres, ellipsoids, or any other suitable polyhedron in the art. According to some embodiments, each pad I l l is made from an elastic or soft material.

[00124] According to some embodiments, the junction 107 of the support member 102 is coupled to at least one pull wire 115 (see Fig. 3), wherein pull wire 115 can extend therefrom and in the direction of the cervix of the user. According to some embodiments, the pull wire 115 can extend several millimeters into the cervix of the user, to enable the easy and safe extraction of the IUD 100 from the uterine cavity 150, by a care-provider or a physician.

[00125] According to some embodiments, the IUD 100 or portions thereof comprises copper, for use in preventing pregnancy (birth control). According to some embodiments, a copper-based wire or thin layer is wrapped around the at least a portion of the first arm 109, at least a portion of the second arm 110, at least a portion of the junction 107, or any combinations thereof. According to some embodiments, a copper-based thin layer is at least partially encompassing the first arm 109, the second arm 110, the junction 107, or any combinations thereof. According to some embodiments, one or more portions of the foldable sheet 120 comprises a thin coating layer comprising copper coupled/attached thereto. According to some embodiments, the foldable sheet 120 comprises one or more copper wires 140 (e.g., stripes) coupled to one or more external surface(s) thereof (see Fig. 2A). In some embodiments, the copper wires 140 are attached/coupled to one or more external surface(s) of the foldable sheet 120. In some embodiments, the copper wires 140 are 3D printed on one or more external surface(s) of the foldable sheet 120. In some embodiments, each copper wire 140 has a surface area in the range of about 200-380 mm². [00126] According to some embodiments, as was disclosed herein above, the foldable sheet 120 comprises the drug releasing matrix 130 comprising a polymer and at least one pharmaceutical active agent. According to some embodiments, the foldable sheet 120 comprises one or more layers, wherein at least one of those layers is the drug releasing matrix 130. According to some embodiments, the drug releasing matrix 130 is adapted to enable the sustained release of the at least one pharmaceutical active agent therefrom and into the endometrium layer 152 within the uterine cavity 150. Specifically, in some preferred embodiments, the drug releasing matrix 130 is adapted to enable the sustained release of tranexamic acid (TA) therefrom and into the endometrium layer 152 within the uterine cavity 150.

[00127] According to some embodiments, the foldable sheet 120 and the drug releasing matrix 130 are biocompatible. According to some embodiments, the IUDs of the present invention (e.g., IUD 100) are made from biocompatible materials. The term "biocompatible" as used herein, refers to materials having affinity with living tissues, low toxicity and no unacceptable foreign body reactions in the living body.

[00128] According to some embodiments, in the expanded configuration of IUD 100, the foldable sheet 120 has a sheet thickness T1 (see Fig. 2B), wherein the foldable sheet 120 comprises a first surface parallel and opposite to a second surface, wherein the distance therebetween defines the thickness T1 thereof. According to some embodiments, the thickness T1 is selected from the range of about 10 pm to about 5 mm. According to further embodiments, the thickness T1 of the foldable sheet 120 is in the range of about 50 pm to about 1 mm. According to still further embodiments, the thickness T1 of the foldable sheet 120 is in the range of about 100 to about 500 pm. According to specific embodiments, the thickness T1 of the foldable sheet 120 is in the range of about 200 to about 400 pm. It is contemplated, in some embodiments, that the thickness T1 of the foldable sheet 120 as disclosed herein allows to reduce the external dimensions of the IUD 100 during the compressed configuration, and thus to enable the effortless and safe insertion thereof thought the IUD inserter and into the uterine cavity 150. It is further contemplated, that the thickness T1 of the foldable sheet 120 is adapted/designed to ensure that during the compressed configuration, the folded or coiled/curled sheet 120 will fit into a typical IUD inserter.

[00129] According to some embodiments, the foldable sheet 120 comprises a single layer consisting of the drug releasing matrix 130, as illustrated at Fig. 2B. According to further embodiments, the drug releasing matrix 130 comprises a first surface 132 parallel and opposite to a second surface 134 thereof, wherein the distance therebetween defines the thickness T1 of the foldable sheet 120. According to some embodiments, the drug releasing matrix 130 can release the at least one pharmaceutical active agent therefrom towards the endometrium layer 152, from the first surface 132, the second surface 134, or both. It is suggested, in some embodiments, that the release of the pharmaceutical composition from both surfaces 132 and 134 can enhance the delivery efficiency thereof.

[00130] According to some embodiments, the foldable sheet 120 comprises one or more copper wires (e.g., copper wires 140) coupled the first surface 132, the second surface 134, or both, for use in preventing pregnancy (birth control). According to some embodiments, the copper wires can be 3D printed on the first surface 132 of the sheet 120, the second surface 134 thereof, or both. Alternatively or additionally, in some embodiments, one or more portions of the foldable sheet 120 comprises a thin copper layer coupled thereto.

[00131] According to some embodiments, the drug releasing matrix 130 comprises the at least one pharmaceutical active agent, wherein the at least one pharmaceutical active agent is selected from, but not limited to, tranexamic acid (TA), progestogen, progestin (synthetic progestogen), estrogen, additional various hormones, chemotherapeutic drugs, different analgesics such as NSAIDs and corticosteroids, and combinations thereof. Each possibility represents a different embodiment. According to a preferred embodiment, the at least one pharmaceutical active agent is tranexamic acid (TA).

[00132] According to some embodiments, the drug releasing matrix 130 is adapted to maintain its shape and functionality before, during, and after the transition of the IUD 100 from the compressed configuration to the expanded configuration, and to enable the sustained release of the pharmaceutical active agent therefrom and into the endometrium layer 152. According to some embodiments, the drug releasing matrix 130 is adapted to enable the controlled or sustained release of the pharmaceutical active agent therefrom, for a time duration selected from the range of about 3 months to about 5 years. According to some embodiments, the drug releasing matrix 130 is adapted to enable the controlled or sustained release of the pharmaceutical active agent therefrom, for a time duration of at least 3 months, alternately at least 6-12 month, or optionally at least 18 month, or more. [00133] According to some embodiments, the drug releasing matrix 130 is in the form of a polymeric sheet or a film, comprising one or more polymers and/or layers. According to some embodiments, the drug releasing matrix 130 comprises a linear polymer, a crosslinked polymer, a copolymer, an interpenetrating polymer network, and combinations thereof.

[00134] According to some embodiments, the drug releasing matrix 130 comprises one or more polymers selected from, but not limited to, poly(dimethyl siloxane) (PDMS), polycaprolactone (PCL), methyl-vinyl siloxane, ethylene/vinyl acetate copolymers, polyethylene, polypropylene, polypropylene glycol (PPG), ethylene/propylene copolymers, acrylic acid polymers, ethyl ene/ethyl acrylate copolymers, polytetrafluoroethylene (PTFE), polyurethanes, thermoplastic polyurethanes and polyurethane elastomers, polybutadiene, polyisoprene, poly(methacrylate), polymethyl methacrylate, styrene-butadiene-styrene block copolymers, poly(hydroxyethyl-methacrylate) (pHEMA), polyvinyl chloride, polyvinyl acetate, polyethers, polyacrylo-nitriles, polyethylene glycol (PEG), polymethylpentene, polybutadiene, polyhydroxy alkanoates, poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyanhydrides, polyorthoesters, polyethylene imine (PEI), Parylene (poly - parabenzenediyl with ethanediyl bridges), and copolymers thereof. Each possibility represents a separate embodiment of the present invention.

[00135] According to some embodiments, the drug releasing matrix 130 comprises a copolymer and at least one pharmaceutical active agent, wherein the copolymer comprises at least one first region and at least one second region. According to some embodiments, the copolymer is a block-copolymer. According to some embodiments, the drug releasing matrix 130 comprises a block-copolymer and at least one pharmaceutical active agent, wherein the block-copolymer comprises at least one first block and at least one second block. In some embodiments, the block-copolymer comprises a plurality of first blocks/regions and a plurality of second blocks/regions.

[00136] According to some embodiments, the first region/block is more polar relative to the second region/block. In some embodiments, the first region/block is more hydrophilic relative to the second region/block. In some embodiments, the second region/block is more hydrophobic relative to the first region/block. In some embodiments, the first region/block is polar and the second region/block is non-polar. [00137] As used herein, the term “copolymer” refers to a polymer synthesized from two or more monomers with different chemical structures. Each monomer forms a repeating unit in the polymer chain or block. The term “block copolymer” is a polymer that has at least one series of repeating units of one monomer and at least one series of repeating units of a second monomer. The "series of repeating units" of the block copolymer are also referred as "blocks", terms, which may be used interchangeably. Each block includes at least one, at least two, at least three, at least four, at least five, at least ten, or more, repeating units. Each possibility represents a separate embodiment of the present invention. Also, each block may have different chemical or physical properties. For example, one block may by hydrophilic, whereas the other hydrophobic. The term "region", as used herein, refers to one or more blocks arranged consecutively within the copolymer structure. Exemplary configurations of block copolymers include, di-block, tri-block, tetra-block and the like.

[00138] According to some embodiments, the copolymer is an elastomer. According to some embodiments, the copolymer comprises one or more elastomeric blocks or regions. According to some embodiments, the drug releasing matrix 130 comprises an elastomeric copolymer. According to some embodiments, each first region/block and/or second region/block within the copolymer comprises an elastomer. As used herein, the term "elastomer" refers to a polymer that displays rubber-like elasticity, and can be reversibly extended/str etched. According to some embodiments, the copolymer can be reversibly extended/stretched from about 1-500%, due to its elasticity as disclosed herein. According to some embodiments, the copolymer can be reversibly extended/stretched from about 1-100%, 100-200%, 200-300%, 300-400%, 400-500%, or more, due to its elasticity as disclosed herein. Each possibility represents a separate embodiment of the present invention. According to some embodiments, the copolymer can be reversibly extended/stretched from at least about 5% to about 500%, from at least about 10% to about 350%, or from at least about 20% to about 300%. Each possibility represents a separate embodiment of the present invention.

[00139] In some embodiments, said copolymer is a crosslinked copolymer system. In some embodiments, the drug releasing matrix 130 is a crosslinked block-copolymer composite. In some embodiments, each first region/block and/or second region/block within the copolymer comprises at least 2 repeating units. In further embodiments, each first region and/or second region comprises at least 4 repeating units, at least 6 repeating units, at least 8 repeating units, at least 10 repeating units, or more. Each possibility represents a different embodiment.

[00140] According to some embodiments, the first regions/blocks comprise polyols such as, but not limited to, polypropylene glycol (PPG), polyethylene glycol (PEG), polybutylene glycol (PBG), polyvinyl alcohol (PVA), polysaccharide, and copolymers thereof. Each possibility represents a different embodiment. According to certain embodiments, the first regions comprise PPG, PEG, or both. According to some embodiments, the units of the first regions of the block-copolymer of the drug releasing matrix 130 are selected from, but not limited to, propylene glycol, ethylene glycol, vinyl alcohol, glycerol, pentaerythritol, sorbitol, and combinations thereof. Each possibility represents a different embodiment. According to some embodiments, the units of the first regions of the block-copolymer of the drug releasing matrix 130 comprise propylene glycol, ethylene glycol, or both

[00141] According to some embodiments, the second regions of the block-copolymer of the drug releasing matrix 130 are less polar relative to the first regions thereof, wherein the second regions comprise one or more of a polyester, a polyurethane, a polyurea, and copolymers thereof. Each possibility represents a different embodiment.

[00142] According to some embodiments, the repeating units of the second regions/blocks are represented by the formula: (-CO-X-(CH-R)n-Y-), wherein X is O, NH or absent and Y is O or NH, wherein n is an integer selected from 1 to 10, and R is selected from H, alkyl, aryl, hydroxyl and amine. According to some embodiments, R is H or alkyl. According to some embodiments, the repeating units of the second blocks are represented by the formula: (-CO- (CH-R)_n-O-), wherein n is an integer selected from 1 to 10, and R is selected from H, alkyl, aryl, hydroxyl and amine. According to some embodiments, the repeating units of the second blocks can be a polyurethane and are represented by the formula: (-CO-NH-(CH-R)n-O-), wherein n is an integer selected from 1 to 10, and R is as defined above. According to some embodiments, the repeating units of the second blocks can be a polyurea and are represented by the formula: (-CO-NH-(CH-R)n-NH-), wherein n and R are as defined above.

[00143] According to a certain embodiment, the repeating units of the second blocks are represented by the formula: (-CO-(CH2)_n-O-), wherein n is an integer selected from 2 to 8, or preferably wherein n is 5. [00144] According to some embodiments, the block copolymer is a crosslinked blockcopolymer.

