METHOD OF CONTRACEPTION

Abstract

The invention is related to an improved method of contraception, for preventing or suppressing abnormal and/or irregular endometrial bleeding and achieving a rapid induction of amenorrhea by using an intrauterine delivery system comprising controlled release levonorgestrel over a prolonged period of time and at a therapeutic level required for contraception, and a sufficient amount of NSAID capable of suppressing abnormal and/or irregular endometrial bleeding

Claims

1. An intrauterine delivery system for the controlled release of levonorgestrel and an NSAID over a prolonged period of time, wherein said intrauterine delivery system releases levonorgestrel at a rate of 9.4 μg per day and an NSAID at a rate of between 47 μg per day and 141 μg per day, wherein the intrauterine delivery system comprises a body construction and at least one reservoir comprising a core and a membrane encasing the core, the core and membrane essentially consisting of a same or different polymer composition, the polymer compositions of the core, membrane and inert separating membrane or segment in the delivery system are selected from the group consisting of: a polymer composition comprising poly(dimethylsiloxane), a polymer composition comprising a siloxane-based polymer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units, a polymer composition comprising poly(alkylene oxide) groups, said poly(alkylene oxide) groups being present as alkoxy-terminated grafts or blocks linked to the polysiloxane units by silicon-carbon bonds, or a mixture of these forms, and a combination of at least two thereof.

2. The intrauterine delivery system according to claim 1, wherein the levonorgestrel and NSAID are in separate reservoirs.

3. The intrauterine delivery system according to claim 1, wherein the siloxane-based polymer from 1 to approximately 50% of the substituents attached to the Si-atoms of the siloxane units are 3,3,3-trifluoropropyl groups.

4. The intrauterine delivery system according to claim 1, wherein the poly(alkylene oxide) groups are poly(ethylene oxide) groups.

5. The intrauterine system according to claim 1, wherein the levonorgestrel is released at a rate of 9.4 μg per day.

6. The intrauterine system according to claim 1, wherein the NSAID is released at a rate of between 47 μg per day and 141 μg per day.

7. The intrauterine delivery system according to claim 6, wherein the NSAID is indomethacin.

8. The intrauterine delivery system according to claim 6, wherein the NSAID is indomethacin and it is released at a rate of between 94 μg per day and 141 μg per day.

9. The intrauterine delivery system according to claim 6, wherein the NSAID is indomethacin and it is released at a rate of 141 μg per day.

10. The intrauterine delivery system according to claim 1, wherein the levonorgestrel and the NSAID are in the same reservoir.

11. The intrauterine delivery system according to claim 6, wherein the levonorgestrel is released at a rate of 9.4 μg per day.

12. A method for contraception and suppressing abnormal or irregular endometrial bleeding comprising the step of administering to a patient in need thereof an intrauterind delivery system comprising a body construction and at least one drug reservoir optionally coated by a membrane, levonorgestrel located in a first drug reservoir and being present in an amount required for contraception, and an NSAID located in the first drug reservoir with the levonorgestrel or in a second drug reservoir, the NSAID being present at an amount capable of suppressing irregular endometrial bleeding.

13. The method according to claim 12, wherein the intrauterine delivery system releases levonorgestrel at a rate of 9.4 μg per day.

14. The method according to claim 12, wherein the NSAID is released at a rate of 47-141 μg per day.

15. The method according to claim 12, wherein the NSAID is naproxen, indomehtacin, ibuprofen, mefenamic acid or Fluribiprofen.

16. The method according to claim 12, wherein the NSAID is indomethacin.

17. A method according to claim 14, wherein the indomethacin is released at a rate of 141 μg per day.

18. The method according to claim 10, wherein the levonorgestrel and NSAID are in the same drug reservoir, the drug reservoir comprising a core and optionally a membrane encasing the core, wherein the core comprises two or more segments separated by a separating membrane, each segment consisting of a polymer composition and either the levonorgestrel or the NSAID.

19. The method according to claim 15, wherein the polymer compositions of the core, the membrane encasing the core, and the separating membranes independently are poly(dimethylsiloxane); a polymer composition comprising a siloxane-based polymer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units; a polymer composition comprising at least one poly(alkylene oxide) group, said at least one poly(alkylene oxide) group being present as alkoxy-terminated grafts or blocks linked to the polysiloxane units by silicon-carbon bonds; or a mixture or combination thereof.

20. The method according to claim 15, wherein the polymer composition comprising a siloxane-based polymer comprises from 1% to approximately 50% 3,3,3-trifluoropropyl groups.

21. The method according to claim 15, wherein the poly(alkene oxide) of the polymer composition comprising at least one poly(alkylene oxide) group is poly(ethylene oxide).

Description

BRIEF DESCRIPTION OF THE FIGURES

[0027] The invention is further illustrated by the following figures describing a common T-shaped frame as an example of an intrauterine system and various constructions of the reservoir according to the invention.

