A three-layered intravaginal ring

Abstract

The present invention relates to a three-layered intravaginal ring (1;1'), a core (2;9), an intermediate layer (3;10), and a sheath (6) comprising a second ethylene-vinyl acetate copolymer (7) having a vinyl acetate content from 20 to 40 wt%, and at least wt% of a progestational steroid (8) based on the weight of the sheath, wherein one of the core (9) and intermediate layer (3) comprises a first ethylene-vinyl acetate copolymer (4) having a vinyl acetate content from 26 to 40 wt% and an estrogenic steroid (5), and the other one of the core (2) and intermediate layer (10) is an inactive layer (2;10). Using the intravaginal ring according to the present the inventors have found that it is possible to attain independent and optimal release of the two active ingredients; an estrogenic steroid and a progestational steroid, without the need for complex assembly of parts.

Description

[0001] A three-layered intravaginal ring. The present invention relates to a three-layered intravaginal ring, and a method of manufacturing said ring. Various types of intravaginal rings (IVRs) have been developed for the controlled and sustained release of active ingredients preferably by diffusion through the surface of the ring. Examples of such devices are the Estring®, Femring®, and Nuvaring®, all of which provide controlled and sustained release of steroid molecules over a prolonged period, e.g. several weeks / months. In addition to preventing undesired pregnancies, the device provides several advantages: its use is controlled by the female; it allows for a better regulated dose of drug without attention by the user; and it avoids the destruction (by the intestine and by first pass through the liver) of an appreciable portion of the daily dosage of the drugs compared to their orally delivered counterparts. These known vaginal rings have been found particularly useful for the release of steroids, whose relatively small molecular size and substantially water-insoluble nature permit effective permeation through the hydrophobic elastomer / polymer, such that therapeutic concentrations may be readily achieved in the body. However, diffusion in polymers is complex and is known to depend on a number of different factors, e.g. temperature, the manufacturing process, the solubility and diffusivity of the drug in the polymer, the surface area of the drug reservoir, the distance the drug must diffuse through the device to reach its surface and the molecular weight of the drug. Consequently, it remains a challenge to understand, predict and control the diffusion of small and large molecules in polymer systems. In this respect, the use of intravaginal rings to deliver drugs requires a design that regulates the release rate so as to reliably provide the user with the appropriate daily dose throughout the lifetime of the device. In reservoir systems, i.e. a drug loaded core surrounded by a non-medicated membrane / sheath, the drug first partitions into the sheath from the reservoir and then diffuses to the other side of the sheath, where it is taken up by the receiving medium. While the reservoir is saturated, a constant concentration gradient of drug is maintained in the membrane, the rate of drug flux is constant, and zero order release is achieved. However, when drug concentration in the reservoir falls, the gradient across the membrane and the release rate of the drug also decreases. Furthermore, reservoir systems can be difficult to fabricate reliably, and pinhole defects and cracks in the sheath surrounding the reservoir, can lead to dose dumping, i.e. unintended, rapid drug release over a short period of time. Simultaneous drug delivery / release finds application in a number of different areas. However, the placement of a blend of drugs in a single intravaginal ring in a proportion equal to the desired delivery rate ratio will almost never achieve the desired result. In many cases, the drugs will not diffuse together through the surface or membrane at the same ratio, as they exist in the blend. The ratio would instead be dependent on the inherent ratio of the normalized permeation rates for the drugs through e.g. a rate-controlling membrane. Flexibility would therefore be limited to the selection of suitable polymer candidates for the sheath. Accordingly, the range of, and degree of control over, the delivery rate ratio, is extremely limited. Of course the need for maintaining a specified delivery rate ratio can be met by using a separate intravaginal ring for each drug. However, this is clearly undesirable, since the presence of two or more intravaginal rings will compound the disruption which even a single ring might create in the normal physiological activity of an animal or human. In addition, if one intravaginal ring malfunctions, the desired delivery ratio will be lost. Further, complete therapy in a single intravaginal ring is more acceptable to patients and more efficient to insert and remove. Adjustment of a specified delivery rate can also be met by two or multi-compartments intravaginal rings, and ring bodies containing drug release capsules. The industrial scale manufacturing of such rings is however complex and expensive. A further problem with the known intravaginal rings arranged for releasing more than one drug is that such rings usually show sub-optimum release patterns for the different drugs, whereas it is generally preferred that all drugs are released in a controlled rate during a specified duration of time. Thus, there is a demand for a novel intravaginal ring arranged for releasing two active ingredients / drugs in a controlled manner and in the correct ratio, and a method for manufacturing the system that is simple and inexpensive. Thus, it is a first aspect of the present invention to provide a three-layered intravaginal ring, which can be loaded with both an estrogenic steroid and a progestational steroid and wherein each steroid is released at a controlled rate independently of the other steroid. In a second aspect according to the present invention is provided a three-layered intravaginal ring that reduces the variability of the release rate of steroids over time. In a third aspect according