[00145] As used herein, the term “cross-linking” means linking of polymer chains or blocks to promote a change in the polymer's mechanical properties. Cross-linking may also include curing and includes, without limitation, cross-linking by chemical reaction, radiation exposure, polymerization, electron beam exposure, gamma-radiation, UV light exposure, and vulcanization. As used herein, the term “cross-linked polymer” means a polymer comprising bonds linking one polymer chain or block to another as a result of cross-linking. As used herein, the term “cross-linkable polymer” means a polymer comprising polymer chains (i.e., a series of repeating units) capable of bonding to another polymer chain, either directly or indirectly, as a result of cross-linking. As used herein, the term “cross-linking agent” means a chemical formulated to interact with a cross-linkable polymer or partially cross-linked polymer so as to promote cross-linking of the polymer, whether or not the cross-linking occurs upon mixing of the cross-linking agent with the polymer or only upon subjecting the mixture to additional cross-linking processes or energy forms, such as those mentioned above.

[00146] According to some embodiments, the polymer is crosslinked by a crosslinking moiety such as 2- isocyanatoethyl methacrylate (IEMA), or any other suitable crosslinker in the art. According to some embodiments, the crosslinking moiety comprises an acrylate connected to an isocyanate.

[00147] Without wishing to being bound to any theory or mechanism of action, it is contemplated in some embodiments, that the drug releasing matrix 130 is a crosslinked copolymer composite comprising the at least one pharmaceutical active agent dispersed, encapsulated, retained, or housed therein, preferably within the second blocks/regions thereof. According to some embodiments, the pharmaceutical active agent is TA, and wherein the TA is dispersed, retained, encapsulated, or housed in the second regions of the copolymer. It is contemplated, in some embodiments, that the TA is dispersed, retained, encapsulated by, or housed in the second (less polar) regions due to dipoledipole intermolecular forces and/or hydrogen bonds. Additionally or alternatively, in some embodiments, the TA is at least partially dispersed, encapsulated by, retained, or housed in the first regions of the drug releasing matrix 130, due to similar forces and/or bonds as disclosed herein above. [00148] According to some embodiments, the weight ratio between the pharmaceutical active agent (e.g., TA) to the drug releasing matrix 130 (i.e., the crosslinked copolymer composite) is selected from the range of about 1:30-1 :3. According to some embodiments, the weight of the pharmaceutical active agent (e.g., TA) is in the range of about 0.1-50% w/w based on the total weight of the drug releasing matrix 130. According to some embodiments, the weight of TA is in the range of about 1-30% w/w based on the total weight of the drug releasing matrix 130. According to some embodiments, the weight of TA is in the range of about 5-30% w/w based on the total weight of the drug releasing matrix 130. According to some embodiments, the pharmaceutical active agent (e.g., TA) is present within the drug releasing matrix 130 in a minimal weight percent of above about 5% w/w. According to some embodiments, TA is present within the drug releasing matrix 130 in a weight percent of above about 10% w/w. According to some embodiments, TA is present within the drug releasing matrix 130 in a weight percent of above about 15% w/w.

[00149] According to some embodiments, the drug releasing matrix 130 as disclosed herein above is designed to enable the sustained slow release of tranexamic acid (TA) therefrom, by aqueous aided diffusion into the endometrium layer 152 within the uterine cavity 150. It is contemplated that in order to do so, the drug releasing matrix 130 is a crosslinked copolymer composite comprising the TA dispersed, encapsulated by, or housed therein, preferably within the second (i.e., less polar) regions thereof. The first (i.e., polar) regions may act as hydrophilic areas which enable and encourage diffusion of various bodily fluids (e.g., aqueous based), while the second (less polar) regions may house the TA. Additionally or alternatively, the first (polar) regions may also at least partially house the TA. Advantageously, the combination between the first regions and the second regions of the crosslinked copolymer composite as disclosed herein above, wherein the first regions are more polar relative to the second regions, can enable to enhance and adjust the diffusion rate of TA from the drug releasing matrix 130, and thus to provide enhanced drug release capabilities to the IUD.

[00150] According to some embodiments, the drug releasing matrix 130 as disclosed herein above is designed to enable the release of TA therefrom in a rate selected from the range of about 0.05-1000 pg per day. In some embodiments, the release rate is selected from the range of about 0.1-50 pg per day. In some embodiments, the release rate is selected from the range of about 10-1000 pg per day. In certain embodiments, the release rate is selected from the range of about 0.05-0.25 pg per day.

[00151] Reference is now made to Figs. 4A-C. Fig. 4A illustrates a view in perspective of an IUD 200 in an expanded configuration, according to some embodiments. Figs. 4B-C illustrates cross sectional top views of the IUD 200 of Fig. 4A, in the expanded configuration, according to some embodiments.

[00152] IUD 200 of Figs. 4A-C is similar to IUD 100 of Figs. 1A-3, and therefore share many common features as can be appreciated by the skilled in the art. Specific features or components are described below.

[00153] Thus, Figs. 4A-C shows exemplary alternative implementations of some components of the IUD 100. Specifically, the foldable sheet 220 of IUD 200 comprises one or more additional layer(s).

[00154] According to some embodiments, IUD 200 comprises a foldable sheet 220, wherein the foldable sheet 220 is identical to the foldable sheet 120 of IUD 100, except that sheet 220 further comprises a support layer 236 connected to one or more portions of the support member 102. In some embodiments, the support layer 236 is extending between at least two ends, such that one end thereof is at least partially coupled to an external surface of the first arm 109 of the support member 102, and another end thereof is at least partially coupled to an external surface of the second arm 110 of the support member 102. In further such embodiments, the support layer 236 is extending between the first arm 109 and the second arm 110 of the support member 102, and is coupled thereto.

[00155] In some embodiments, the support layer 236 is in the form of a mesh structure. In further embodiments, said mesh comprises woven or knitted thin filaments, wherein the mesh can be secured to the one or more portions of the support member 102 by adhesives or directly by an intertwine arrangement. In further embodiments, each thin filament has a diameter of about 100-150 pm.

[00156] In some embodiments, the support layer 236 is biocompatible.

[00157] In some embodiments, the support layer 236 is made from a metal or metal alloy, one or more polymer(s), and combinations thereof. In some embodiments, the support layer 236 comprises at least one polymer selected from polypropylene (PP), polyester, polyamide (PA), polyacrylate, polymethacrylate, and copolymers thereof. Each possibility represents a separate embodiment of the present invention. In some embodiments, the polyester is selected from but not limited to, polyethylene terephthalate (PET), polybutylene terephthalate (PBT), styrene-ethylene-butylene-styrene (SEBS), polyhydroxybutyrate (PHB), and the like. Each possibility represents a separate embodiment of the present invention. In some embodiments, the support layer 236 is made from a polyester-based mesh, similar to a mesh used during abdominal hernia surgery. In some embodiments, the polyamide is selected from but not limited to, PA 6, PA 6.6, PA 11, PA12 and the like. Each possibility represents a separate embodiment of the present invention.

[00158] According to some embodiments, the support layer 236 comprises at least one biocompatible material selected from but not limited to, polytetrafluoroethylene (PTFE - Teflon), polyethylene terephthalate (PET - Dacron), fluorocarbon -based fluoroelastomer materials (FKM - Viton), silicone, and combinations thereof. Each possibility represents a separate embodiment of the present invention.

[00159] In some embodiments, the support layer 236 has a thickness T2 (see Fig. 4B) in the range of about 5 pm to about 2 mm. According to further embodiments, the thickness T2 of the support layer 236 ranges from about 10 pm to about 500 pm. According to still further embodiments, the thickness T2 of the support layer 236 ranges from about 50 to about 200 pm. According to some embodiments, the thickness T2 of the support layer 236 ranges from about 20 to about 50 pm. According to some embodiments, the thickness T2 of the support layer 236 ranges from about 5 to about 30 pm.

[00160] Advantageously, in some embodiments, the support layer 236 can provide flexibility, mechanical stability and support for the entire foldable sheet 120, and thus to ensure that the foldable sheet 120 will not lose structural integrity (e.g., suffer tears) during the transition from the compressed configuration to the expanded configuration of the IUD 100, and/or during the deployment or placement thereof within the uterine cavity 150. For example, the support layer 236 can prevent the foldable sheet 120 from tearing during the transition from the compressed configuration to the expanded configuration of the IUD 100, and/or during the folding thereof into the folded configuration prior to the insertion into the uterine cavity 150. [00161] Furthermore, in some embodiments, it is contemplated that the dimensions or size of the support layer 236 can limit the expansion of the IUD 100 during the transition from the compressed configuration to the expanded configuration thereof, and thus to protect the integrity of the foldable sheet 120 and to ensure that the expanded configuration of the IUD 100 as disclosed herein above will correspond to the anatomical dimensions or shape of the uterine cavity 150.

[00162] According to some embodiments, the drug releasing matrix 130 is enveloping or surrounding at least a portion of the support layer 236, as illustrated at Fig. 4B. According to further such embodiments, the foldable sheet 120 comprises: the support layer 236 as an inner layer, and the drug releasing matrix 130 as an outer layer which surrounds the support layer 236. According to other embodiments, the foldable sheet 120 comprises two outer layers accommodating therebetween an inner layer, wherein the inner layer is the support layer 236, wherein each outer layer is attached to an opposite surface of the support layer 236, and wherein each outer layer is the drug releasing matrix 130 (not shown).

[00163] According to some embodiments, the drug releasing matrix 130 is attached to (or is embedded on) at least a portion of the support layer 136, such that the drug releasing matrix 130 can release the pharmaceutical composition therefrom towards the endometrium layer 152, from the first surface 132, the second surface 134, or both.

[00164] According to some embodiments, the drug releasing matrix 130 is attached to the support layer 236 utilizing biocompatible adhesives, such as, but not limited to: cellulose, cellulose derivatives, hydroxy-ethyl cellulose, sodium carboxymethylcellulose, partially crosslinked polyacrylic acid, carboxy vinyl polymers, lectin, alginates, various gums, carbomers and cornstarch, and the like, and any combination thereof. Each possibility represents a separate embodiment of the present invention. Furthermore, the drug releasing matrix 130 can be attached to the support layer 236 utilizing thermal means, such as the utilization of heat (i.e., melting).

[00165] In some embodiments, the foldable sheet 120, the drug releasing matrix 130, the support layer 236, or any combination thereof, are made of bio-degradable materials, meaning polymers or oxides that degrade and break down in the body over time in a biocompatible fashion. Such materials tend to leave no structural residue and thus eliminate the need to be removed over time. Some embodiments incorporate such polymers as for example poly-esters, poly-amides, poly-ethers or polysaccharides. Said materials can include the incorporation of catalysts for their break down as part of their structural components.

[00166] According to some embodiments, the IUD 200 comprises at least one biocompatible radiopaque metal material, selected from but not limited to: gold, platinum, titanium, silver, copper, tantalum, barium, bismuth, iridium, tungsten, rhenium, osmium, iridium, palladium, and biocompatible oxides and combinations thereof. Each possibility represents a separate embodiment. It is contemplated that the use of radiopaque materials can enable the detection of the IUD 100 by scanning devices using penetrating wave or particle technologies such as x-ray or ultrasound. The radiopaque metal material can be incorporated within the drug releasing matrix 130, the support layer 236, the foldable sheet 120, the support member 102, or any combination thereof. Each possibility represents a separate embodiment. As used herein, the term “radiopaque” refers to a material, or any other fiduciary marker, that prevents, blocks, scatters, refracts, reflects or obstructs in any way the passage of electromagnetic radiation therethrough, and therefore is detectable by a scanning device using an x-ray or other penetrating wave or particle technologies, such as neutron beams or gamma rays, fluoroscopy, ultrasound, MRI, infrared, near-infrared, laser, electromagnetic or radio waves technologies, and the like.

[00167] According to some embodiments, the foldable sheet 220 comprises an outer layer 238, as illustrated at Fig. 4C. According to some embodiments, said outer layer 238 is enveloping or surrounding at least a portion of the drug releasing matrix 130. According to some embodiments, the foldable sheet 120 comprises: the support layer 236 as an inner layer; the drug releasing matrix 130 surrounding the support layer 236; and the outer layer 238 surrounding the drug releasing matrix 130 (see Fig. 4C). According to other embodiments, the foldable sheet 120 comprises: the drug releasing matrix 130 as an inner layer; and the outer layer 238 surrounding the drug releasing matrix 130 (not shown). In further embodiments, the layers are vertically stacked one on top of the other, perpendicularly to a longitudinal axis (e.g., longitudinal axis 680), and are attached/coupled to one another.

[00168] According to some embodiments, the foldable sheet 120 comprises two outer layers 238 accommodating therebetween the drug releasing matrix 130, so that one outer layer 238 is attached to the first surface 132 of the drug releasing matrix 130, and the other outer layer 238 is attached to the second surface 134 thereof. According to some embodiments, the outer layer 238 is attached to the drug releasing matrix 130 utilizing biocompatible adhesives and/or thermal means, as disclosed herein above.