[0028] FIG. 1 illustrates an intrauterine system comprising a body (1), and a reservoir (2) containing therapeutically active agent(s).

[0029] FIG. 2 illustrates an intrauterine system comprising a body (1), and two reservoirs (2 and 3) being positioned one on the other and separated by a separation membrane or a metal ring (4)

[0030] FIG. 3 illustrates an intrauterine system comprising a body (1), and two reservoirs (2 and 3) attached at different parts of the body. Reservoir (2) is held at the correct position by locking means (5a and 5b).

[0031] FIG. 4 illustrates a reservoir of an intrauterine system (2) comprising a core (6) containing a therapeutically active substance or substances and encased by a membrane (7).

[0032] FIG. 5 illustrates a reservoir of an intrauterine system (2) comprising two core segments (6a and 6b) attached one on the other, each containing same or different therapeutically active substance or substances and encased by a membrane (7).

[0033] FIG. 6 illustrates a reservoir of an intrauterine system (2) comprising two core segments (6a and 6b), each containing same or different therapeutically active substance or substances and encased by a membrane (7). The segments are separated from each other by a separation membrane (4).

[0034] FIG. 7 illustrates a reservoir of an intrauterine system (2) comprising two core segments (6a and 6b), each containing a same or different therapeutically active substance or substances and encased by a membrane (7). The segments are separated from each other by an inert placebo segment (8).

[0035] FIG. 8 illustrates a cross section of an assembly where two reservoirs (2 and 3) are positioned one inside the other, the assembly being encased by a membrane (7).

[0036] FIGS. 9A-9B illustrate the results of a comparison study conducted in an animal model of uterine bleeding. The model compares the effects of administering via an IUS: 2 μg/day of levonorgestrel alone vs. 2 μg/day of levonorgestrel plus 10 μg/day of indomethacin vs. 2 μg/day of levonorgestrel plus 30 μg/day of indomethacin.

[0037] FIG. 10 illustrates the difference in the percentage of bleeding days for each dosage group tested: Group 1—2 μg per day of levonorgestrel; Group 2—2 μg/day of levonorgestrel plus 10 μg/day of indomethacin; and Group 3—2 μg/day of levonorgestrel plus 30 μg/day of indomethacin.

[0038] FIG. 11 illustrates the difference in percentage between the mean values obtained for Group 1 (2 μg per day of levonorgestrel), Group 2 (released 2 μg per day of levonorgestrel and 10 μg per day of indomethacin), and Group 3 (2 μg per day of levonorgestrel and 30 μg per day of indomethacin).

DETAILED DESCRIPTION

[0039] The object of the present invention is to provide a method of contraception and for preventing or suppressing abnormal and/or irregular endometrial bleeding and achieving a rapid induction of amenorrhea by using an intrauterine delivery system comprising a progestogen, or a drug having a progestogenic activity, for the controlled release over a prolonged period of time and at a level required for contraception, and a sufficient amount of one or more therapeutically active substances capable of suppressing abnormal and/or irregular endometrial bleeding.

[0040] According to an embodiment of the invention the intrauterine delivery system comprises a body construction and at least one reservoir comprising a core and optionally a membrane encasing the core, said core and membrane essentially consisting of a same or different polymer composition, wherein at least one reservoir comprises a progestogen or a drug having a progestogenic activity and at least one reservoir comprises a therapeutically active substance or substances capable of suppressing abnormal and/or irregular endometrial bleeding. The intrauterine delivery system has an uncomplicated design and can be prepared by an economically attractive manufacturing process.

[0041] According to another embodiment the intrauterine delivery system consists of a body construction and one reservoir comprising a core and optionally a membrane encasing the core, said core and membrane essentially consisting of a same or different polymer composition, wherein the reservoir comprises a progestogen, or a drug having a progestogenic activity, and a therapeutically active substance or substances capable of suppressing abnormal and/or irregular endometrial bleeding.

[0042] According to a further embodiment the intrauterine delivery system consists of a body construction and at least two reservoirs comprising a core and optionally a membrane encasing the core, said core and membrane essentially consisting of a same or different polymer composition, wherein one reservoir comprises a progestogen or a drug having a progestogenic activity, and the other reservoir comprises a therapeutically active substance or substances capable of suppressing abnormal and/or irregular endometrial bleeding.

[0043] The core comprises essentially a polymer composition, that is, the core is a polymer matrix wherein the therapeutically active substance or substances are dispersed. The polymer compositions are chosen according to the release rates desired. The release rates can be controlled by the membrane or by the membrane together with the core, but the release rate can also be controlled by the core alone. Therefore, even in the case there is no membrane or when the membrane primarily regulating the release of the therapeutically active substance would be damaged, the substance or substances would not be released in a completely uncontrolled manner thus causing side effects to the patient.