to the present invention is provided a three-layered intravaginal ring in which the known problems relating to complicated and expensive manufacturing processes, and dose dumping are eliminated, and which at the same time provides a substantially zero-order release rate of the estrogenic steroid. In a fourth aspect according to the present invention a provided a three-layered intravaginal ring which can comprise a relatively low concentration of estrogenic steroid in solid form and still maintain a desired release rate of said steroid. The novel and unique features whereby these and further aspects are achieved according to the present invention is by providing a three-layered intravaginal ring comprising − a core, − an intermediate layer, and − a sheath comprising a second ethylene-vinyl acetate copolymer having a vinyl acetate content from 20 to 40 wt%, and at least 10 wt% of an progestational steroid based on the weight of the sheath, wherein one of the core and intermediate layer comprises a first ethylene-vinyl acetate copolymer having a vinyl acetate content from 26 to 40 wt%, and an estrogenic steroid, and the other one of said core and intermediate layer is a inactive layer. The intravaginal ring according to the invention relates to a system that comprises a core surrounded, at least partly and preferably completely, by first an intermediate layer (shell) and then completely by a sheath, which is the outer layer of the vaginal ring. The three-layers of the intravaginal ring are preferably co-axially / concentric arranged, i.e. the core, intermediate layer and sheath share a common axis. Such a three-layered intravaginal ring provide an improved delivery system compared to the known delivery systems, since the release rate of the estrogenic steroid and the progestational steroid can be adjusted independently from one another. The estrogenic steroid may be present in either the core or the intermediate layer, but not in both the core and intermediate layer, at least not initially, e.g. at the time of manufacturing. Thus, in a first embodiment of the intravaginal ring according to the invention the intermediate layer comprises the estrogenic steroid and the core is the inactive layer; and in a second embodiment the core comprises the estrogenic steroid and the intermediate layer is the inactive layer. The sheath is the same for both embodiments. Within the context of the present invention the term ”inactive layer” means a layer / section of the vaginal ring, which in the present case may be either the core or intermediate layer, that has no active properties, i.e. said inactive layer does not contain or comprise any active ingredients such as medicaments, steroids, or other components that may have an active effect on the patient and / or the intravaginal ring. A person skilled in the art will understand that a small part of the steroids present in the three-layered vaginal ring will dissolve in the ring, and that a fraction of the dissolved steroid may / will re-distribute in the vaginal ring until a thermodynamic equilibration has been reached. Thus, the point of time when the core and / or intermediate layer are the inactive layer, i.e. has no active properties, is before said equilibration process has been initiated, e.g. at the time of manufacture. The equilibration process may take several weeks to months depending on the dimensions of the core, intermediate layer and sheath, as well as on storage and use conditions. According to the present invention the estrogenic steroid is placed in either the core or intermediate layer, but contrary to the conventional vaginal rings where the sheath comprises no active ingredient e.g. known from WO2009 / 036999 and WO2004 / 103336, the sheath of the present invention comprises a high concentration of progestational steroid (at least 10wt%), whereby simultaneous and individual release of both the progestational steroid and the estrogenic steroid is provided. It must be noted that even though it is known to have small concentrations of active ingredient in a sheath surrounding a drug loaded core, see e.g. WO2013 / 120888 and WO2015 / 086489, it is not known to have a progestational steroid in the sheath (as the outer layer) in the high concentrations claimed in the present invention. Small concentrations of progestational steroid i.e. concentrations well below 10 wt%, will have no or only a very limited effect on the release rate of the estrogenic steroid in the core / intermediate layer, and are accordingly not relevant for the present invention. Dual administration of both a progestational steroid and an estrogenic steroid finds application in a number of different areas, e.g. in contraceptive vaginal rings and in vaginal rings providing hormone replacement. For such intravaginal rings it is required to release the two steroids simultaneously and at the same time. It is therefore necessary to adjust the release rate of these steroids independently to the physiological optimal rate (mg / day). Using the intravaginal ring according to the present invention the inventors have found that it is possible to attain independent and optimal release of the two steroids; an estrogenic steroid and a progestational steroid without the need for complex assembly of parts. Thus, using an intravaginal ring in which the concentration of the progestational steroid in the sheath is at least 10wt%, it is ensured that the desired near zero-order release behavior of the estrogenic steroid in either the intermediate layer or in the core are observed for a longer period of time. In addition such high concentrations of the progestational steroid are associated with good physical stability of said steroid. By substantially zero order is meant that a substantially constant amount of the estrogenic steroid is released over a given period of time. In some embodiments, the system exhibit a substantially zero order release profile of the estrogenic steroid over a treatment period of at least 14 days, preferably at least 28 days, and even more preferred around two to three months. As discussed earlier it is a well known problem that if the core contains an active ingredient, the release rate of said active ingredient