[00169] According to some embodiments, the outer layer 238 has a thickness which can be identical to the thickness T2 of the support layer 236, as disclosed herein above. According to some embodiments, the thickness of the outer layer 238 ranges from about 5 to about 100 pm. According to further embodiments, the thickness of the outer layer 238 ranges from about 5 to about 30 pm.

[00170] According to some embodiments, the outer layer 238 is made from an electrically responsive porous layer, which is configured to enable the controlled release of the pharmaceutical active agent from the drug releasing matrix 130 therethrough (through the pores thereof) and into the uterine cavity 150. It is contemplated that the characteristics of the outer layer 238, such as porosity, chemical and physical properties, and the like, can determine and change the permeability abilities thereof, and thus to affect the pharmaceutical active agent diffusion rate therethrough and into the uterine cavity 150. According to some embodiments, the electrically responsive porous outer layer 238 is configured to have variable or adjustable permeability, which can enable various bodily fluids (e.g., aqueous based) from within the uterine cavity to penetrate/diffuse therethrough and to contact the drug releasing matrix 130. Thus, the electrically responsive porous outer layer 238 can enable the release of the pharmaceutical active agent therethrough by aqueous aided diffusion, and into the endometrium layer 152 within the uterine cavity 150.

[00171] According to some embodiments, the abovementioned electrically or magnetically responsive layer can be based on a variety of phenomena, and among others yet not limited to, to the change of pore size due to heating, that can for example be actuated with Joule (electrical) heating, electrostatic response to an electric field in the molecular level, or piezoelectric responsiveness to direct currents or to an applied frequency, for example as disclosed by PURKAIT, M. K., et al. (PURKAIT, M. K., et al., Electric field-responsive membranes. In: Interface Science and Technology. Elsevier, 2018. p. 173-191).

[00172] According to other embodiments, the electrically or magnetically responsive layer can comprise a material specific or ion specific, for example ALLIOUX, F. M., et al. discloses the manipulation of electrical properties of a resin in a membrane (ALLIOUX, F. M., et al., Smart electrically responsive hybrid ion-selective membranes for selective gated transport of ionic species. Materials Horizons, 2018, 5.6: 1185-1193).

[00173] According to some embodiments, the outer layer 238 is an electrically or magnetically responsive porous membrane. In further embodiments, the outer layer 238 is an electrically or magnetically responsive nanoporous membrane. Said nanoporous membrane has pores in the size of about 100 nanometers or smaller, which is configured to be reversibly actuated from a closed or semi closed state to an open state due to the influence of an electric or magnetic field, or an electric current. It is contemplated that the electrically responsive nanoporous membrane is configured to have variable permeability, i.e. to reversibly adjust its pore size, in response to the influence of at least one of: electric field or current, magnetic field, or a combination thereof.

[00174] According to some embodiments, the outer layer 238 is configured to be reversibly actuated from a closed or semi closed state to an open state (and vice versa), in response to the influence of at least one of: electric field or current, magnetic field, or a combination thereof, and thus to enable the controlled release of the pharmaceutical active agent from the drug releasing matrix 130 therethrough. According to some embodiments, in the closed or semi closed state the pores of the outer layer 238 are fully closed or semi closed, thereby preventing or nearly preventing or substantially preventing the drug release therethrough.

[00175] As used herein, the term “open state” refers to a state of the outer layer 238, wherein the pores of the layer are open, thereby enabling the drug release from the drug releasing matrix 130 therethrough.

[00176] As used herein, the term “closed state” refers to a state of the outer layer 238, wherein the pores of the layer are closed, thereby terminating or stopping the drug release from the drug releasing matrix 130 therethrough.

[00177] As used herein, the term “semi closed state” refers to a state of the outer layer 238, wherein the pores of the layer are semi closed, so that the drug release rate of the pharmaceutical active agent from the drug releasing matrix 130 therethrough is reduced by at least 5 times, optionally at least 10 times, or alternatively at least 20 times, relative to the release rate of the pharmaceutical active agent therethrough during the open state thereof. [00178] According to some embodiments, the outer layer 238 is configured to be reversibly actuated from a closed or semi closed state to an open state (and vice versa), in response to a change in the direction and/or in the intensity of an external magnetic field. According to some embodiments, the electrically responsive nanoporous membrane is configured to be reversibly actuated from a closed or semi closed state to an open state (or vice versa), in response to the activation or deactivation of the external magnetic field.

[00179] According to some embodiments, the influence of an external magnetic or electric field can be generated by an external electromagnet positioned externally to the skin of the user. According to other embodiments, a magnetic or electric field (or current) can be generated by an internal electric component disposed within a portion of the IUD 400 (see Fig. 6B).

[00180] According to some embodiments, the outer layer 238 is an electrically or magnetically responsive porous membrane comprising at least one material selected from but not limited to, a polypyrrole doped with dodecylbenzene sulfonate anions (PPy/DBS) (Nano Lett. 2011, 11, 3, 1284-1288, Publication Date: January 31, 2011); a polycarbonate (BORMASHENKO, Edward, et al. Electrically controlled membranes exploiting Cassie- Wenzel wetting transitions. Scientific Reports, 2013, 3.1: 1-5.); a graphene oxide (Zhou, KG., Vasu, K.S., Cherian, C.T. et al. Electrically controlled water permeation through graphene oxide membranes. Nature 559, 236-240 (2018)), and combinations thereof. It is to be understood, however, that other suitable electrically or magnetically responsive porous membranes can be also used in the context of the present invention.

[00181] According to some embodiments, as was disclosed herein above, the permeability of the outer layer 238 can be controlled or adjusted by the influence of a magnetic or an electric field (or current), so that the outer layer 238 will be reversibly actuated from a closed or semi closed state to an open state, which can affect the release rate and duration of the pharmaceutical active agent from the drug releasing matrix 130 therethrough. Furthermore, by reversibly actuating the outer layer 238 from a closed or semi closed state to an open state, the release of the pharmaceutical active agent can be initiated or terminated (or nearly terminated). In some embodiments, the magnetic or an electric field (or current) can be generated internally within a portion of the IUD, or externally by an external designated device, wherein the user can directly control the activation thereof, and thereby to directly control the variable or adjustable permeability of the outer layer 238. Advantageously, the electrically or magnetically responsive porous outer layer 238 as disclosed above can enable the user to directly control and adjust the release rate of the pharmaceutical active agent therethrough and into the uterine cavity 150. Thus, the controlled drug release abilities of the IUD 400 can be customized according to individual requirements upon user demand.

[00182] According to some embodiments, the outer layer 238 can be divided to at least two independent sections. In further embodiments, the outer layer 238 is divided to at least 4 independent sections. In still further embodiments, the outer layer 238 is divided to 4-10 sections, thereby forming an array of independent sections. In some embodiments, each section of the outer layer 238 can be controlled separately by a different field or current. In some embodiments, the permeability of each section of the outer layer 238 can be controlled or adjusted by the influence of a different magnetic or an electric field (or current). Thus, the array of independent sections of the outer layer 238 can enable to adjust the release rate and duration of the pharmaceutical active agent therethrough from each section separately, and thereby to adapt the overall release rate from the entire outer layer 238 according to individual physiological requirements and needs from various users.

[00183] Reference is now made to Figs. 5A-B, illustrating a view in perspective and a cross sectional top view, accordingly, of an IUD 300 in an expanded configuration, according to some embodiments.

[00184] IUD 300 of Figs. 5A-B is similar to IUD 100 of Figs. 1-3 or IUD 200 of Figs. 4A- C, and therefore share many common features as can be appreciated by the skilled in the art. Specific features or components are described below.

[00185] Thus, Figs. 5A-B shows exemplary alternative implementations of some components of the previous IUDs. Specifically, IUD 300 comprises a foldable sheet 320 forming a pocket-shape and encompassing at least a portion of the support member 102.

[00186] According to some embodiments, IUD 300 comprises a foldable sheet 320. According to some embodiments, the foldable sheet 320 of IUD 300 has the same properties and is made from the same materials/layers as the foldable sheet 120 of IUD 100 or to the foldable sheet 220 of IUD 200, as disclosed above.

[00187] According to some embodiments, the foldable sheet 320 forms a pocket like shape encompassing at least a portion of the first arm 109 and the second arm 110 of the support member 102, as well as the junction 107 extending therebetween. According to some embodiments, the pocket shape of the foldable sheet 320 is open ended at the end opposite to the junction 107, such that both the first arm 109 and the second arm 110 can extend therethrough away from the open end 322.

[00188] According to some embodiments, the foldable sheet 320 is made from at least two separate sheets coupled to each other at the ends thereof, so as to form a pocket like shape having one open end. According to other embodiments, the foldable sheet 320 in a unitary sheet. As used herein, the term “unitary” refers to a one-piece component or part.

[00189] Reference is now made to Figs. 6A-B. Fig. 6A illustrates an IUD 400 in an expanded configuration disposed within a uterine cavity 150, according to some embodiments. Fig. 6B illustrates an enlargement of a portion of the IUD 400, according to some embodiments.

[00190] IUD 400 of Figs. 6A-B is similar to IUD 100 of Figs. 1-3 or IUD 200 of Figs. 4A- C, and therefore share many common features as can be appreciated by the skilled in the art. Specific features or components are described below.

[00191] Thus, Figs. 6A-B shows exemplary alternative implementations of some components of the previous IUDs. Specifically, IUD 400 features a curvilinear support member 402.

[00192] According to some embodiments, IUD 400 comprises a foldable sheet 420. According to some embodiments, the foldable sheet 420 of IUD 400 has the same properties and is made from the same materials/layers as the foldable sheet 120 of IUD 100 or to the foldable sheet 220 of IUD 200. According to some embodiments, the curvilinear support member 402 is made from the same material(s) and has the same features as the support member 102 of IUD 100 as disclosed above.

[00193] According to some embodiments, IUD 400 comprises at least one at least one support member 402 comprising a first arm 409 and a second arm 410 joined at a junction 407, wherein the first arm 409 is extending between a first end 403 and the junction 407, and wherein the second arm 410 extending between the junction 407 and a second end 405 thereof. [00194] According to some embodiments, the first arm 409 and the second arm 410 have a non-linear shape in the spread configuration thereof, such that each arm can define a curvilinear shape. In some embodiments, the first arm 409 is bent such that a first bending point 415 is formed, defining a first arm section 440 between the junction 407 and the first bending point 415; and a second arm section 442 is formed between the first bending point 415 and the first end 403. In some embodiments, the second arm 410 is bent such that a second bending point 416 is formed, defining a first arm section 444 between the junction 407 and the second bending point 416; and a second arm section 446 is formed between the second bending point 416 and the second end 405. In further embodiments, in the spread configuration of the support member 402, both first arm sections 440 and 444 are substantially parallel to each other defining together with the junction 407 a U-shaped configuration. In further embodiments, in the spread configuration of the support member 402, both second arm sections 442 and 446 have similar curvilinear shapes.

[00195] According to some embodiments, the sheet 420 is attached/coupled to the second arm sections 442 and 446. In some embodiments, the sheet 420 is not attached to the first arm sections 440 and 444.

[00196] Advantageously, it is contemplated in some embodiments, that during the expanded configuration of IUD 400, the curvilinear shapes of the first arm 409 and the second arm 410 of the support member 402 can enable an enhanced fit between the anatomical dimensions or shape of the uterine cavity 150 and the IUD 400, so that the surface area or proximity between the drug releasing matrix 130 of the sheet 420 and the endometrium layer 152 within the uterine cavity 150 is further enhanced. Furthermore, it is contemplated in some embodiments, that the curvilinear first arm 409 and second arm 410 having the first and second bending points 415 and 416, accordingly, enables an improved and rapid transition from the folded configuration to the spread configuration of the support member 402, thus providing enhanced mechanical stability to the expansion of the foldable sheet 420 within the uterine cavity 150.

[00197] According to some embodiments, the first arm sections 440 and 444 extend into a member 460, and are optionally coupled thereto (see Fig. 6B). According to some embodiments, the IUD 400 comprises a member 460 configured to accommodate therein various electrical elements, such as for example, a power source, a communication module, a controller, an electric field generator, and combinations thereof (illustrated at Figs. 11A-C). According to some embodiments, the member 460 can accommodate therein various electrical elements, such as an electromagnetic force generator which is configured to generate a magnetic or an electric field (or current), and thus to enable a user to directly control and adjust the release rate of the pharmaceutical active agent from the IUD 400, as was disclosed herein above with regards to the porous outer layer 238. According to some embodiments, the member 460 is similar or identical to the elongated member 660 of Figs. 11 A-C, as disclosed herein below.