[0044] The polymer composition of the core and/or the membrane can be chosen so that the intrauterine system releases a sufficient predetermined amount of both progestogen, or a compound having progestogenic activity, and a therapeutically active substance capable of suppressing and/or preventing abnormal and/or irregular endometrial bleeding. By using the intrauterine system according to the invention it is possible even to deliver sufficient daily amounts of water soluble substances, for example such as tranexamic acid, which has not shown to be possible by using the prior art intrauterine systems.

[0045] According to the embodiment in which the delivery system consists of two or more reservoirs, said reservoirs may be positioned separately on the body of the intrauterine system. They may also be positioned one inside the other or one on the other, in which case they may be attached next to each other or may be separated from each other by a separation membrane or by an inert placebo compartment.

[0046] According to the embodiment in which said at least two therapeutically active substances are in the same reservoir, the substances may be homogeneously mixed in the core material. The core may also comprise more than one segment or part, for example two, three, four or five segments or parts consisting of a same or different polymer composition. At least one of these segments comprises a progestogen, or a drug having a progestogenic activity, or one or more therapeutically active substances capable of suppressing abnormal and/or irregular endometrial bleeding.

[0047] One or more of the segments may be an inert separation membrane or a placebo segment without any therapeutically active substance.

[0048] An advantage of using a separation membrane or an inert placebo segment to separate reservoirs or core segments from each other is, that the release rates are more easily controllable since there is no or only a minimal interaction between the active substances. The material and the thickness of a separation membrane or of a placebo segment depend on the capacity of the material to prevent permeation of the active substances. Most ideally the separation membrane or the placebo segment completely prevents mixing of the active substances, which otherwise might disturb the release pattern. Any combination of structure is naturally possible and within the scope of the invention.

[0049] The membrane may cover the whole reservoir or cover only a part of the system, for example one segment of the core, whereby the degree of extension can vary depending on a number of factors, for example such as the choice of materials and the choice of active substances. The polymer composition used in the membrane is such that it allows the predetermined, constant release rates of the therapeutically active agents. The thickness of the membrane depends on materials and active substances used as well as on desired release profiles, but generally the thickness is smaller than the thickness of the core member.

[0050] The membrane may consist of more than one layer. Each layer has a certain thickness, and the thickness of the layers may be the same or different. The combination of different membrane layers either in thickness or in material or both, gives a further possibility for controlling the release rates of the active agents.

[0051] Polymer compositions, namely the polymer compositions of the core, the membrane and the possible separation membrane or the inert placebo segment, can be the same or different and may stand for one single polymer, or the polymer composition may be made up of two or more polymers.

[0052] In principle any polymer, either biodegradable or non-biodegradable, can be used as long as it is biocompatible. As known in the art, the release kinetics of a therapeutically active agent from a polymer based delivery system depends on the molecular weight, solubility, diffusivity and charge of the therapeutically active agent as well as on the characteristics of the polymer, on the percentage of the loading of the therapeutically active agent, on the distance the therapeutically active agent must diffuse through the device body to reach its surface and on the characteristics of any matrix or membrane.

[0053] Polysiloxanes, in particular poly(dimethyl siloxane) (PDMS), are highly suitable for use as a membrane or matrix regulating the permeation rate of drugs. Polysiloxanes are physiologically inert, and a wide group of therapeutically active substances are capable of penetrating polysiloxane membranes, which also have the required strength properties. The permeation rate of the therapeutically active substances can be adjusted at a desired level by modifying the polymeric material in a suitable way, e.g. by adjusting hydrophilic or hydrophobic properties of the material. It is for example known from the literature that addition of poly (ethylene oxide) groups or trifluoropropyl groups to a PDMS polymer change the permeation rate of therapeutically active substances.

[0054] Further examples of suitable materials include, but are not limited to, copolymers of dimethylsiloxanes and methylvinylsiloxanes, ethylene/vinyl acetate copolymers (EVA), polyethylene, polypropylene, ethylene/propylene copolymers, acrylic acid polymers, ethylene/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 glycols, polymethylpentene, polybutadiene, polyhydroxy alkanoates, poly(lactic acid), poly(glycolic acid), polyanhydrides, polyorthoesters, hydrophilic polymers such as the hydrophilic hydrogels, cross-linked polyvinyl alcohol, neoprene rubber, butyl rubber, hydroxyl-terminated organopolysiloxanes of the room temperature vulcanizing type which harden to elastomers at room temperature following the addition of cross-linking agents in the presence of curing catalysts, one- or two-component dimethylpolysiloxane compositions cured by hydrosilylation at room temperature or under elevated temperatures, as well as mixtures thereof. It is also clear for an expert in the field that suitable materials may be composed of the copolymers of the above mentioned homopolymers.

[0055] The structural integrity of the material may be enhanced by the addition of a particulate material such as silica or diatomaceous earth. The elastomers can also be mixed with other additives to adjust elastomer's hydrophilic or hydrophobic properties while taking into account that all additives need to be biocompatible and harmless to the patient. The core or the membrane may also comprise additional material to further adjust the release rate of one or several of the therapeutic substances, for example complex forming agents such as cyclodextrin derivatives to adjust the initial burst of the substance to the accepted or desired level. Auxiliary substances, for example such as tensides, anti-foaming agents, solubilisers or absorption retarders, or a mixture of any two or more of such substances, can also be added in order to impart the desired physical properties to the body of the delivery system.