decreases as active ingredient(s) that is deeper inside the core / reservoir must diffuse to the surface. This problem is eliminated by providing a vaginal ring comprising an inactive layer in the form of either an inactive core or an inactive intermediate layer. Thus, having a three- layered vaginal ring comprising a inactive layer (core or intermediate layer), an opposite core or intermediate layer comprising the estrogenic steroid, and a sheath comprising a high concentration of a progestational steroid, the inventors of the present invention has found that the release rate of the estrogenic steroid from the core or the intermediate layer, is substantially constant over time, thereby providing a substantially zero-order release rate of the estrogenic steroid during the desired treatment period. For the embodiment with the inactive core the zero order release rate can be attributed to the barrier properties of the sheath, where the particles of the progestational steroid will act as 'filler' and likely contribute to the barrier properties of said sheath. For the embodiment with the inactive intermediate layer, zero order release is likely attributed to the combined barrier properties of an inactive intermediate layer and the sheath with particles of progestational steroid. The three-layered intravaginal ring according to the invention may have the estrogenic steroid present in either the core or the intermediate layer, the other being the inactive layer, and even though both embodiments / constructions provide an improved release rate and lower steroid burst, the two different ring embodiments also have individual advantages. For instance, when the estrogenic steroid is present in the intermediate layer and the core is the inactive layer (inactive core), the inventors of the present invention have found that the use of a inactive core (layer) ensures that a small fraction of the estrogenic steroid loaded in the intermediate layer and a small fraction of the progestational steroid loaded in the sheath can diffuse back into the “empty” inactive core. This mechanism can / will eliminate any persisting super saturation and provide a more reliable and constant release rate, and a lower initial burst, of said steroids. Thus, said embodiments provide an intravaginal ring with an even better release profile than hitherto known. Furthermore, desirable release rates of the estrogenic steroid can be obtained with lower amounts of estrogenic steroid placed in the intermediate layer of the three-layered ring according to the invention, compared to a two-layered intravaginal ring (core / sheath) in which the estrogenic steroid is present in the core. For instance, if a two-layered intravaginal ring comprises 10wt% of the estrogenic steroid an acceptable physical stability of the ring is obtained, however this will also result in an excess drug load. Loading with an even higher concentration of estrogenic steroid in the core of a two-layered ring would result in a further increased excess of estrogenic steroid and other unfavorable properties like too high stiffness of the ring and supersaturation. In a three-layer design however the volume of the intermediate layer can be controlled and reduced or increased if required. Hence much higher drug loads can be used without overloading the system. Using e.g. 25wt% of estrogenic steroid in the intermediate layer would have the advantage of flatter profiles as at the same release rate the penetration of the depleted layer is less deep. The inventors of the present invention have in this respect compared a two-layered intravaginal ring (core / sheath) with a three-layered intravaginal ring according to the invention (estrogenic steroid placed in the intermediate layer). Thus, in the two-layered ring estradiol (estrogenic steroid) is present in the core, and in the three-layered ring estradiol is present in the intermediate layer, the core being the inactive layer. The ethylene-vinyl acetate copolymers were the same for the layers containing the respective steroids. Both rings were surrounded by a sheath with about 33,9 wt% progesterone (progestational steroid.) The inventors found that a release rates around 160µg / day could be obtained with the three-layered ring using significantly less of the estradiol concentration required for obtaining the same release rate for the desired duration period. In one example, the inventors found that for a release rate of estradiol of about 250 µg / day, the two-layered ring required 210-215 mg estradiol in order to obtain said release rate of about 28 days, and the three-layered ring (5 wt% estradiol in a 200 µm thick intermediate layer) only required about 17-18 mg estradiol. It should in this respect be noted that in a two-layered intravaginal ring higher drug loads aims at provides a higher degree of physical stability in the intravaginal ring. However, the inventors of the present invention found that only a small percentage of said drug amount were in fact used for therapeutic purposes. Although the two-layered ring provided a zero order release, and was physically stable, the use of a three-layered intravaginal ring according to the invention, with an inactive core, and the estrogenic steroid placed in an intermediate layer, is a clear improvement over the two-layered ring. Said improvement relates to both the benefit of being able to tailor the amount of active ingredients loaded in the intravaginal ring, and to the fact that a higher percentage of the estrogenic steroid loaded in the intravaginal ring can be delivered to the surrounding environment, leaving a reduced remnant content of estrogenic steroid in the intravaginal ring after use, thereby both reducing manufacturing cost and the impact on the environment. Furthermore, since the thickness (volume) of the intermediate layer comprising the estrogenic steroid can be adjusted, the drug load of the estrogenic steroid in the three-layered vaginal ring according to the invention can be tailored to meet specific demands, e.g. a certain drug load to sustain the release of said steroid for the intended duration of use. In relation to the ring-construction in which estrogenic steroid is present in the core, and