[00198] According to some embodiments, the second arm sections 442 and 446 of the first and second arms 409 and 410 are extending away from the member 460.

[00199] According to some embodiments, the member 460 is in the shape of a hollow cylinder. In further embodiments, the member 460 is an elongated member. In further embodiments, the member 460 is in the shape of an elongated cylinder. However, it is to be understood that member 460 can have the same utilization while having a different shape, such as a sphere, an ellipsoid, a box, or any other suitable polyhedron in the art.

[00200] Reference is now made to Figs. 7A-B illustrating views in perspective of an IUD 500, in a compressed configuration and in an expanded configuration, accordingly, according to some embodiments.

[00201] IUD 500 of Figs. 7A-B is similar to IUD 100 of Figs. 1-3 or IUD 200 of Figs. 4A- C, and therefore share many common features as can be appreciated by the skilled in the art. Specific features or components are described below.

[00202] Thus, Figs. 7A-B shows exemplary alternative implementations of some components of the previous IUDs. Specifically, IUD 500 comprises an elongated member 560 coupled to one of the arms of the support member 102.

[00203] According to some embodiments, the IUD 500 comprises an elongated member 560 configured to accommodate therein various electrical elements, such as for example, a power source, a communication module, a controller, an electric field generator, and combinations thereof (illustrated at Figs. 11 A-C). According to some embodiments, the elongated member 560 can accommodate therein various electrical elements, such as an electromagnetic force generator which is configured to generate a magnetic or an electric field (or current), and thus to enable a user to directly control and adjust the release rate of the pharmaceutical active agent from the IUD 500, as was disclosed herein above with regards to the porous outer layer 238. According to some embodiments, the elongated member 560 is similar or identical to the elongated member 660 of Figs. 11 A-C, as disclosed herein below.

[00204] According to some embodiments, the elongated member 560 is in the shape of a hollow cylinder. In further embodiments, the elongated member 560 is in the shape of an elongated cylinder. However, it is to be understood that elongated member 560 can have the same utilization while having a different shape, such as a sphere, an ellipsoid, a box, or any other suitable polyhedron in the art.

[00205] According to some embodiments, the elongated member 560 is coupled to at least a portion of the support member 102. In some embodiments, the elongated member 560 is coupled to at least a portion of the first arm 109.

[00206] According to some embodiments, during the transition from the compressed configuration to the expanded configuration, the second arm 110 of the support member 102 is configured to expand in the opposite direction relative to the elongated member 560. According to some embodiments, the foldable sheet 120 is coupled to the second arm 110 at one end, and to the elongated member 560 and/or the first arm 109 at the other end, such that when the IUD 500 transitions between the compressed configuration to the expanded configuration, the sheet 120 spreads therewith and expands/spreads as well.

[00207] Reference is now made to Figs. 8A-10B. Figs. 8A-D illustrates views in perspective of an IUD 600, in compressed configurations, according to different embodiments. Fig. 9 illustrates a view in perspective of the IUD 600 of Figs. 8B-C, in an expanded configuration, according to some embodiments. Figs. 10A-B illustrates cross sectional top views of the IUD 600, in the expanded configuration, according to some embodiments.

[00208] IUD 600 of Figs. 8A-10B is similar to IUD 500 of Figs. 7A-B, and therefore share many common features as can be appreciated by the skilled in the art. Specific features or components are described below.

[00209] Thus, Figs. 8A-10B shows exemplary alternative implementations of some components of the previous IUDs. Specifically, IUD 600 comprise a foldable sheet 620 comprising two sections and an elongated member 660. [00210] According to some embodiments, IUD 600 comprises an elongated member 660. According to some embodiments, IUD 600 comprises at least one support member 602 comprising a first arm 609 and a second arm 610 joined at a junction 607, wherein the first arm 609 is extending between a first end 603 and the junction 607, and wherein the second arm 610 extending between the junction 607 and a second end 605 thereof. According to some embodiments, the first arm 609 and the second arm 610 are separate components attached to each other indirectly via an intermediate component (i.e., elongated member 660). According to some embodiments, the first arm 609 and the second arm 610 are defining a plane 601 therebetween (see Fig. 9). According to some embodiments, the first arm 609 and the second arm 610 are coupled to opposite portions of an external surface of the elongated member 660. According to some embodiments, a first surface 661 A of the elongated member 660 defines the junction 607 (see Fig. 1 IB).

[00211] According to some embodiments, IUD 600 comprises at least one foldable sheet 620 comprising at least two separate sections. According to some embodiments, the foldable sheet 620 comprises two separate sheet sections defining a first sheet section 620A and a second sheet section 620B. In some embodiments, each of the sheet sections 620 A and 620B is attached to a corresponding arm.

[00212] According to some embodiments, the first sheet section 620A extends between at least two sides, wherein a first side 621 A thereof is connected/coupled to an external surface of the first arm 609, and a second side 622A thereof is connected to an external surface of the elongated member 660 (see Fig. 9). According to some embodiments, the second sheet section 620B extends between at least two sides, wherein a first side 62 IB thereof is connected/coupled to an external surface of the second arm 610, and a second side 622B thereof is connected to an external surface of the elongated member 660. According to some embodiments, the first and second sheet sections 620A and 620B are coupled to substantially opposite portions of an external surface of the elongated member 660. According to some embodiments, each of the first and second sheet sections 620A and 620B further comprises a third side 623A and 623B, respectively, which is configured to face the uterine cavity in the spread configuration.

[00213] According to some embodiments, the elongated member 660 is configured to provide mechanical support to each one of the sheet sections 620A and 620B connected thereto. According to some embodiments, elongated member 660 has a rigid or semi rigid structure. According to some embodiments, elongated member 660 is flexible. According to other embodiments, elongated member 660 is hollow and is configured to accommodate therein various electronic components.

[00214] According to some embodiments, during the folded configuration of the first and second arms 609 and 610, the IUD 600 is in the compressed configuration. According to some embodiments, during the folded configuration, the first end 603 and the second end 605 are in the vicinity of each other and/or the elongated member 660. According to some embodiments, during the folded configuration, the first arm 609 and the second arm 610 are in the vicinity of each other and/or the elongated member 660 (see Figs. 8A-D).

[00215] According to some embodiments, during the folded configuration, the first and second arms 609 and 610 are configured to maintain the sheet sections 620A and 620B, respectively, in a curled/coiled or folded configuration or state, in order to reduce the external dimensions of IUD 600, and thereby to enable effortless and safe insertion thereof thought the IUD inserter.

[00216] According to some embodiments, during the folded configuration, the first and second arms 609 and 610 are configured to maintain the sheet sections 620A and 620B, respectively, in accordion-like fold confirmations, between the arms and the elongated member 660 (see Fig. 8A).

[00217] According to some embodiments, during the folded configuration, the first and second arms 609 and 610 are configured to maintain the sheet sections 620A and 620B, respectively, in a curled (or coiled) configuration, such that the sheet sections 620A and 620B are curled around each other, and around an external surface of the elongated member 660 (see Fig. 8B).

According to some embodiments, during the folded configuration, the first and second arms

609 and 610 are configured to maintain the sheet sections 620 A and 620B, respectively, in a curled (or coiled) configuration, such that each sheet section 620A or 620B is separately curled around itself relative to opposite portions of the external surface of the elongated member 660 (see Fig. 8C). In further such embodiments, the first and second arms 609 and

610 are coupled to opposite portions of the external surface of the elongated member 660 in an offset position relative to one another (see Fig. 8D), in parallel to a longitudinal axis 680, in order to enable enhanced compression of the sheet sections. In still further such embodiments, the second arm 610 is coupled to the elongated member 660 so that it is positioned about 0.1-5 mm, alternately about 0.5-3 mm, or optionally about 1-2 mm, above or below the first arm 609 in parallel to the longitudinal axis 680.

[00218] According to some embodiments, following delivery, the support member 602 is configured to transition between the folded configuration to the spread configuration which facilitates transition of the IUD 600 from the compressed configuration to the expanded configuration, wherein during the expanded configuration the first arm 609, the second arm 610, and each of the sheet sections 620A and 620B all reside in the same plane 601 (see Fig. 9). According to some embodiments, the sheet sections 620A and 620B are coupled to the first and second arms 609 and 610, such that when the arms 609 and 610 transitions between the folded configuration to the spread configuration, the sheet sections 620A and 620B moves/ spreads therewith to form expanded/stretched states thereof.

[00219] According to some embodiments, during the transition from the folded configuration to the spread configuration, the first arm 609 and the second arm 610 are configured to expand or extend in opposite directions relative to each other, such that the first end 603 and the second end 605 are distanced from each other, within the uterine cavity, such that in the expanded configuration both arms are substantially linear relative to one another. According to some embodiments, the transition from the folded configuration to the spread configuration of the first arm 609 and the second arm 610 results in the expansion of the sheet sections 620A and 620B within the uterine cavity, and thus forms the expanded configuration of the IUD 600.

[00220] According to some embodiments, during the expanded configuration, device 600 is configured to fit within the dimensions of the uterine cavity of a female human. According to some embodiments, the maximum length of device 100 during the expanded configuration, along the longitudinal axis 680, is in the range of about 10 to about 40 mm. According to further embodiments, the maximum length of device 100 during the expanded configuration, along the longitudinal axis 680, is in the range of about 32 to about 35 mm.

[00221] The first and second arms 609 and 610 of IUD 600 can be identical to the first and second arms 109 and 110, accordingly, of IUD 100, and can comprise the same materials. According to some embodiments, the first and second arms 609 and 610 of IUD 600 are made from one or more shape memory material(s) configured to enable the transition thereof from the folded configuration to the spread configuration, upon exposure to inner body heat residing within the uterine cavity 150, following delivery thereto, as disclosed herein above.

[00222] According to some embodiments, each one of the sheet sections 620A and 620B has the same properties and is made from the same materials/layers as the foldable sheet 120 of IUD 100 and/or the foldable sheet 220 of IUD 200, as disclosed herein above. According to some embodiments, each one of the sheet sections 620A and 620B comprises the drug releasing matrix 130 and is configured to enable the controlled or sustained release of the pharmaceutical active agent (e.g., TA) therefrom and into the uterine cavity 150, as disclosed herein above.

[00223] According to some embodiments, each one of the sheet sections 620A and 620B comprises: an inner layer 624; an intermediate layer 626 covering the inner layer 624; and an outer layer 628 covering the intermediate layer 626 (see Fig. 10A). According to some embodiments, each one of the sheet sections 620A and 620B comprises: an inner layer 624; two intermediate layers 626 covering two opposite surfaces of the inner layer 624; and two outer layers 628 each covering opposite intermediate layers 626 (see Fig. 10B). In further embodiments, the layers are vertically stacked one on top of the other, perpendicularly to the longitudinal axis 680.

[00224] In some embodiments, the inner layer 624 comprises the support layer 236 of Fig. 4B, as disclosed herein above. In some embodiments, the intermediate layer 626 comprises the drug releasing matrix 130 comprising the crosslinked copolymer and the at least one pharmaceutical active agent, as disclosed herein above. In some embodiments, the outer layer 628 comprises the electrically or magnetically responsive porous outer layer 238 of Fig. 4C, as disclosed herein above.

[00225] According to some embodiments, the expanded configuration of the IUD 600 as disclosed herein is configured to correspond to the anatomical dimensions and/or physical shape of the uterine cavity 150, in order to optimize the contact area or proximity between the drug releasing matrix 130 disposed within each one of the sheet sections 620A and 620B and the inner epithelial layer(s) within the uterine cavity 150. Advantageously, by maximizing the contact or surface area between the drug releasing matrix 130 of the sheet sections 620 A and 620B and the endometrium layer 152 within the uterine cavity 150, the IUD 600 can enable the effective and direct administration of the pharmaceutical active agent thereto. [00226] Reference is now made to Figs. 11A-C, illustrating functional block diagrams of the elongated member 660 of the IUD 600, according to various embodiments.

[00227] According to some embodiments, the elongated member 660 is extending between a first surface 661A to a second surface 661B. According to some embodiments, at least one of the first surface 661 A and the second surface 66 IB are dome-shaped or cone-shaped surfaces (not shown). According to some embodiments, at least one of the first surface 661A and the second surface 66 IB are flat surfaces. It is to be understood, however, that the cross- sectional geometry of each one of the first surface 661A and the second surface 661B may be of a different shape, such as a circular, elliptic, triangular or any other curvilinear or rectilinear cross-section. Each possibility represents a separate embodiment of the present invention.