[0056] According to an embodiment, the core and the membrane are made of a siloxane based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer.

[0057] The term “elastomer composition” may stand for one single elastomer, the deformation of which caused by the strain is reversible so that the elastomer's shape recovers to a certain level after the strain. The elastomer composition may also be made up of two or more elastomers blended with each other.

[0058] The term “siloxane-based elastomer” shall be understood to cover elastomers made of poly (disubstituted siloxanes) where the substituents mainly are lower alkyl, preferably alkyl groups of 1 to 6 carbon atoms, or phenyl groups, wherein said alkyl or phenyl can be substituted or unsubstituted. A widely used and preferred polymer of this kind is poly(dimethylsiloxane) (PDMS).

[0059] The elastomer composition may be selected from the group consisting of [0060] an elastomer composition comprising poly(dimethylsiloxane) (PDMS), [0061] an elastomer composition comprising a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the silicon atoms of the siloxane units, [0062] an elastomer composition comprising poly(alkylene oxide) groups, said poly(alkylene oxide) groups being present as alkoxy-terminated grafts or blocks linked to the polysiloxane units by silicon-carbon bonds or as a mixture of these forms, and [0063] a combination of at least two thereof.

[0064] According to a preferred embodiment of the invention, in the siloxane-based elastomer from 1 to approximately 50% of the substituents attached to the silicon atoms of the siloxane units are 3,3,3-trifluoropropyl groups. The percentage of the substituents that are 3,3,3-trifluoropropyl groups can be for example 5-40%, 10-35%, 1-29% or 15-49.5%. The term “approximately 50%” means that the degree of 3,3,3-trifluoropropyl substitution is in fact somewhat below 50%, because the polymer must contain a certain amount (about 0.15% of the substituents) of cross-linkable groups such as vinyl or vinyl-terminated groups.

[0065] According to another preferred embodiment of the invention, the siloxane-based elastomer comprises poly(alkylene oxide) groups so that the poly(alkylene oxide) groups are present in the said elastomer either as alkoxy-terminated grafts of polysiloxane units or as blocks, said grafts or blocks being linked to the polysiloxane units by silicon-carbon bonds. Preferably poly(alkylene oxide) groups mentioned above are poly(ethylene oxide) (PEO) groups.

[0066] The methods for the preparation of suitable polymers are given for example in international patent applications WO 00/00550, WO 00/29464 and WO 99/10412 (each assigned to Leiras Oy).

The Therapeutically Active Agent

[0067] Progestogen can be any therapeutically active substance having progestogenic activity enough to achieve contraception. In a further embodiment, the progestogenic compound is a steroidal progestogenic compound. Examples of suitable progestogenic compounds include compounds such as progesterone and its derivatives, cyproterone acetate, desogestrel, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone acetate, norethisterone, norethisterone acetate, norgestimate, drospirenone, gestodene, 19-nor-17-hydroxy progesterone esters, 17α-ethinyltestosterone and derivatives thereof, 17α-ethinyl-19-nortestosterone and derivatives thereof, ethynodiol diacetate, dydrogesterone, norethynodrel, allylestrenol, medrogestone, norgestrienone, ethisterone and dl-norgestrel.

[0068] In a particular embodiment the progestogenic compound is levonorgestrel. Other progestogens than levonorgestrel with pronounced angiostatic features could be used in combination with the drugs mentioned above.

[0069] Therapeutically active substances that can be used in conjunction with the invention to prevent or suppress endometrial bleeding can, without limiting the scope of the invention, be selected from the group of prostaglandin synthesis inhibitors like diclofenac sodium, NSAIDs, such as naproxen, indomethacin, ibuprofen, mefenamic acid, flurbiprofen, inhibitors of leukotriene, e.g. zafirlukast and montelukast and its salts, oxytocin antagonists, pancreatic trypsin inhibitors like Trasylol, COX-inhibitors, antifibrinolytic drugs, such as tranexamic acid and precursors thereof, aminocapronic acid, PAI-1, desmopressin, clomiphene citrate, p-aminomethyl-benzoic acid, estrogens, antiestrogens, aromatase inhibitors, cytokine inhibitors, glucocorticoids, progestogens with pronounced glucocorticoid acticity, danazol and gestrinone.

[0070] The above mentioned drugs are to some extend already used for systemic treatment of hypermenorrhea. Moreover, it may be possible to use also inhibitors of angiogenesis, such as angiostatin, endostatin.

[0071] The release of progestin should preferably last for from one up to ten years, or from one to five years, or preferably from three to five years, and the release of additional drugs should last for at least from a week to the maximum of five years, or from a week to one year, or preferably form a week to six months.