the intermediate layer is the inactive layer, said embodiment has the surprising advantage than the intermediate inactive layer will act as a rate limiting barrier layer, that can be used to adjust the release profile of the estrogenic steroid in the core, without affecting progestational steroid release from the sheath. In this way it is possible to attain independent and optimal release of the two steroids in a simpler way than hitherto known. For comparison purposes, it should be noted that for a two- layered intravaginal ring (core / sheath) wherein the estrogenic steroid is present in crystalline state in the core and surrounded by a sheath, the concentration of estrogenic steroid driving release is equal to the saturation concentration. Hence, varying the estrogenic steroid drug load will not substantially affect release of the estrogenic steroid when said steroid is present in crystalline state. Thus, the only way to influence estrogenic steroid release in a two-layered ring is by varying the permeation resistance (barrier properties) of the progestational steroid sheath. The barrier properties of the sheath are determined by sheath thickness, the properties of the sheath polymer and the content of progestational steroid particles in the sheath. However, the properties of the polymer and the content of progestational steroid particles cannot be changed without affecting progestational steroid release and hence the only variable left to adjust the estrogenic steroid release independently of other factors, is the sheath thickness. In this respect the inventors found, based on simulations and experimental data, that a sheath having a thickness of at least 400µm, such as 500 - 600 µm is required to reduce estrogenic steroid release to one desired range of about 160µg / day in a two-layered ring comprising about 10 wt% estradiol in the core and about 33.9wt% progesterone in the sheath. If a lower estrogenic steroid release was desired an even thicker sheath would be required. The latter is hampered by fundamental physics resulting in practical limitations. The estrogenic steroid loaded in solid state (particles) in the core will be in equilibrium with the steroid dissolved in the core at saturation solubility. This small fraction of dissolved steroid will re-distribute in the vaginal ring until uniform activity through-out the intravaginal ring (thermodynamic meaning) has resulted. For practical reasons, it is required that this equilibration process is relatively rapid as only after equilibration stable release profiles are obtained. Furthermore, as is confirmed by the data in the present invention a reduction to 80µg / day or lower would require sheath thicknesses above 700 µm, which would lead to unacceptable equilibration times. Accordingly, such high sheath thicknesses are not desired from a practical point of view. However, the inventors of the present invention have found that by a three-layered ring, in which the estrogenic steroid is placed in the core, and an inactive intermediate layer is placed between the sheath and the core, will solve the above problems, as the inactive intermediate layer will function as additional barrier layer whereby the release rate of the estrogenic steroid can be varied without affecting progestational steroid release from the sheath. For instance if a lower release rate of the estrogenic steroid is desired, the inactive intermediate layer can be thicker and vice versa. Alternatively, the inactive intermediate layer can be made of e.g. an ethylene-vinyl acetate copolymer with a lower or higher VA-content in order to adjust the release rate to the desired level. Thus, the use of a three-layered ring according to the present invention in which the intermediate layer is the inactive layer provides an optimal intravaginal ring compared to a corresponding two-layered vaginal ring, i.e. without the intermediate inactive layer. In order to obtain one or more of the above advantages, it is relevant that the progestational steroid is dispersed and / or incorporated in the second ethylene-vinyl acetate copolymer to an extent sufficient to control the diffusion rate of the estrogenic steroid through the sheath. Without being bound by theory, it is believed that the progestational steroid in the sheath will function as a filler and control the release rate of the estrogenic steroid, irrespectively of whether the estrogenic steroid is present in the core or in the intermediate layer. When the progestational steroid present in the sheath is released to the surroundings, the concentration of said progestational steroid is reduced and it is believed that the diffusion of water into the sheath may be facilitated leaving behind an empty porous matrix and / or empty pockets / holes and / or the sheath may collapse thereby ensuring the desired zero-order release profile of the estrogenic steroid. Thus, it is believed that the space initially occupied by the progestational steroid leaves behind an empty porous matrix which may become water filled due to ingress of water and / or may leave behind empty pockets / holes. This is contrary to the conventional findings in which the release rate of an active ingredient in a core surrounded by a non-medicated sheath slightly decreases over time, i.e. the desired zero order release rate cannot be maintained over a desired treatment period for such conventional vaginal rings. In some embodiments it is preferred that at least 15 wt% of the progestational steroid is dispersed in the second ethylene-vinyl acetate copolymer, even more preferred at least 20 wt%, and even more preferred at least 25 wt%. In order to ensure that the estrogenic steroid can be released through the sheath it is preferred that the sheath comprises a concentration of the progestational steroid based on the weight of the sheath of not more than 40 wt%, preferably 35 wt% or below, e.g. 27 wt% or 33.9 wt%. The presence of the progestational steroid in the relatively high concentrations (e.g. between 10 and 40 wt%) in the sheath will not only lead to an increase in the mean path length the molecules of the estrogenic steroid have to travel between two points in the sheath, but will also reduce the amount