[00228] According to some embodiments, the elongated member 660 is made from at least one biocompatible material selected from a polymer, a metal or metal alloy, and combinations thereof. According to some embodiments, the metal or metal alloy comprises copper. According to some embodiments, the elongated member 660 is made from a polymeric tube at least partially surrounded by a metallic coating. According to further embodiments, said metallic coating comprises copper. The copper can be used for preventing pregnancy (birth control).

[00229] According to some embodiments, the elongated member 660 is in the shape of a hollow cylinder. In some embodiments, the elongated member 660 is in the shape of an elongated cylinder. However, it is to be understood that elongated member 660 can have the same utilization while having a different shape, such as a sphere, an ellipsoid, a box, a ring, or any other suitable polyhedron in the art. Each possibility represents a separate embodiment of the present invention. Moreover, the cross-sectional geometry of elongated member 660 may be circular, elliptic, triangular or any other curvilinear or rectilinear cross-section. Each possibility represents a separate embodiment of the present invention.

[00230] According to some embodiments, elongated member 660 has an outer diameter DI selected from the range of about 0.1 mm to about 1.5 cm. According to further embodiments, diameter DI of elongated member 660 is in the range of about 0.5 mm to about 5 mm. According to still further embodiments, diameter DI of elongated member 660 is in the range of about 1 mm to about 4 mm. According to yet still further embodiments, diameter DI of elongated member 660 is in the range of about 2 mm to about 3 mm.

[00231] According to some embodiments, elongated member 660 has a length LI selected from the range of about 1 mm to about 3 cm. According to further embodiments, length LI of elongated member 660 is in the range of about 5 mm to about 40 mm. According to still further embodiments, length LI of elongated member 660 is in the range of about 20 mm to about 25 mm.

[00232] According to some embodiments, the elongated member 660 is at least partially hollow and accommodates therein various electrical elements, comprising at least one of: a power source 662, a communication module 664, a controller 666, an electromagnetic force generator 668, and combinations thereof, as illustrated at Fig. 11 A. Each possibility represents a separate embodiment.

[00233] According to some embodiments, the power source 662 comprises at least one battery. According to some embodiments, power source 662 is selected from: nickel cadmium (NiCd) battery, lithium-ion (Li-ion) battery, lithium-ion polymer (Li-ion polymer) battery, lead-acid battery, nickel-metal hydride (NiMH) battery, combination thereof, and other known batteries in the art. Each possibility represents a separate embodiment. According to some embodiments, power source 662 is configured to be electronically connected, directly or indirectly, to the other electrical elements accommodated within elongated member 660, and to provide electric power thereto. According to some embodiments, the power source 662 can be rechargeable or disposable. According to some embodiments, the power source 662 can be replaceable.

[00234] According to some embodiments, the controller 667 is in electrical and/or functional/operative communication with at least one of the other electrical elements accommodated within the elongated member 660. According to some embodiments, controller 667 comprises at least one processor configured to send and receive data (such as, but not limited to, digitized signals, data, etc.) to and from the various electronic components of elongated member 660. The at least one processor of controller 667 can be selected from, but not limited to, a microprocessor, a microcontroller, a Digital Signal Processor (DSP), an Application Specific Integrated Circuit (ASIC), a Field Programmable Gate Array (FPGA), a Programmable Logic Device (PLD), a controller, a state machine, gated logic, discrete hardware components, or any other suitable device or a combination of devices that can perform calculations or other manipulations of information. Each possibility represents a separate embodiment. According to some embodiments, controller 667 is mounted on at least one printed circuit board (PCB).

[00235] The term “processor”, as used herein, refers to a single chip device which includes a plurality of modules which may be collected onto a single chip in order to perform various computer-related functions.

[00236] According to some embodiments, the communication module 664 comprises electronic communication systems and methods, including a wireless link. Said wireless link can incorporate any suitable wireless connection technology known in the art, including but not limited to NFC, Wi-Fi (IEEE 802.11), Bluetooth, other radio frequencies, Infra-Red (IR), GSM, CDMA, GPRS, 3G, 4G, W-CDMA, EDGE or DCDMA200 and similar technologies. Each possibility represents a separate embodiment of the present invention. According to some embodiments, communication module 664 further comprises a radio-frequency (RF) antenna. According to some embodiments, communication module 664 further comprises at least one of a transmitter module and/or a receiver module. According to some embodiments, communication module 664 is configured to perform wireless communication utilizing Bluetooth and/or Wi-Fi.

[00237] According to some embodiments, the electromagnetic force generator 668 is configured to generate an inner magnetic or electric field or an electric current, wherein the field (or current) is configured to reach the at least one foldable sheet 620 and the sections thereof (i.e., each one of the sheet sections 620A and 620B), so that the field (or current) can affect the permeability of the outer layer 628 comprising the electrically or magnetically responsive porous outer layer 238, as disclosed herein above.

[00238] The term "inner magnetic or electric field", as used herein, means a field which is generated by electromagnetic force generator 668, as opposed to a field generated by an electromagnetic force generator external to IUD 600.

[00239] In some embodiments, during the expanded configuration of the IUD 600, the electromagnetic force generator 668 can generate an inner magnetic or electric field or current, so that the outer layer 238 will be reversibly actuated from a closed or semi closed state to an open state (or vice versa), which can affect the release rate and duration of the pharmaceutical active agent from the drug releasing matrix 130 (of each one of the sheet sections 620A and 620B) therethrough. Advantageously, by controlling the activation of the electromagnetic force generator 668, different users can directly control and adjust the drug release rate of the IUD 600 upon demand, according to their individual requirements and needs.

[00240] According to some embodiments, the electromagnetic force generator 668 is configured to generate the inner magnetic or electric field in response to an external magnetic field, due to an inductive coupling or charging mechanism (i.e., a form of wireless power transfer), wherein the external magnetic field is generated by a designated device (not shown), optionally positioned externally to the body of the user. According to further embodiments, the electromagnetic force generator 668 comprises an inner induction coil 672 (illustrated at Fig. 11C), configured to generate an alternating electric current in response to the influence of the external magnetic field.

[00241] In some embodiments, the alternating electric current induced by the inner induction coil 672 can be converted into direct current, which can be used to power additional inner component(s) (e.g., a capacitor and/or miniature electrical circuitry) configured to induce an inner magnetic or electric field, and thus to affect the permeability of the outer layer 628 (by inductive charging). Additionally or alternatively, in some embodiments, the alternating electric current induced by the inner induction coil 672 can be converted into direct current as disclosed above, which can be transferred via suitable electrical wiring to at least a portion of the outer layer 628, in order to affect the permeability thereof. In further such embodiments, said suitable electrical wiring can be implemented or coupled to at least a portion of the outer layer 628, the first arm 609, the second arm 610, elongated member 660, and a combination thereof. In other embodiments, the alternating electric current induced by the inner induction coil 672 can be used to power an additional inner induction coil, thus creating an inner magnetic field which can affect the permeability of the outer layer 628.

[00242] It is suggested, in some embodiments, that the permeability of the outer layer 628 can be highly affected by the influence of the inner magnetic or electric field generated by the generator 668, as opposed to the effect induced thereon by a field generated by an external electromagnetic force generator positioned externally to IUD 600 (e.g., positioned externally to the body of the user). Such an external electromagnetic force generator may be more distanced from the outer layer 628 so that the generated field thereof will have a lower effect thereon. Therefore, the inner magnetic or electric field generated by the generator 668 can have an advantageous effect on the permeability of the outer layer 628, as disclosed above.

[00243] According to some embodiments, upon the deactivation of the electromagnetic force generator 668, due to the termination of the external magnetic field by the designated device, the inner magnetic or electric field or current is terminated, thus further affecting the permeability of the outer layer 628, as disclosed above.

[00244] According to alternative embodiments, the electromagnetic force generator 668 is configured to generate the inner magnetic or electric field or current as disclosed herein above, in response to receiving power from the power source 662, controlled by the controller 667. According to further embodiments, controller 667 is configured to activate the electromagnetic force generator 668 upon receiving commands from a remote device (illustrated at Fig. 11 A). According to some embodiments, the electromagnetic force generator 668 comprises the inner induction coil 672, wherein responsive to a current provided by power source 662, the inner induction coil 672 is configured to generate an inner magnetic field which can affect the permeability of the outer layer 628. According to further embodiments, upon the deactivation of the electromagnetic force generator 668, controlled by the controller 667, the inner magnetic or electric field or current is terminated, thus further affecting the permeability of the outer layer 628, as disclosed above.

[00245] According to other embodiments, the electromagnetic force generator 668 is configured to generate the inner magnetic or electric field or current as disclosed herein above, in response to receiving power from a peptide-based piezoelectric generator. In some embodiments, the IUDs of the present invention (e.g., IUD 600) comprises at least one peptide-based piezoelectric generator (not shown) coupled to one or more portions thereof. In some embodiments, the peptide-based piezoelectric generator is biocompatible and is configured to generate electrical energy in response to mechanical deformation. The mechanical deformation can be a result of various forms of movement by the user (e.g., walking, jumping, etc.), which can affect the peptide-based piezoelectric generator coupled to the IUD disposed within the uterine cavity 150. In some embodiments, the peptide-based piezoelectric generator comprises a tripeptide-based power generator (Bera, S., et al. Molecular engineering of piezoelectricity in collagen-mimicking peptide assemblies. Nat Commun 12, 2634 (2021)). [00246] According to some embodiments, the elongated member 660 further accommodates within an optic detection module 669 (see Figs. 11B-C). According to some embodiments, elongated member 660 further comprises at least one optic member 670, as illustrated at Fig. 11C. According to some embodiments, optic member 670 is integrally formed and/or is flush with at least one of the surfaces of the elongated member 660 (e.g., first surface 661 A and second surface 661B), as illustrated at Fig. 11B. According to some embodiments, optic member 670 is extending away from at least one of the first surface 661A and/or second surface 66 IB, towards the uterine cavity, as illustrated at Fig. 11C. According to some embodiments, optic detection module 669 is electrically and/or functionally/operatively connected to the at least one optic member 670. According to some embodiments, optic detection module 669 is in communication with the controller 667 (i.e., receive and transfer data/commands) and controller 667 enables the operation of the optic member 670. According to some embodiments, the optic detection module 669 is embedded within the controller 667 or a portion thereof.

[00247] According to some embodiments, the optic member 670 comprises at least one optic sensor 674. According to some embodiments, the optic member 670 comprises at least one LED light 676, or preferably at least two LED lights 676. According to some embodiments, the optic member 670 is in the shape of at least one transparent or semitransparent spherical dome, extending away from at least one of the surfaces of the elongated member 660 (e.g., first surface 661 A or second surface 661B), as illustrated at Fig. 11C, wherein said dome comprises the at least one LED 676 and the at least one sensor 674 disposed therein. According to some embodiments, the optic member 670 is configured to enable the at least one LED light 676 and the at least one optic sensor 674 to transfer and to detect light therethrough, respectively, for the purpose of illuminating the area in proximity to the optic member 670 within the uterine cavity, in order to detect and optionally measure at least one physiological or biological indicator therearound. In some embodiments, the at least one physiological or biological indicator comprises blood cells, or preferably red blood cells (RBC). In further such embodiments, the optic member 670 is configured to detect and optionally measure red blood cells (RBC) concentration.

[00248] According to some embodiments, the optic member 670 comprises at least two transparent or semi-transparent spherical domes, each positioned at a different surface of the elongated member 660 and comprises the LED 676 and the sensor 674, wherein each LED light 676 is configured to transfer light through each spherical dome, respectively, to enable the improved detection capabilities of RBC on either side of the elongated member 660.

[00249] According to some embodiments, the transparent or semi-transparent spherical dome (e.g., optic member 670) is coated by a hydrophobic layer configured to prevent the adherence of blood clots or other deposits thereon, to prevent light transfer disturbances.

[00250] According to some embodiments, the LED light(s) can be configured to generate light in a wavelength of about 660 nm and/or 905 nm.

[00251] According to some embodiments, the optic member 670 is configured to detect the presence of blood cells, or optionally the presence of red blood cells (RBC), in the vicinity thereof, within the uterine cavity. According to some embodiments, the at least one LED light 676 of optic member 670 is configured to transfer light and to illuminate the RBC residing in the vicinity thereof, within the uterine cavity.

[00252] According to some embodiments, the optic detection module 669 is configured to intermittently activate the at least one LED light of optic member 670 at repeating intervals of about every 1-24 hours, preferably about every 6-12 hours, wherein the at least one LED light is activated for a time duration of about 10 seconds to about 20 minutes, preferably 1-10 minutes, thereby transferring light and illuminate RBC in the vicinity thereof within the uterine cavity. According to some embodiments, the at least one optic sensor of optic member 670 is configured to detect reflected photons from RBC, which were illuminated by the at least one LED light, and thereby to detect and optionally measure the presence of RBC in the vicinity thereof, utilizing the optic detection module 669. In some embodiments, upon receiving data indicative of the RBC reflected photons from optic member 670 and/or module 669, the controller 667 can calculate the RBC concentration.