[0072] The amount of a therapeutically active substances incorporated in the delivery system, both the progestogen and the therapeutically active substance capable of preventing or suppressing endometrial bleeding, varies depending on the particular therapeutically active agent and the time for which the intrauterine system is expected to provide therapy. There is no critical upper limit on the amount of therapeutically active agent incorporated in the device since, depending on the selected body construction, the size, shape and number of reservoirs for administering dosages can be varied and modified. The lower limit depends on the efficacy of the therapeutically active agent and the expected release time.

[0073] The delivery system according to the invention provides sufficient amounts and rates of release of said therapeutically active compounds for use in contraception and/or hormone therapy and for suppressing or preventing endometrial bleeding. By these sufficient amounts and rates for release is understood that throughout the release period needed, at each point in time a safe and sufficient effective amount of the compounds are released. In particular the release profile of the progestogenic compound may not be too steep. The mean release required is dependent on the use. In an even further embodiment for use in contraception the mean release may also not be too low. A person skilled in the art is readily able to determine the amount of the therapeutically active agent needed for each specific application of the delivery system.

[0074] Therapeutic dosages of active substances reducing menstrual bleeding are to be adapted due to their local activities on the endometrium. Significantly lower dosages than needed for the systemic application are sufficient if released by the intrauterine system. These lower dosages must be in the range of pharmacological equivalency to total dosages of 4-6 g of tranexamic acid administered orally per day.

[0075] Preferably, the amount of progestogen or a substance having a progestogenic activity, as well as the amount of the therapeutically active substance capable of preventing or suppressing endometrial bleeding vary from almost zero to 60 wt-%, when it is mixed into the core matrix, the preferred amount being between 5-50 wt-%. Other possible ranges of the amount of the therapeutically active agent are 0.5-60 wt-%, 5-55 wt-%, 10-50 wt-%, 25-60 wt-%, 40-50 wt-% and 5-40 wt-%.

Manufacture of the Intrauterine Delivery Systems

[0076] The shape and size of the delivery system discussed in this application may be chosen by the person skilled in the art within the dimensions of the uterine cavity. It is also evident that the systems according to the invention may be designed to apply to human as well as to animal mammals.

[0077] An intrauterine delivery system preferably comprises a body forming the frame of the system and a reservoir or reservoirs containing therapeutically active substances attached on the body. A commonly used intrauterine system is a T-shaped object fabricated of any biocompatible material and consisting of an elongate member having at one end a transverse member comprising two arms, the elongate member and the transverse member forming a substantially T-shaped piece when the system is positioned in the uterus. The medicated reservoir or reservoirs can be attached to the elongate member, to the transverse member or members, or both to the elongate member and the transverse member(s). The body of the intrauterine system may naturally have various other forms, for example continuous curved shapes, like circular, angular, oval-shaped, shield shaped or polygonal, as long as their shape and size fit to the size and geometry of the endometrial cavity.

[0078] The manufacturing of these systems is discussed below, even though it is well known in the art.

[0079] The body and the reservoir(s) may be manufactured simultaneously or separately followed by their assembly. The body may preferably be manufactured by injection or compression moulding. The drug containing cores can be manufactured by mixing the therapeutically active substance or substances within the core matrix material for example such as polydimethylsiloxane (PDMS) or the components forming the polymer composition as defined above, processed to the desired shape by moulding, casting, extrusion, or by any other appropriate methods known in the art.

[0080] The membrane layer, if any, can be applied onto the core according to known methods such as by using extrusion or injection moulding methods, spraying or dipping. As an alternative, the prefabricated membrane tube can be expanded mechanically for example with a suitable device or by using for example pressurized gas, such as air, or by swelling it in a suitable solvent, such as cyclohexane, diglyme, isopropanol, or in a mixture of solvents, where after the swollen membrane tube is mounted onto the core. When the solvent evaporates, the membrane tightens on the core.

[0081] The reservoir can be fixed on the frame by using different methods. The frame may for example comprise an elongated extension in the form of a metal or polymer shaft, core, rod or pin or the like at a suitable point on which the hollow tube-like reservoir is assembled, preferably by first enlarging the diameter of the reservoir tube to some degree, for example by using pressure or solvent swelling, and thereafter by simply sliding the reservoir onto the extension or inserting the extension into the hollow reservoir. It is also possible to assemble first the hollow tube-like core onto the body and then assemble the membrane onto the core. Other methods to attach the reservoir to the frame include for example known techniques of welding, use of an adhesive, or use of special metal or polymer inserts, clips, connectors, adapters, clothespin-type means or clamps or like.

[0082] If needed, one or each end of the reservoirs so obtained may be sealed by using known techniques, for example by applying a drop of an adhesive or silicon glue.

[0083] The delivery system can also be manufactured by coating the body with the drug containing core material by using known technology, for example such as dipping, spraying, injection molding and like. According to the embodiment where the reservoirs are inside one another, the delivery system may for example be manufactured by coating the body first with a progestogen containing polymer layer followed optionally a membrane layer, and then coating the system with a polymer layer comprising a therapeutically active substance capable of preventing or suppressing endometrial bleeding, and if needed, followed by a outer membrane layer.