of the estrogenic steroid which can be dissolved in the second ethylene-vinyl acetate copolymer of the sheath, accordingly decreasing the release rate of the estrogenic steroid though said sheath. Accordingly, the sheath can be made smaller, providing a smaller product with a significant lower burst of the estrogenic steroid. It is in this respect preferred that the progestational steroid is incorporated and / or dispersed in the second ethylene-vinyl acetate copolymer in the form of particles, preferably crystals. Such particles / crystals will form a repository of solid, undissolved crystals which will act as seed crystals i.e. as a slow release depot. Over time, when the progestational steroid is delivered to the surroundings, some of the crystals will be unlocked in the second ethylene- vinyl acetate copolymer, thereby providing a prolonged release of the progestational steroid. Furthermore, the stability of the progestational steroid in the intravaginal ring is improved when the progestational steroid is incorporated into the sheath as undissolved particles / crystals. Without being bound by theory it is believed that maintaining a concentration of the progestational steroid at high concentrations in the sheath it is assumed that a porous network path is created by crystals and wherein a number of sites / openings / pores in the matrix of the second ethylene- vinyl acetate copolymer remains empty, ensuring that the estrogenic steroid only can be released through a tortuous path in the sheath, thereby the diffusion length increases and the release rate is controlled. A person skilled in the art will based on the context of the present invention understand that it will be possible to control and / or adjust the diffusion rate through the sheath by varying the amount / concentration of the progestational steroid in said sheath, by using different grades of the second ethylene-vinyl acetate copolymer, and / or by using different particle sizes of the progestational steroid or blends of different particles sizes. In order to obtained the desired zero order release profile of the estrogenic steroid during the treatment period, it is preferred that the estrogenic steroid is present in the intermediate layer or core in the form of particles, preferably crystals, for the same reasons relating to release and stability as disclosed for the progestational steroid . In this way the stability of both the estrogenic steroid and progestational steroid, and accordingly the intravaginal ring according to the intention, is improved. When the estrogenic steroid is present as particles in either the core or intermediate layer, it is preferred that said estrogenic steroid is dispersed and / or incorporated in the first ethylene-vinyl acetate copolymer of the core or intermediate layer in a concentration of at least 5 wt% of the total weight of the respective intermediate layer or core, preferably at least 10 wt%, and even more preferred at least 15 wt% or even higher e.g. at least 20 wt%. A load of 5wt% is above estradiol (estrogenic steroid) saturation concentration, but such high loads is preferred to avoid delayed crystallization of estradiol which may dissolve in the polymer e.g. during the extrusion process. Due to a low solubility of the steroids in the first and second ethylene-vinyl acetate copolymer, the use of the relatively high drug loads used (at least 10wt% progestational steroid and at least 5 wt% estrogenic steroid) assist with ensuring that said steroids will be incorporated in the first and second ethylene-vinyl acetate copolymer as particles, preferably in a crystalline state. In a preferred embodiment the particles / crystals of the progestational steroid and the estrogenic steroid have a mean particle size of between 1 µm and 40 µm, preferably between 2 µm and 24 µm, and even more preferred between 3 and 10 µm, such as around 5µm as it has been proven that such particle sizes provide the desired near zero order relate rate for a prolongs period of time, i.e. for at desired treatment period of at least 14 days, preferably at least 28 days e.g. one to two months.. As used herein, the term “crystals” refers to particles of the steroids arranged in an ordered microscopic structure, forming a crystal lattice. The term "crystal size" or “particle size” refers to a crystal’s or particle’s mean particle diameter. Particle size, crystal size and / or particle size distribution is preferably measured using laser diffraction e.g. using a Malvern laser scattering particle size analyzer. However any other particle size measurement apparatus or technique known to person’s skilled in the art can also be used, e.g. dynamic light scattering, a sieve analysis or a microscopic determination. As used herein, the term "crystal size" or “particle size” relates to the particle distribution diameter of the particle / crystal. As an example can be mentioned that D50 means that 50% of the particles have a diameter below the given value when measured using e.g. laser diffraction, dynamic light scattering, or a sieve analysis. For instance, for the steroid progesterone the D50 is preferably less than 10 µm, and the particle size is usually between 4 – 6 µm, such as around 5 µm. For the steroid estradiol, D90 is less then 5 µm. The first and second ethylene-vinyl acetate (EVA) copolymers, used in the intravaginal ring of the present invention are suitable for placement in the vaginal tract, i.e. the materials are non-toxic and non-absorbable in a patient or an animal, and are considered to have both excellent mechanical and physical properties. The vinyl acetate concentration of the EVA-copolymer determines the rate of diffusion of the active ingredient through the system and generally, the lower the vinyl acetate concentration, the slower the active ingredient will be release from the copolymer or migrate through it. In order to provide the desired zero order release profile of the estrogenic steroid it is preferred that the first ethylene-vinyl acetate copolymer comprises an ethylene-vinyl acetate copolymer with a vinyl acetate content from 26 to 40%, preferably 26%, 33% or 40%. In a similar way the second ethylene-vinyl acetate copolymer preferably has a