[00253] According to some embodiments, the optic member 670 is configured to detect an increase in the concentration or amount of RBC, optionally relative to a threshold value, in the vicinity thereof and to transfer optic data indicative thereof to the controller 667, optionally via the optic detection module 669. According to some embodiments, the controller 667 is configured to automatically activate the electromagnetic force generator 668 which induces the inner magnetic or electric field or current, upon receiving the optic data indicating the increase in the concentration or amount of RBC relative to the threshold value (e.g., an 'automatic mode'), and thus to affect the permeability of the outer layer 628. According to alternative embodiments, the controller 667 is configured to activate the electromagnetic force generator 668 upon receiving commands from the remote device (e.g., an 'on-demand mode'). According to some embodiments, upon the detection of a decrease in the concentration of RBC in the vicinity of optic member 670, below the threshold value, the controller 667 is configured to deactivate the electromagnetic force generator 668, thereby terminating the inner magnetic field and thus further affecting the permeability of the outer layer 628.

[00254] According to some embodiments, the threshold value can be determined by the user, or preprogramed according to statistic RBC concentration during typical menstruation periods.

[00255] The optic member 670 as presented herein can be used to detect an increase in the concentration or amount of RBC in the uterine cavity, which can indicate menstrual bleeding during menstruation. The menstrual bleeding can be optionally affected by a menstrual bleeding disorder. Furthermore, IUD 600 can be automatically activated upon the detection of the increase in the concentration of RBC (relative to a threshold value), so that the permeability of the outer layer 628 will be reversibly actuated upon the influence of an inner magnetic or electric field or current induced by the electromagnetic force generator 668. As was disclosed above, changing the permeability of the outer layer 628 can affect and control the release rate and duration of the pharmaceutical active agent from the drug releasing matrix 130 therethrough. Advantageously, IUD 600 as disclosed herein, can be automatically activated to release the pharmaceutical active agent, upon detecting physiological requirements at specific periods.

[00256] For example, in some embodiments, a high concentration of RBC during menstruation can indicate a menstrual bleeding disorder, and therefore the IUD 600 can be automatically activated to release the pharmaceutical active agent therefrom, for the treatment thereof. Additionally or alternatively, in some embodiments, the IUD 600 can be automatically activated to release the pharmaceutical active agent therefrom, upon detecting a concentration of RBC indicative of a typical menstruation period, thereby enabling subjects in need thereof to reduce or manage menstrual bleeding.

[00257] According to some embodiments, the controller 667, communication module 664, and the optic detection module 669 can be mounted on the same PCB. According to some embodiments, at least one of the communication module 664 and optic detection module 669 are embedded within controller 667.

[00258] According to some embodiments, the communication module 664 is configured to enable wireless communication between the controller 667 and the remote device. According to some embodiments, the remote device is used to send wireless commands to communication module 664 through the wireless link. According to some embodiments, communication module 664 is configured to transfer said commands to controller 667. According to some embodiments, the controller 667 is configured to transfer data (e.g., including indications) to the remote device, optionally indicative of the presence and/or the levels of physiological or biological indicators in the vicinity of the optic member 670, such as RBC concentration, and thus to alert the user.

[00259] According to some embodiments, there is provided a remote device 690, as illustrated at Fig. 11 A. It should be understood that the figures are not to scale visually, and that difference in scale can facilitate visual representation.

[00260] The term “remote device”, as used herein, refers to a device which supports wireless communication (utilizing a wireless link), that enable wireless communication with communication module 664 of elongated member 660. The remote device 690 is able to send wireless commands to, and optionally receive signals or data from, controller 667 of elongated member 660. The remote device can be selected from, but not limited to, a cell phone, a smartphone, a tablet, a smart-watch, a laptop, a computer, or the designated device (detailed below). An application can be installed on at least one of said smartphone, tablet, laptop, smart-watch, and the like, in order to control the wireless communication with controller 667 of elongated member 660.

[00261] According to some embodiments, the remote device 690 or the application installed thereon can be configured to provide monthly reminders (e.g., indications) to the user, thereby reminding the user to activate the designated device in order to initiate the TA release from within the IUD 600, during menstruation. In some embodiments, the monthly reminders can be adjusted by the user according to previous menstrual cycles.

[00262] According to other embodiments, the remote device 690 or the application installed thereon can be configured to control the activation of the IUD 600, by controlling the activation of the electromagnetic force generator 668 (utilizing power source 662 or the designated device), in order to generate the inner magnetic or electric field or current and to initiate the TA release from within the IUD 600. The user can operate the remote device (e.g., a smartphone application) to control the activation and/or drug release capabilities of the IUD (e.g., by controlling the operation of the controller 667), via wireless communication therebetween.

[00263] The term “designated device”, as used herein, refers to a remote device that is manufactured specifically to control the various electrical elements of elongated member 660, including the activation of the electromagnetic force generator 668, as presented herein above, and can be sold together with any one of the IUDs of the present invention, or separately. According to some embodiments, the designated device supports wireless communication. According to some embodiments, the designated device comprises at least one of a button, a touch screen and/or a display screen. Each possibility represents a separate embodiment. According to some embodiments, the designated device comprises a plurality of buttons. According to some embodiments, the designated device comprises a coil and is configured to generate and transmit the external magnetic field. According to some embodiments, the designated device comprises a Radio-frequency identification (RFID) reader device configured to transmit electromagnetic pulses (i.e., the external magnetic field), and wherein the electromagnetic force generator 668 comprises a respective RFID tag. In such an embodiment, the RFID reader device outputs the generated external field to the RFID tag, which in turn generates an inner field, as described above.

[00264] According to some embodiments, the designated device is configured to be fastened externally to a body portion of the user (e.g., to the abdomen) utilizing various wrapping means. The term “wrapping means”, as used herein, refers to any elongated flexible structure known in the art, capable of being wrapped and unwrapped around any limb or portion of the body of a user, such as a strap, a band, a belt, a cord, a cable, a pouch, a chain and the like.

[00265] According to some embodiments, the designated device comprises an induction coil, configured to generate an alternating electric current, thereby generating the external magnetic field, wherein the external magnetic field is configured to generate the inner magnetic field within the electromagnetic force generator 668, due to inductive coupling/charging. According to some embodiments, the designated device is configured to generate the external magnetic field at a wavelength selected from the range of about 420 to about 900 MHz. According to some embodiments, the designated device is configured to generate the external magnetic field at RF frequency.

[00266] According to some embodiments, the designated device is configured to be positioned externally to the uterine cavity, such as against a body portion of the user (preferably against the abdomen of the user), so that the distance between the designated device and the electromagnetic force generator 668 within the IUD 600 is less than a certain distance, which enables the formation of inductive coupling/charging therebetween. It is contemplated that the external magnetic field is sufficient to penetrate inner tissues of the body of the user, thereby activating the electromagnetic force generator 668, when placed and activated within a distance which is less than the certain distance. It is further contemplated that if the designated device will be activated in a distance larger than the certain distance from IUD 600, the external magnetic field induced by the designated device will not be able to cause the electromagnetic force generator 668 to generate the inner magnetic or electric field.

[00267] According to some embodiments, the designated device is configured to be placed within the vagina of the user, by the user or by a physician, so that the distance between the designated device and the electromagnetic force generator 668 is less than the certain distance, which enables the formation of inductive coupling/charging therebetween.

[00268] As used herein, the term “certain distance” refers to a distance of less than about 50 cm, preferably less than about 25 cm, more preferably less than about 10 cm, or even more preferably less than about 5 cm.

[00269] According to some embodiments, the external magnetic field generated by the designated device comprises a coded or an encrypted signal, configured to enable the generation of the inner magnetic field within the electromagnetic force generator 668 solely due the presence of the external magnetic field. Advantageously, the utilization of such a coded or encrypted signal prevents accidental activation of the inner magnetic field by the electromagnetic force generator 668, due to the presence of any other external source of electromagnetic waves. According to some embodiments, the designated device, the remote device, or both, are configured to wirelessly communicate with the IUDs of the present invention (e.g., IUD 600) via the standard approved protocol for medical implants, the medical implant communication service (MICS). [00270] According to some embodiments, the designated device is configured to be manually activated by the user relative to the beginning of the menstrual period (i.e., 12-24 hours prior thereto) or following the appearance of signs and symptoms that predict the start of the menstruation period, or optionally upon user demand.

[00271] According to some embodiments, controller 667 is configured to receive commands from the remote device via the communication module 664, and to control the activation and deactivation of the electromagnetic force generator 668 and optic member 670.

[00272] According to some embodiments, controller 667 is further configured to receive signals/data from at least one of electromagnetic force generator 668, power source 662, and optic member 670, and to transfer said signals/data to communication module 664. According to some embodiments, communication module 664 is configured to transfer said signals to the remote device through the wireless link. Said signals can include at least one of the condition of electromagnetic force generator 668, the condition of power source 662, and the readings of optic member 670. The condition of power source 662 can include the battery’s discharge status.

[00273] According to some embodiments, IUD 600 can detect the presence of at least one physiological or biological indicator by measuring the impedance (electrical resistance to alternative current) between two electrodes. The physiological or biological indicator can comprise bodily fluids, as well as RBC concentration. In further embodiments, IUD 600 comprises at least two metal-based electrodes 682 (see Fig. 11 A), wherein each electrode is coupled to each one of the surfaces of the elongated member 660 (e.g., first surface 661 A and second surface 66 IB), thus covering the entire length of the elongated member 660. In other embodiments, each one of the two electrodes 682 is coupled to each end of each arm (i.e., the first arm 609 and the second arm 610), thus covering the entire widths of the uterus (not shown). The presence of fluids and RBC can affect the measured impedance levels measured between the two electrodes. In some embodiments, the controller 667 is configured to measure the impedance levels between the two electrodes 682, so that when detecting a value above a certain threshold, the controller 667 will either automatically activate the electromagnetic force generator 668 to affect the permeability of the outer layer 628, or issue a notification indicating the user. Adventitiously, it is contemplated that the measurement of the impedance levels between the two electrodes 682 is less power consuming relative to the activation of the optic member 670, so that the impedance measurement can provide an indication for menstrual bleeding during menstruation while preserving the power capacity of power source 662, which may extend the battery life thereof.

[00274] According to some embodiments, the IUD 600 comprises at least one sensor 684 configured to detect the presence of a physiological or a biological indicator in the vicinity thereof within the uterine cavity, and to transfer data indicative thereof to the controller 667. In further embodiments, the sensor 684 can measure the levels of the biological indicator and to transfer data indicative thereof to the controller 667. The biological indicator can be selected from but not limited to, hemoglobin concentration, temperature, pH levels, other biochemical markers, and combinations thereof. In some embodiments, the sensor 684 is functionally/operatively and/or electrically coupled to the controller 667, the power source 662, or both. In some embodiments, the at least one sensor 684 is coupled to each one of the surfaces of the elongated member 660 (e.g., first surface 661A and second surface 661B), or to another portion thereof. In other embodiments, the at least one sensor 684 is coupled to at least one arm (i.e., the first arm 609 and the second arm 610). In some embodiments, the controller 667 is configured to measure the levels of the biological indicator, so that when detecting a value above or below a certain threshold, the controller 667 will either automatically activate the electromagnetic force generator 668 to affect the permeability of the outer layer 628, or issue a notification indicating the user.

[00275] Once the operating period of the IUDs of the present invention (e.g., IUD 600) is completed, the user can refer to a care-provider or a physician to remove or replace the IUD.

[00276] According to some embodiments, the activation of the IUDs of the present invention (e.g., IUD 600) can be automatically and/or directly controlled by the user, wherein the activation thereof can be operated at a 'latch' mode, i.e. the IUD will continue its operation in the same setting, until a termination (OFF) command will be received and then the discharge of the drug will be discontinued or semi-discontinued, by controlling the permeability of the outer layer 628, as was disclosed herein above. For example, upon issuing a termination (OFF) command (by the controller 667), the magnetic or an electric field can be activated or deactivated, and thus actuate the outer layer 628 to the closed or semi closed state, thereby preventing or nearly preventing the drug release therethrough.

[00277] According to some embodiments, the IUDs of the present invention (e.g., IUD

600) can be configured to operate at an 'automatic mode'. During the 'automatic mode', the controller 667 can automatically activate the electromagnetic force generator 668 to affect the permeability of the outer layer 628, thus controlling the release of the pharmaceutical active agent from the drug releasing matrix 130 therethrough, as disclosed herein above. The controller 667 can automatically activate the electromagnetic force generator 668, in response to a change (i.e., increase or decrease) in one or more of the following physiological or biological indicators (optionally relative to a threshold value): RBC concentration or amount; impedance levels; hemoglobin concentration; temperature; pH levels, other suitable physiological or biological indicators, and combinations thereof. Furthermore, the controller 667 can automatically activate the electromagnetic force generator 668 according to a preprogrammed monthly timetable. Thus, the IUDs of the present invention can enable automatic controlled drug release based on individual needs, without depending upon the compliance and responsibility of the user for the activation thereof.