[0084] The reservoirs, the cores of which consist of several parts or segments, can also be prepared for example by using a coextrusion method described in the Finnish patent FI 97947. A therapeutically active substance is mixed within the core matrix polymer composition, and processed to the desired shape and size by using known extrusion methods. The membrane layer may then be applied onto the prefabricated cores by feeding each of the core segments to the extruder followed either by another segment without any active ingredient or by leaving an empty space filled with air between the segments, which during the extrusion process will be filled with the membrane material to form a separation membrane.

[0085] The body of the system may further comprise specific locking means to keep the cores or reservoirs in place during the insertion step, during the use of the device or during the removal of the device. To improve the visualization and the detection of the intrauterine system for example in X-ray or an ultrasound examination, the system may comprise inert metal clips, rings or sleeves on the body or on the reservoir, or an inert metal coating on at least part of the body, or metal powder, metal particles or X-ray contrast agents mixed with the raw materials of the body, core matrix or membrane of the system during the compounding step, or anchoring a metallic loop to the body of an IUS.

[0086] The delivery system according to the invention can be manufactured in any size as required, the exact size being dependent on the mammal and particular applications. In practice, the dimensions of the delivery system should be close to the size of the uterine cavity. For a human female the length of the IUS body is normally in the order of from 20 to 40 mm. in length, preferably from 25 to 38 mm and the width of the body is in the order of from 20 to 32 mm corresponding generally to the width of the fundal portion of the endometrial cavity. The cross-sectional diameter of the body member is in the order of from 1 to 4 mm, preferably from 1.5 to 3 mm.

[0087] The lengths of the cores of the drug delivery system are chosen to give the required performance. Ratios of the core lengths will depend upon the particular therapeutic application, including the desired ratio and dosage of each drug to be delivered. The length of the reservoir as well as of a core segment can be for example from 1 to 35 mm. The length of a placebo segment separating the reservoirs or core segments may generally vary between 1-5 mm and depends on the nature of the material and its capacity to prevent permeation of the active materials.

[0088] The thickness of a separation membrane can be about 0.2 to 5 mm. The thickness, i.e. the outer diameter of the core or core segment, can be from 0.1 to 5.0 mm, and preferably from 0.2 to 3.5 mm. The thickness of the membrane encasing the core or core segment is from 0.1 to 1.0 mm, preferably from 0.2 to 0.6 mm.

EXPERIMENTAL PART

[0089] The invention is described below in greater detail in the following, non-limiting examples.

Example 1

Core Preparation

[0090] 45 parts by weight of levonorgestrel, 10 parts by weight of tranexamic acid and 50 parts by weight of poly(dimethylsiloxane-co-vinylmethylsiloxane) and 1.2 parts by weight of dichlorobenzoylperoxide-polydimethylsiloxane paste (50% of dichlorobenzoylperoxide) were mixed with a 2-roll mill. The mixture was extruded to a tube-like form with a wall thickness of 0.8 mm and outer diameter of 2.8 mm and cured by heat at +150° C. for 15 minutes, during which crosslinking took place. The crosslinked core was cut into 24 mm length.

Preparation of the Delivery System

[0091] The core was swollen in cyclohexane and pulled over the IUS body. Cyclohexane was allowed to evaporate.

Example 2

Core Preparation

[0092] 50 parts by weight of levonorgestrel, 50 parts by weight of poly(dimethylsiloxane-co-vinylmethylsiloxane) and 1.2 parts by weight of dichlorobenzoylperoxide-polydimethylsiloxane paste (50% of dichlorobenzoylperoxide) were mixed with a 2-roll mill. The mixture was extruded to a tube-like form with a wall thickness of 0.8 mm and outer diameter of 2.8 mm and cured by heat at +150° C. for 15 minutes, during which crosslinking took place. The crosslinked core was cut into 15 mm length.

[0093] Second core was prepared in a similar manner by using 10 parts by weight of danazol in place of levonorgestrel. The crosslinked core was cut into 8 mm length.

Membrane Preparation

[0094] 99 parts of silica-filled poly(dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species) and 0.03 parts of inhibitor (ethynyl cyclohexanol) and approximately 0.6 parts of poly(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a 2-roll mill. Based on the method described in FI 97947, the membrane material was coextruded to a tube-like form by simultaneously inserting the above prepared two cores through the inner nozzle in the die by leaving an empty space between the cores to be filled by membrane material. The wall thickness of the membrane was 0.23 mm. The thickness of the separation membrane formed between the cores was 1.8 mm.

Example 3

Core Preparation

[0095] 54 parts of commercial poly(dimethylsiloxane-co-vinylmethylsiloxane), 45.5 parts by weight of levonorgestrel, 0.4 parts of poly(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker, 0.02 parts of ethynyl cyclohexanol inhibitor and 10 ppm of Pt-catalyst (of the reaction species) in vinyl-methyl-siloxane were mixed in a kneating mill. The mixture was extruded to a tube-like form with a wall thickness of 0.7 mm and cured by heat at +115° C. for 30 minutes and cooled.