vinyl acetate content from 20 to 40 wt%, such as e.g. 24 wt%, 28 wt%, 33 wt% or 40 wt% as these materials will provide the desired release profile through the sheath, e.g. by ensuring that the progestational steroid release rate is at the optimal level. Since the polymers used for the inactive core will not directly affect release of the steroids in the sheath and intermediate layer, the polymers of the inactive layer may in principal be made of any relevant polymer that are suitable for placement in the vaginal tract. However, when the inactive layer is the core, it is preferred that said inactive core comprises a third ethylene-vinyl acetate (EVA) copolymer e.g. having a vinyl acetate content from 1 to 33 wt%, or alternatively a thermoplastic polyurethane (TPU) or a low-density polyethylene (LDPE). Low VA-content EVAs, typically between 9 and 20wt% vinyl acetate, is especially relevant if a reduced back diffusion into the inactive core is desired, and EVA with a VA-content of 33 wt% may be useful in case a sink for persisting super saturation is needed as it can contain more dissolved steroid. TPU or LDPE is relevant for three-layered vaginal rings with a smaller cross-sectional diameter, e.g. around 3 – 4 mm is desired in order to maintain sufficient ring stiffness for said vaginal ring to resist compression forces when placed in the vaginal tract. In this respect the relevant stiffness may also be achieved by using polymers with relatively high tensile modulus or by increasing cross-sectional diameter or by adjusting both to arrive at the desired target. These materials will provide the desired mechanical strength of the three-layered vaginal ring and at the same time ensure that the core as an inactive layer can function as an empty reservoir allowing the steroids from the intermediate layer and sheath to diffuse into said core in order to eliminate any persisting super saturation in said intermediate layer and sheath, thereby providing a vaginal ring with constant release profiles and lower burst release. The inventors of the present invention have found that a three-layered vaginal ring with a inactive core, relative to a intravaginal ring having a core loaded with solid particles improves the mechanical properties of the vaginal ring, e.g. provides a reduced stiffness, and thereby better flexibility and recovery of shape after compression. When the inactive layer is the intermediate layer, it is preferred that said inactive intermediate layer is made of a linear polyethylene (LPE) or an ethylene-vinyl acetate (EVA) copolymer having a VA content above 0 wt% but not more than 24 wt%, preferably 6wt% - 20wt%, even more preferably 9wt% - 18wt%, e.g. 15wt% (EVA15) as these polymers have proven highly efficient in acting as a barrier layer to adjust the release profile of the estrogenic steroid in the core, without affecting progestational steroid release from the sheath. In one embodiment of the present invention the first and second and optionally the third ethylene-vinyl acetate copolymer have the same vinyl acetate content, i.e. the first and second and optionally the third ethylene-vinyl acetate copolymer are the same. When a specific vinyl acetate (VA) content e.g. 20 wt% is mentioned it refers to the weight% content provided by the manufacture. However, manufactures may use different internal analytical methods for determining vinyl acetate content, and there may therefore be variations in the range of 1 – 2 % in the actual vinyl acetate content depending on the manufacture. Thus, in the present invention the vinyl acetate content refers to the vinyl acetate content in the ethylene-vinyl acetate copolymer determined by high resolution NMR according to standard methods. The wt% of the vinyl acetate content in the ethylene-vinyl acetate copolymer is the wt% content based on the weight of the ethylene-vinyl acetate copolymer. The intravaginal ring according to the invention is a dual- drug delivery intravaginal ring i.e. it comprises both an estrogenic steroid and a progestational steroid. In a preferred embodiment the estrogenic steroid is estradiol or estriol and / or the progestational steroid is selected from a group consisting of a progestogen, progesterone, etonogestrel, levonorgestrel, d-1-norestrel, segesterone, segesteronacetat and norethindrone, preferably levonorgestrel. The steroids can be selected for preventing contraception, or to treat a conditions, e.g. vaginal atrophy, or for hormone replacement therapy e.g. relating to symptoms associated with menopause, such as hot flashes. The intravaginal ring according to the invention is adapted to deliver pharmaceutically effective amounts of the steroids. By "pharmaceutically effective," it is meant an amount, which is sufficient to affect the desired physiological or pharmacological change in the subject. This amount will vary depending upon such factors as the potency of the steroid, the desired physiological or pharmacological effect, and the time span of the intended treatment. Those skilled in the arts will be able to determine the pharmaceutically effective amount for any given steroid in accordance with standard procedures. The thickness of the sheath, which is the outer layer of the three-layered intravaginal ring according to the present invention, can be varied to further control the release rate of the estrogenic steroid. The dimensions of the intravaginal ring may vary depending upon the anatomy of the subject, the amount of active ingredient to be delivered to the patient, the time over which the active ingredient is to be delivered, the diffusion characteristics of the active ingredient and other manufacturing considerations. The only requirement being that the intravaginal ring should be flexible enough to enable bending and insertion inside the vaginal cavity and rigid enough to withstand the expulsive forces of the vaginal musculature without causing abrasion to the vaginal epithelium. The outer diameter of such intravaginal rings may range, e.g., from about 45 mm to about 65 mm, and / or the length of the fiber elements forming the intravaginal ring may have a length from 150 to 170 mm, preferably from 154 to 160 mm, such as about 157 mm or 163.5 mm. The