[00278] According to some alternative embodiments, the IUDs of the present invention (e.g., IUD 600) can be configured to operate at an 'on-demand mode'. During the 'on-demand mode' the controller 667 can activate the electromagnetic force generator 668 upon receiving orders/commands from the remote device 690 or the application installed thereon, operated by the user. The controller 667 can provide (i.e., communicate) notifications or indications to the user, via the remote device 690, thus alerting the user to the condition of the physiological or biological indicators as disclosed above, within the uterine cavity 150. Thus, the IUDs of the present invention can enable customized controlled drug release upon individual user demand.

[00279] According to some embodiments, the IUDs of the present invention can support any one of the 'automatic mode' and the 'on-demand mode', wherein the user can choose a desired mode of operation, optionally via the remote device 690.

[00280] Advantageously, the IUDs of the present invention (e.g., IUD 600) as disclosed herein can be automatically and/or directly controlled by the user upon demand, to release the pharmaceutical active agent (e.g., TA) therefrom, optionally at an adjustable release rate during menstruation. Therefore, the IUDs of the present invention can enable customized treatments according to individual requirements and desires from various users. Furthermore, the IUDs of the present invention can initiate the drug release therefrom solely during menstruation, and thus to prevent (or nearly prevent) exposure of the uterus to the drug during the rest of the monthly cycle. [00281] According to some embodiments, there is provided a kit comprising at least one of the IUDs of the present invention as disclosed herein above (e.g., any of IUDs 100-600) and the designated device.

[00282] According to another aspect, there is provided a method for treating or suppressing a gynecological -related disease or a disorder (e.g., menstrual bleeding disorder, cancer, or both), comprising delivering any one of the IUDs of the present invention as disclosed herein above, into the uterine cavity of a subject in need thereof, and inducing the controlled or sustained release of the pharmaceutical active agent (e.g., TA) therefrom, utilizing the designated device and/or the remote device. According to some embodiments, the method of the present invention comprises reducing or managing menstrual blood loss in a subject in need of treatment thereof. According to some embodiments, the method of the present invention comprises reducing the volume of menstrual blood loss in a subject in need thereof. According to some embodiments, the method of the present invention can be further used for birth control.

[00283] According to another aspect, there is provided the drug releasing matrix 130 as disclosed herein above comprising at least one pharmaceutical active agent. In some embodiments, TA is the pharmaceutical active agent. According to some embodiments, the drug releasing matrix 130 is for use in treating a gynecological disease or a disorder, selected from a menstrual bleeding disorder, cancer, or both. In some embodiments, the drug releasing matrix is in the form of a polymeric sheet or a film. According to some embodiments, the drug releasing matrix 130 is provided in a dosage form suitable for intra-uterine delivery (e.g. intrauterine device).

[00284] The term “plurality”, as used herein, means more than one.

[00285] The term “about”, as used herein, when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of +/-10%, more preferably +/-5%, even more preferably +/-1%, and still more preferably +/-0.1% from the specified value, as such variations are appropriate to the disclosed devices, systems and/or methods.

[00286] 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 sub-combination or as suitable in any other described embodiment of the invention. No feature described in the context of an embodiment is to be considered an essential feature of that embodiment, unless explicitly specified as such.

[00287] Although the invention is described in conjunction with specific embodiments thereof, it is evident that numerous alternatives, modifications and variations that are apparent to those skilled in the art may exist. It is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth herein. Other embodiments may be practiced, and an embodiment may be carried out in various ways. Accordingly, the invention embraces all such alternatives, modifications and variations that fall within the scope of the appended claims.

[00288] Examples

[00289] Example 1- First synthesis protocol

[00290] In order to synthesize a complex crosslinked copolymer adapted to enable the water aided diffusion of TA therefrom for drug release applications, a copolymer composite film was synthesized. It was suggested that the copolymer should have polar regions (or blocks) preferably adapted to encourage water diffusion, and less polar regions (or blocks) preferably adapted for housing the TA, thus forming a copolymer-TA complex having desired drug release abilities.

[00291] The main base units (e.g., polar regions) of the copolymer were polyethylene glycol (PEG) or poly (propylene glycol) (PPG), with a molecular weight of less than 10000 Da. PEG with a molecular weight of 8000 Da was used, while different types of PPG were tested (2000, 4000, and 8000 Da). In order to build the polymer system, 2 units of PEG or PPG were connected with chain extenders (spacers): hexamethylene diisocyanate (C6) or ethylene diisocyanate (C2).

[00292] The goal of the first synthesis was to determine the ratio between the PEG or PPG and the spacer(s), which are required for enabling proper hydrophilic characteristics of the final copolymer, while still housing a large amount of TA, without the deterioration of the mechanical properties thereof. [00293] The reaction system was initially thoroughly dried. Under an atmosphere of nitrogen, 2.25 mmol PPG (Alfa Aesar) of different molecular weights (samples 1-5 in Table 1 below) were dissolved in 3-5ml n-hexane. 93mg (0.23 mmol) tin 2-ethylhexanoate (SnOc2 - Aldrich) was added. 1.13 mmol spacer (C2 or C6) was added in batches over 10 minutes. The mixture is allowed to stir at 85 °C for 30 minutes. Alternatively, PEG (Sigma Aldrich) was also tested (sample 6 in Table 1 below).

[00294] Then, mixtures of caprolactone (CL - Fischer) (e.g., the less polar regions) were polymerized on OH end-groups of the PPG (or PEG) basic unit chain. CL was added either in tandem or sequentially. In the synthesis, 8g (70 mmol) CL was added and the temperature was raised to 145 °C for 3h. Then, the mixture was cooled to 85 °C.

[00295] 2-isocyanatoethyl methacrylate (IEMA - Aldrich) was added as a crosslinker and attached to the OH end-groups. The IEMA amount was increased until it was equivalent to both the end groups and amide nitrogen from the spacer used for linking 2 units of PPG or PEG (more or less 80% molar of the PPG/PEG). In the synthesis, 0.42g (2.7 mmol) IEMA was dissolved in 4g hexane and added slowly to the mixture. The mixture was left to stir at 85 °C for Ih. The solvent was evaporated in vacuo to produce the polymer.

[00296] The formula of the copolymer prior to the addition of TA, without specific attention to the length of each block, can be illustrated by the formula shown at Fig. 12.

[00297] Tranexamic acid (TA - Aldrich) was ground mechanically. The polymer was melted and vigorously stirred with TA. The copolymers complex was then crosslinked by UV (>60W) by being irradiated at 254 nm for 2 series of 30 seconds intervals, depending on the desired thickness, to produce the final copolymer-TA complex.

[00298] Several samples of the copolymer-TA complex were produced according to the above synthesis, and were tested for melting point (MP) and swelling. Differential scanning calorimetry (DSC) was used to determine the MP of the below materials, wherein DSC measurement were performed under nitrogen, and temperature was increased from room temperature to 250 °C at 10 °C/min intervals. Swelling was tested by the incubation of each sample for 24h in water, followed by measuring the weight difference thereof. The compositions and results are summarized in Table 1 below. [00299] Table 1 : first synthesis compositions and results

[00300] From Table 1, it can be determined that the best system contained the 2K PPG lined with a C6 spacer (sample 1.1). It is suggested that PPG based systems can be easier to process, due to lower MP and other properties (Fig. 13). FTIR results of the copolymer without TA vs. the copolymer-TA complex showed the adequate incorporation of the TA therein (Figs. 14A-B).

[00301] A liquid chromatography-mass spectrometry (LCMS) protocol was developed for the measurement of the TA release rate. The conditions were 10-90% acetonitrile (ACN), 4min, Xbridge C18 50x3.0mm, 3.5u, Iml/min, 40 °C, A: lOmM ammonium carbonate, B: ACN. In these conditions the TA was released at 0.27 minutes and ionizes well both in the positive and negative mode using El ionization. This method was used to develop a calibration graph for TA. The calibration graph was found to be accurate to above 96% (Fig. 15).

[00302] Samples 1.1 and 1.4 from Table 1 were tested for release rate by floating over a water reservoir (Figs. 16A-B). Water samples were collected and measured according to the LCMS protocol. It was observed that the release rate of both samples was asymptotic, and exhibited a significant daily deterioration. It is contemplated that the release rate was dependent on the type of polymer used. Additionally, the initial rates appeared to be too high, so that if these rates were to be maintained, the entire load of the TA would be released from the polymer in about 4-5 weeks. [00303] Example 2- Second synthesis protocol

[00304] Sample 1 from Table 1 (Example 1) was reformulated so as to contain L-lactide (L) in addition to CL, preferably in order to affect the polymer structure and resulting properties.

[00305] The reaction system was thoroughly dried. Under an atmosphere of nitrogen, 2.25 mmol PPG 2000 Da were dissolved in 3-5ml n-hexane. 93mg (0.23 mmol) tin 2- ethylhexanoate (SnOc2) was added. 1.13 mmol hexamethylene diisocyante (C6) was added in batches over 10 minutes. The mixture was allowed to stir at 85 °C for 30 minutes. 8g (70 mmol) CL and 2.25g L-lactide were added and the temperature was raised to 145 °C for 3h. The mixture was cooled to 85 °C. 0.42g (2.7 mmol) IEMA was dissolved in 4g hexane and added slowly to the mixture. The mixture was left to stir at 85 °C for Ih. The solvent was evaporated in vacuo to give the uncrosslinked polymer. The polymer was melted and vigorously stirred with TA, similar to as described at Example 1 above. The copolymers complex was then crosslinked by UV (>60W) by being irradiated at 254 nm for 2 series of 30 seconds intervals, to produce the final copolymer-TA complex.

[00306] The composition and results are summarized in Table 2 below. Swelling and MP were tested similarly to Example 1.

[00307] Table 2- second synthesis composition and results

[00308] It is suggested that the resulting copolymer-TA complex had improved mechanical properties, as can be seen at Table 2 above, and as was observed during the experiment.

[00309] The sample from Table 2 was tested for release rate by floating over a water reservoir and measured according to the LCMS protocol of Example 1 (Fig. 17). It was observed that the release rate of the sample was asymptotic, and exhibited a significant daily deterioration. It is contemplated that the release rate was dependent on the type of polymer used. Additionally, the initial rate appeared to be too high, so that if this rate was to be maintained, the entire load of the TA would be released from the polymer in about 4-5 weeks. [00310] Example 3- Third synthesis protocol

[00311] According to the results of the above examples, it was suggested that the copolymer-TA complex synthesis should be adjusted, in order to decrease the initial release rate and to prevent daily release rate deterioration (i.e., the slope of the release rate graph). It is contemplated that in order to do so, the regions/blocks containing the TA should become steadier; and that the diffusion (release) rate of the TA should be reduced.

[00312] In order to achieve the synthesis adjustments as disclosed herein above, the following copolymer-TA complex sample was produced based on sample 2.1 of Table 2, so that: the ratio of CL to L was increase from 4: 1 to 2: 1. In order to achieve this, the amount of L-lactide (L) was increased to 4.5 g, relative to the protocol of the previous example.

[00313] The composition is summarized in Table 3 below.

[00314] Table 3- third synthesis composition

[00315] * L amount is doubled relative to the amount in Example 2.

[00316] Example 4- Fourth synthesis protocol

[00317] Another route to achieve the synthesis adjustments as disclosed and suggested at Example 3 was tested. The following copolymer-TA complex sample was produced based on sample 2.1 of Table 2, so that: the CL was fully reacted before the addition of L, thus creating a block copolymer system, wherein the ratio of CL to L was 4: 1.

[00318] In short, the reaction system was thoroughly dried, above 120 °C and below 20 mbar. Under nitrogen, 9g (4.5 mmol) PPG 2000 Da was added. 0.2g (0.49 mmol) SnOc2 in 2 ml petroleum ether60-80 was added and the system was heated to 80 °C. 0.4g (2.4 mmol) hexamethylene diisocyante (C6) in 5 ml petroleum ether 60-80 was added dropwise over 30 minutes. The mixture was allowed to react for an additional 30 minutes. Then, temperature was increased to 145 °C and 16g CL (140 mmol) was added and mixed for 2h. 4.5g L was then added and stirred for an additional 2h. The temperature was reduced to below 90 °C and 1.75g IEMA was added in 3 doses over 10 minutes and the mixture was mixed for an additional 10 minutes. The solvent was evaporated to give the polymer. The polymer was melted and vigorously stirred with TA, similarly to as described at Example 1 above. The copolymer complex was then crosslinked by UV (>60W) by being irradiated at 254 nm for 2- 3 series of 30 seconds intervals, to produce the final copolymer-TA complex.