[0096] Second core was prepared in a similar manner by using 79.5 parts of commercial poly(dimethylsiloxane-co-vinylmethylsiloxane) and in place of levonorgestrel 20 parts by weight of mefenamic acid.

Membrane Preparation

[0097] 9 parts of α,ω-divinylether terminated poly(ethylene oxide)-b-poly(dimethylsiloxane) multiblock copolymer (PEO-b-PDMS), 89 parts of silica-filled poly(dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species), 0.03 parts inhibitor (ethynyl cyclohexanol), and approximately 2 parts of poly(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill. The mixture was extruded to a tube-like form with a wall thickness of 0.2 mm and cured by heat.

Preparation of the Delivery System

[0098] The membrane was swollen in isopropanol and pulled over both cores. Isopropanol was allowed to evaporate. Levonorgestrel containing reservoir was cut to the length of 22 mm and mefenamic acid containing reservoir to the length of 4 mm. Next the tube-like reservoirs were swollen in cyclohexane and assembled on the vertical stem of a T-shaped body by separating the reservoirs form each other by a silver ring having essentially the inner diameter of the vertical stem and outer diameter just slightly smaller than the outer diameter of the reservoirs. Cyclohexane was again allowed to evaporate.

Example 4

Core Preparation

[0099] 29 parts of PEO-b-PDMS, 29 parts of poly(dimethylsiloxane-covinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species), 0.02 parts inhibitor (ethynyl cyclohexanol), and approximately 2.4 parts of poly(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill and 39 parts of levonorgestrel was added. The mixture was extruded to a tube-like form with a wall thickness of 0.8 mm and outer diameter of 2.8 mm and cured by heat at +150° C. for 15 minutes, during which crosslinking took place. The crosslinked core was cut into 12 mm length.

[0100] Second core was prepared in a similar manner by using 20 parts by weight of mefenamic acid in place of levonorgestrel. The crosslinked core was cut into 10 mm length. Third core, a placebo segment, was prepared in a similar method but without adding any active substance. The crosslinked core was cut into 3 mm length.

Membrane Preparation

[0101] 9 parts of PEO-b-PDMS, 89 parts of silica-filled poly(dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species), 0.03 parts inhibitor (ethynyl cyclohexanol), and approximately 2 parts of poly-(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill. The membrane material was coating extruded on the above prepared three cores by successively inserting them through the inner nozzle (in the order of levonorgestrel core, placebo, mefenamic acid core) in the die. The formed wall thickness of the membrane was 0.22 mm.

Example 5

Core Preparation

[0102] 24 parts of PEO-b-PDMS, 24 parts of poly(dimethylsiloxane-covinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species), 0.02 parts inhibitor (ethynyl cyclohexanol), and approximately 2.4 parts of poly-(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill and 35 parts of levonorgestrel and 14.5 parts of mefenamic acid was added. The mixture was extruded to a tube-like form with a wall thickness of 0.8 mm and outer diameter of 2.8 mm and cured by heat at +150° C. for 15 minutes, during which crosslinking took place. The crosslinked core was cut into 24 mm length.

Membrane Preparation

[0103] 100 parts by weight of silica-filled poly(trifluoropropylmethylsiloxane-co-vinylmethylsiloxane), in which the content of trifluoropropyl-methylsiloxane units was 99 mol-%; i.e. degree of trifluoropropyl substitution was 49.5%, and 1.2 parts by weight of dichlorobentsoylperoxide-polydimethylsiloxane paste (50% of dichlorobenzoylperoxide) were mixed with a 2-roll mill. The mixture was extruded into a tube-like form with a wall thickness of 0.22 mm and cured by heat.

Preparation of the Delivery System

[0104] The membrane was swollen in isopropanol and pulled over the core. Solvent was allowed to evaporate. Next the tube-like reservoir was swollen with cyclohexane and assembled on a T-shaped IUS body. Cyclohexane was again allowed to evaporate. The ends of the reservoir were sealed by using silicone glue.

Preparation of the Delivery System, Examples 2 and 4

[0105] The core-membrane reservoir was swollen in cyclohexane and the stem of the body was inserted into the hollow reservoir. Cyclohexane was again allowed to evaporate.

Drug Release Test

[0106] The release rate of the drug from the implant was measured in vitro as follows:

[0107] The intrauterine delivery systems were attached into a stainless steel holder in vertical position and the holders with the devices were placed into glass bottles containing 250 ml of a dissolution medium. The glass bottles were shaken in shaking water bath 100 rpm at 37° C. The dissolution medium was withdrawn and replaced by a fresh dissolution medium at predetermined time intervals, and the amount of the released drug was analysed by using standard HPLC methods. The concentration of the dissolution medium and the moment of change (withdrawal and replacement) of medium were selected so that sink-conditions were maintained during the test.