surface area of the intravaginal ring determines the drug release, and hence larger diameter rings are assumed to display proportionally higher drug release. In a first embodiment, wherein the core is the inactive layer, i.e. the intermediate layer comprises the estrogenic steroid, said intermediate layer preferably has a thickness from 20 µm to 500 µm, or from 50 µm to 500 µm, preferably from 80 µm to 400 µm, and even more preferred from 100 µm to 300 µm, as such a thicknesses have proven to provide the desired release rate of the estrogenic steroid from the intermediate layer. In certain embodiments the thickness of the intermediate layer is 100 µm, 200 µm, or 300 µm. In an embodiment wherein the intermediate layer is the inactive layer, i.e. it is the core that comprises the estrogenic steroid, said intermediate layer preferably has a thickness from 50 µm to 300 µm, preferably from 50 µm to 200 µm, and even more preferred from 80 µm to 200 µm, as such thicknesses will provide the desired rate controlling barrier. In certain embodiments the thickness of the intermediate layer is 80 µm, 100 µm, or 200 µm. The core preferably has a round cross-section with a cross- sectional diameter of between 2 and 8 mm, more preferably between 3 mm and 6 mm and even more preferably from 4 to 5 mm. Said core diameter may apply to both constructions, i.e. irrespectively of whether the inactive layer is the core or the intermediate layer. The thickness of the sheath determines the amount of progestational steroid present in the ring, assuming the steroid concentration is uniform / not varied. The amount of progestational steroid loaded in the intravaginal ring is an important design parameter as the progesterone release should be sustained over the intended duration of use and on the other hand a large excess should be avoided for economic and environmental reasons. In a preferred embodiment, the thickness of the sheath (for both embodiments) may be between 0.05 mm and 1 mm. Said thickness can preferably be between 50 µm and 600 µm, more preferred between 100 µm and 500 µm, and even more preferred between 200 µm and 500 µm In certain embodiments the thickness of the sheath is 50 µm, 100 µm, 200 µm, 300 µm, 400 µm, 500 µm, or 600 µm. A person skilled in the art will in view of the present invention understand that a thin sheath can contain less active ingredient than a thicker sheath; and that the concentration of the progestational steroid in the sheath should be enough to sustain release over the desired treatment period. By using an ethylene-vinyl acetate copolymer grade with higher or lower vinyl acetate-content the sheath’s thickness can be altered while maintaining essentially the same average release rate of the estrogenic steroid. For instance, if a thicker sheath is desired because more of the progestational steroid has to be accommodated in the sheath, an ethylene-vinyl acetate copolymer grade with higher vinyl acetate content can be chosen. In the context of the present invention the term intravaginal ring, also contemplates ring designs or structures, which have other shapes, e.g. polygonal shapes and / or wavy shapes, or where the structure is not a complete and / or closed circle / shape. In a first preferred embodiment the three-layered intravaginal ring comprises − a inactive core, i.e. a core without any active properties − an intermediate layer comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content from 28 wt% to 33 wt%, and at least 5 wt% of an estrogenic steroid preferably at least 10 wt% of an estrogenic steroid, based on the weight of the intermediate layer, and wherein said estrogenic steroid are incorporated into the first ethylene-vinyl acetate copolymer in the form of particles, and − a outer sheath comprising a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 24 wt% to 40 wt%; and between 25 and 35 wt%, e.g. 27 or 33.9 wt% of an progestational steroid based on the weight of the sheath, and wherein said progestational steroid are incorporated into the second ethylene-vinyl acetate copolymer in the form of particles. Said embodiment has a cross-sectional diameter of 5 mm, the intermediate layer a thickness of 50 - 300 µm and the sheath a thickness of 400 µm or 550 µm. In a second preferred embodiment the three-layered intravaginal ring comprises − a core comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content from 28 wt% to 33 wt%, and at least 5wt% of an estrogenic steroid, preferably at least 10 wt% of an estrogenic steroid based on the weight of the core, and wherein said estrogenic steroid are incorporated into the first ethylene-vinyl acetate copolymer in the form of particles, − a inactive intermediate layer i.e. an intermediate layer without any active properties, and − a outer sheath comprising a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 24 wt% to 40 wt%, and between 25 and 35 wt%, e.g. 27 or 33.9 wt% of an progestational steroid based on the weight of the sheath, wherein said progestational steroid are incorporated into the second ethylene-vinyl acetate copolymer in the form of particles. Said embodiment has a cross-sectional diameter of 5 mm, the intermediate layer a thickness of 50 - 200 µm and the sheath a thickness of 400 µm or 550 µm. In a preferred embodiment the average release rate of estradiol from a three-layered intravaginal ring according to the invention is from 60 µg / day to 160 µg / day during a treatment period of at least 28 days, e.g. one month, and preferably a near zero order release rate is provided. However said average release rate may be higher e.g. up to 300 µg / day, e.g. up to about 250 µg / day, e.g. 180 µg / day or about 165 µg / day, and / or lower if desired. Additionally or alternatively, the average release rate of progestogen may be from 3 mg / day to 10 mg / day, such as about 3 mg / day or 4 mg / day for a treatment period of at least 28 days, e.g. about a month. It is expected that the release rate of progestogen will decrease during the treatment period as the content of progestogen in the sheath is depleted. People skilled in the art will based on the present application understand that combinations of the average release rates of estradiol and