[00319] The composition is summarized in Table 4 below.

[00320] Table 4- forth synthesis composition

[00321] * L amount is doubled relative to the amount in Example 2.

[00322] ** Lactide was added after the CL.

[00323] Samples 3.1 of Table 3 and 4.1 of Table 4 as disclosed herein above were tested in a revised TA release test. In this test, a 2x2 cm² square of a copolymer-TA complex film of each of the samples 3.1 and 4.1 was covered with a 3x3 cm² square of wet Whatman 1 filter paper. The papers were changed at regular intervals. The liquid from the papers was extracted to 1 ml water which was tested according the LCMS protocol of Example 1.

[00324] It can be seen in Fig. 18, that the copolymer-TA complex samples produced the desired effect, wherein the release rate became more linear and exhibited a slight decrease. It was observed that sample 4.1 exhibited a slightly more linear and stable release rate relative to sample 3.1. Based on the average release rate of the experiment, sample 3.1 could release the entire TA load over 352 days, while sample 4.1 could release the entire TA load over 21 days. Optionally, there could be a change in the release rates at a timeframe greater than the one which was tested during the experiment.

[00325] Example 5- Film formation procedures

[00326] Three methods can be used for producing polymeric films or sheets from the copolymer-TA complex systems produced according to the above examples. All methods refer to polymers systems incorporating the TA therein in the molten polymer, with high shear mixing or pestle and mortar mixing. [00327] Doctor Blade - The molten polymer-TA complex was spread with a doctor blade on a heated glass sheet. Crosslinking was performed on the glass plate.

[00328] Teflon Mold - The molten polymer-TA complex was poured into a heated Teflon mold and left at 70 °C for at least half an hour to allow levelling. Crosslinking was performed in the mold.

[00329] Hydraulic Press - Molds were made from aluminum to meet the desired dimensions. The volume of the films was calculated and the cold polymer-TA complex was placed in the center of the molds. The hydraulic press was heated to 110 °C and the samples were thermoformed for 30 seconds at 100 bar or greater pressures. Pressure was released for 1 minute to allow any bubbles to escape and then reapplied for an additional 30 seconds. It was observed that the best results were obtained using this method, thereby producing stable and intact films.

[00330] It should be noted that other suitable film production methods can be utilized.

Claims

1. An intrauterine device (IUD) configured to be inserted into a uterine cavity of a user, the device comprising: a) at least one support member, comprising a first arm and a second arm joined at a junction, wherein the first arm is extending between a first end thereof and the junction, and wherein the second arm is extending between the junction and a second end thereof; and b) and at least one foldable sheet comprising a drug releasing matrix comprising a polymer and at least one pharmaceutical active agent, wherein the sheet is coupled to at least a portion of the support member, wherein the IUD is configured to be delivered into a uterine cavity in a compressed configuration, wherein following delivery, the support member is configured to transition between a folded configuration to a spread configuration which facilitates transition of the IUD from the compressed configuration to an expanded configuration, wherein during the transition between the folded configuration to the spread configuration, the first end and the second end of the support member are configured to extend in opposite directions relative to each other, and wherein the foldable sheet is coupled to the first and second arms such that when the support member transitions to the spread configuration the sheet spreads therewith, thus enabling the release of the pharmaceutical active agent therefrom.

2. The IUD according to claim 1, wherein the first arm and the second arm are integrally formed and are joined in the junction, or wherein the first arm and the second arm are separate components attached to each other directly or indirectly via intermediate components.

3. The IUD according to claims 1 or 2, wherein during the expanded configuration the first arm, the second arm, and the foldable sheet substantially reside in the same plane.

4. The IUD according to any one of claims 1-3, wherein during the compressed configuration the first end of the support member is in the vicinity of the second end thereof.

5. The IUD according to any one of claims 1-4, wherein the foldable sheet extends between at least two sides, wherein a first side of the foldable sheet is coupled to the first arm of the support member, wherein a second side of the foldable sheet is coupled to the second arm of the support member, and wherein during the spread configuration

69 of the support member, the first side and the second side of the foldable sheet are configured to planarly expand in opposite directions relative to each other, due to the expansion of the first and second arms. The IUD according to any one of claims 1-5, wherein during the transition to the spread configuration of the support member, the first and second arms are expanding in opposite directions relative to each other, so that an angle a is formed at the junction therebetween, wherein the angle a is selected from the range of about 5° - 90°. The IUD according to any one of claims 1-5, wherein the first and the second arms have a non-linear shape in the spread configuration thereof, such that each arm defines a curvilinear shape, and wherein the first and second arms are bent such that a first and second bending points are formed, respectively, defining two first arm sections between the junction and the first and second bending points, wherein in the spread configuration of the support member, both first arm sections are substantially parallel to each other defining together with the junction a U-shaped configuration. The IUD according to any one of claims 1-7, wherein the at least one support member comprises at least one shape memory material, configured to enable the transition thereof from the folded configuration to the spread configuration. The IUD according to claim 8, wherein the shape memory material is selected from a nickel titanium alloy, an iron-cobalt-nickel-aluminum alloy, an iron-manganese-silicon alloy, a copper-aluminum-nickel alloy, a zinc-copper-aluminum alloy, a zinc-coppergold-iron alloy, an iron-manganese-silicon alloy, and a combination thereof. The IUD according to any one of claims 1-9, wherein the transition from the compressed configuration to the expanded configuration is facilitated by the expansion of a pressurized balloon inside the uterine cavity. The IUD according to any one of claims 1-10, wherein the weight of the pharmaceutical active agent is in the range of about 1-50% w/w based on the total weight of the drug releasing matrix. The IUD according to claim 11, wherein the weight percent of the pharmaceutical active agent is in the range of about 1-30% w/w based on the total weight of the drug releasing matrix. The IUD according to any one of claims 1-12, wherein the polymer of the drug releasing matrix is a crosslinked copolymer comprising at least one first region and at least one second region,

70 wherein the at least one pharmaceutical active agent is dispersed or retained within the copolymer, wherein the at least one first region and the at least one second region within the copolymer each comprise at least 2 repeating units, wherein the repeating units of the at least one first region are selected from the group consisting of propylene glycol, ethylene glycol, vinyl alcohol, glycerol, pentaerythritol, sorbitol, and combinations thereof, and wherein the repeating units of the at least one second region are represented by the formula: (-CO-X-(CH-R)n-Y-), wherein X is O, NH or absent and Y is O or NH, wherein n is an integer selected from 1 to 10, and R is selected from H, alkyl, aryl, hydroxyl and amine.

14. The IUD according to claim 13, wherein the crosslinked copolymer is an elastomer.

15. The IUD according to any one of claims 1-14, wherein the at least one pharmaceutical active agent is selected from the group consisting of tranexamic acid (TA), a hormone, an analgesic agent, a chemotherapeutic drug, and combinations thereof.

16. The IUD according to claim 15, wherein the pharmaceutical active agent is tranexamic acid (TA).

17. The IUD according to claim 15, wherein the pharmaceutical active agent is a hormone selected from progestogen, progestin, estrogen, and combinations thereof.

18. The IUD according to any one of claims 1-17, wherein the foldable sheet further comprises an inner support layer, wherein the drug releasing matrix envelopes or surrounds at least a portion of the inner support layer, and wherein the support layer is extending between the first arm and the second arm of the support member and is coupled thereto.

19. The IUD according to claim 18, wherein the inner support layer comprises at least one polymer selected from the group consisting of polypropylene, polyester, polyamide, polyacrylate, polymethacrylate, and copolymers thereof.

20. The IUD according to claim 18 or 19, wherein the inner support layer is in the form of a mesh structure.

21. The IUD according to any one of claims 1-20, wherein the foldable sheet further comprises an outer layer, wherein said outer layer envelopes or surrounds at least a portion of the drug releasing matrix, and wherein the outer layer comprises an electrically or magnetically responsive porous membrane having an adjustable

71 permeability, configured to enable the controlled release of the pharmaceutical active agent from the drug releasing matrix therethrough.

22. The IUD according to claim 21, wherein said electrically or magnetically responsive porous membrane is configured to be reversibly actuated from a closed or semi closed state to an open state due to the influence of an electric or magnetic field or current, wherein in the open state the pores of the membrane are open, thereby enabling diffusion and drug release therethrough, and wherein in the closed or semi closed state the pores of the membrane are fully closed or semi closed, thereby preventing or substantially preventing drug release therethrough.

23. The IUD according to claim 22, further comprising at least one elongated member, wherein said at least one elongated member is coupled to at least one of the first arm, the second arm, the junction, or to a combination thereof, and wherein at least a portion of the elongated member is hollow and accommodates therein various electrical elements comprising at least one of a power source, a communication module, a controller, an electromagnetic field generator, and combinations thereof.

24. The IUD according to claim 23, wherein the first arm and the second arm are separate components attached to each other indirectly via the elongated member, wherein the at least one foldable sheet comprises at least two separate sheet sections, such that a first sheet section extends between the first arm and a portion of an external surface of the elongated member, and a second sheet section extends between the second arm and a portion of the external surface of the elongated member, wherein the first and second sheet sections are coupled to substantially opposite portions of the external surface of the elongated member, and wherein during the transition from the folded configuration to the spread configuration, the first arm and the second arm are configured to expand or extend in opposite directions relative to each other, resulting in the expansion of the first and second sheet sections in opposite directions, respectively.

25. The IUD according to claim 23 or 24, wherein the elongated member comprises the electromagnetic force generator comprising an induction coil, configured to generate an inner magnetic or electric field or current, wherein said field or current is configured to affect the permeability of the electromagnetically responsive porous membrane, and thus to control the release rate and duration of the pharmaceutical active agent from the drug releasing matrix therethrough.

72 The IUD according to claim 25, wherein the electromagnetic force generator is configured to automatically generate the inner magnetic or electric field in response to an external magnetic field, generated externally to the uterine cavity. The IUD according to claim 25, wherein the elongated member further comprises the power source and the controller, wherein the electromagnetic force generator is configured to generate the inner magnetic or electric field in response to receiving power from the power source, upon receiving commands from the controller. The IUD according to claim 27, wherein the elongated member further comprises an optic detection module and at least one optic member, wherein said optic detection module is electrically and/or functionally connected to the optic member, wherein the optic detection module is configured to communicate with the controller and enable the operation of the optic member, wherein the optic member comprises at least one optic sensor and at least one LED light, wherein the optic member is configured to enable the at least one LED light and the at least one optic sensor to transfer and to detect light therethrough, respectively, in order to detect the presence of red blood cells (RBC) in the vicinity thereof within the uterine cavity, and/or to measure an increase in a concentration thereof relative to a threshold value, and to transfer optic data to the controller via the optic detection module. The IUD according to claims 28, wherein the controller is configured to automatically activate the electromagnetic force generator, thereby inducing the inner magnetic or electric field or current, upon receiving the optic data indicating the presence of RBC and/or the increase in the concentration thereof relative to the threshold value, or based on a predetermined monthly timetable. The IUD according to any one of claims 27-29, wherein the elongated member further comprises the communication module, wherein the controller is configured to activate the electromagnetic force generator upon user demand, thereby generating the inner magnetic field, wherein the user operates the controller via wireless communication using a remote device. The IUD according to any one of claims 27-30, further comprising at least two electrodes configured to measure impedance levels residing therebetween indicative of the RBC concentration or amount in the vicinity thereof, wherein the controller is configured to detect an increase in the concentration or amount of RBC and to automatically activate the electromagnetic force generator, or to issue a notification indicating the user thereto via wireless communication using a remote device.

73

32. The IUD according to any one of claims 27-31, further comprising at least one sensor configured to measure the levels of a physiological or biological indicator in the vicinity thereof within the uterine cavity, and to transfer data indicative thereof to the controller, and wherein the controller is configured to detect a change in the levels of the physiological or biological indicator and to automatically activate the electromagnetic force generator, or to issue a notification indicating the user thereto via wireless communication using a remote device.

33. The IUD according to any one of claims 1-32, for use in reducing or managing menstrual bleeding in a subject in need thereof. 34. The IUD according to any one of claims 1-32, for use in the treatment of a gynecological disease or a disorder in a subject in need thereof.

35. The IUD according to claim 34, wherein the gynecological disease or a disorder is selected from the group consisting of a menstrual bleeding disorder, cervical cancer, vaginal cancer, endometrial cancer, uterus cancer, and a combination thereof. 36. The IUD according to any one of claims 33-35, for use in birth control.

74