[0108] Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art can in light of this teaching generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. Accordingly, it is to be understood that the drawings and descriptions herein are offered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Example 6

[0109] The effects of administering via an intrauterine system (IUS) levonorgestrel alone, or in combination with indomethacin, were tested in animal model of intrauterine bleeding. The study was conducted using three groups of adult cycling cynomolgus macaques. The macaques were monitored to record regular menstrual cycles. Scheduled (menses) and unscheduled uterine bleeding and spotting was assessed daily by vaginal swabs, and menstrual blood loss was quantified by vaginal tampons.

[0110] After about two menstrual cycles (about 60 days), the macaques were assigned to three separate groups and laparotomized on days 6-9 of the follicular phase. For each macaque, an IUS was inserted by hysterotomy into the uterine lumen and sutured in place. Group 1 included 9 monkeys that were given an IUS that released 2 μg per day of levonorgestrel. Group 2 included 8 monkeys that were given an IUS that released 2 μg per day of levonorgestrel and 10 μg per day of indomethacin. Group 3 included 7 monkeys that were given an IUS that released 2 μg per day of levonorgestrel and 30 μg per day of indomethacin.

Characterization of Bleeding

[0111] The frequency and type of bleeding was assessed by daily vaginal swabs. FIGS. 9A-9B illustrate the results of the different types of bleedings. Gray-shaed cells represent positive swab or frank menses, which is the most heavy form of bleeding. Diagonal-lined cells represent light positive swab, which is an intermediated type of bleeding.

[0112] The gray-shaded cells that were assigned represent the heaviest form of bleeding were assigned a score of 2. The diagonal-lined cells represent an intermediate type of bleeding and were assigned a score of 1.

[0113] For evaluation of bleeding days, the first 7 days after insertion of the IUS were neglected, since the insertion procedure by surgery causes some bleeding that is unrelated to treatment effects. FIGS. 9A-9B include data for a period of 80 days after the IUS was inserted in each of the macaques.

[0114] For Group 1, the total number of bleeding days was 77. The average number of bleeding days per macaque was 8.6. The total score for all of the macaques for both the gray-shaded cells and the diagonal-lined cells was 107. The average score for each of the macaques for both the gray-shaded cells and the diagonal-lined cells was 11.9.

[0115] For Group 2, the total number of bleeding days was 73. The average number of bleeding days was 9.1. The total score for all of the macaques for both the gray-shaded cells and the diagonal-lined cells was 101. The average score for each of the macaques for both the gray-shaded cells and the diagonal-lined cells was 12.6.

[0116] For Group 3, the total number of bleeding days was 30. The average number of bleeding days was 4.3. The total score for all of the macaques for both the gray-shaded cells and the diagonal-lined cells was 41. The average score for each of the macaques for both the gray-shaded cells and the diagonal-lined cells was 5.9.

Difference in Percentage of Bleeding Days

[0117] FIGS. 9A-9B show the difference in percentage between Group 1 (2 μg per day of levonorgestrel alone), Group 2 (2 μg per day of levonorgestrel and 10 μg per day of indomethacin), and Group 3 (2 μg per day of levonorgestrel and 30 μg per day of indomethacin).

[0118] In comparison to Group 1 (2 μg per day of levonorgestrel alone), the combination of 2 μg per day of levonorgestrel and 30 μg per day of indomethacin (Group 3) significantly reduced the bleeding and spotting scores on average by −50% (Mean±SEM, T-test, one-sided, Welch's correction for unequal AD).

Difference in Mean Values

[0119] FIG. 10 shows the difference in percentage between the mean values obtained for Group 1 (2 μg per day of levonorgestrel), Group 2 (released 2 μg per day of levonorgestrel and 10 μg per day of indomethacin), and Group 3 (2 μg per day of levonorgestrel and 30 μg per day of indomethacin).

Human Dosages

[0120] The volume of the uterus in macaques is 40 mm in length and 20 mm in diameter. The volume of the uterus in a human is 75 mm in length, 50 mm in diameter at its upper park, and 25 mm thick. The ratio of the volume of human to macaque is about 4.7. As a result, the dosages administered to the macaques may be multiplied by 4.7 to obtain the human dosage.

[0121] Thus, in some embodiments, irregular endometrial bleeding is suppressed in a human by administering levonorgestrel at a rate of 9.4 μg per day and an NSAID, such as indomethacin, at a rate of between 47 μg per day and 141 μg per day. In some embodiments, irregular endometrial bleeding is suppressed in a human by administering levonorgestrel at a rate of 9.4 μg per day and an NSAID, such as indomethacin, at a rate of between 94 μg per day and 141 μg per day. In some embodiments, irregular endometrial bleeding is suppressed in a human by administering levonorgestrel at a rate of 9.4 μg per day and an NSAID, such as indomethacin, at a rate of 141 μg per day.