estradiol is contemplated within the scope of the present inventing. For instance, in one intravaginal ring the average release rate of estradiol is 80 µg / day and the average release rate of progestogen is 10 mg / day, in a different embodiment the average release rate of estradiol is 100 µg / day and the average release rate of progestogen is 5 mg / day, in a third embodiment the average release rate of estradiol is 160 µg / day and the average release rate of progestogen is 8 mg / day, etc. In a preferred embodiment according to the present invention the intravaginal ring does not comprise more than two steroids, i.e. an estrogenic steroid and a progestational steroid, and / or does not comprise further cores and / or layers such as sheaths and membranes, i.e. the intravaginal ring according to the invention consists of a single core, a single intermediate layer completely surrounding said core and a single sheath completely surrounding said intermediate layer, and wherein the estrogenic steroid is placed either in the core or the intermediate layer, the a progestational steroid in the sheath, and wherein the core or intermediate layer that is not containing the estrogenic steroid, is an inactive layer. The present invention also relates to a method of manufacturing the intravaginal ring according to the present invention. Said method comprises a. providing an inactive core, b. providing an intermediate layer comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content from 26 to 40 wt%, and at least 5wt% estrogenic steroid based on the weight of the intermediate layer, and wherein said estrogenic steroid is incorporated into the second ethylene-vinyl acetate copolymer in the form of particles, c. providing a sheath comprising a second ethylene-vinyl acetate copolymer having a vinyl acetate content from 20 to 40 wt%, and at least 10 wt% of an progestational steroid based on the weight of the sheath, said progestational steroid is incorporated into the first ethylene-vinyl acetate copolymer in the form of particles d. co-extruding the core, intermediate layer and sheath into a fiber, e. cutting the fiber into an appropriate length thereby providing a fiber element, and f. combining the ends of fiber element to form the intravaginal ring. In a modified method according to the invention, steps a and b are respectively modified into a’ and b’ as follows: a’. providing an core comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content from 26 to 40 wt%, and at least 5wt% estrogenic steroid based on the weight of the core, and wherein said estrogenic steroid is incorporated into the first ethylene-vinyl acetate copolymer in the form of particles, and b’. providing an inactive intermediate layer. Step c – f are the same in the two method according to the invention. As the core, intermediate layer and sheath are co-extruded a very simple and inexpensive embodiment according to the invention is provided, however the core, intermediate layer and / or sheath can be formed in separate injection moulding or extrusion steps if preferred. Injection moulding and extrusion are well known in the art and will not be discussed further in this application. During extrusion the two steroids will to some degree dissolve in the polymer melt as result of higher solubility at higher temperatures. Upon cooling the amount dissolved in access relative to the amount that can dissolve at room temperature should re-crystallize. If this process is delayed the result is a physically instable product. It is accordingly preferred that the method further comprises a cooling step in which the provided fiber or fiber element is cooled to a temperature of 20C or below for providing the crystals of the steroids in the sheath and the core or intermediate layer. This may e.g. be obtained by placing the fiber into a cooling water bath. Without being bound by theory, the inventors believe that active substances dissolved at elevated extrusion temperatures in the polymer melts will re-crystallize in the sheath and the core / intermediate layer upon cooling as a result of a sharp drop of the saturation solubility of the active ingredients in the polymers. This process should preferably take place promptly to avoid severe super saturation which is undesirable. The re-crystallization process is believed to be facilitated by "seed" crystals and the relatively high concentration of active ingredient in the sheath and the core / intermediate layer, will result in a higher concentration of “seed” crystals, upon which recrystallization can occur when the fiber is cooled after co-extrusion. Thus, in the cooling step prompt re-crystallization is facilitated by crystals surviving the extrusion process and for this reason a high drug load is desired in order to avoid that most or all crystals disappear during extrusion and no seeds are left to prompt re-crystallization. It is preferred that said cooling step is performed immediately after step d., i.e. as fast as is practically possible from a production point of view, i.e. preferably within less than 30 minutes from completion of the fiber in step d, and even more preferred within a period of a few (1 - 5) seconds to 10 minutes from completion of the fiber in step d, and even more preferred not more than about 2 minutes from completion of said fiber. It is preferred that the rings are produced by heat welding the fiber ends together without the addition of further EVA material or adhesive. The invention will be explained in greater detail below, describing exemplary embodiments of a three-layered intravaginal ring according to the invention, wherein Fig. 1 shows a perspective view of a first embodiment of a three-layered intravaginal ring according to the invention, Fig. 2 shows a perspective view of a second embodiment of a three-layered intravaginal ring according to the invention, Fig. 3 shows simulated release rates of estradiol from rings AE1, AE2, and AE3 having an inactive core, and a 300 µm intermediate layer loaded with 10 wt% estradiol (5 mm fiber diameter), all three-layers of the rings are made of EVA28, Fig. 4 shows simulated release rates of estradiol from rings AE4, AE5, and AE6 having an inactive core, and a 300 µm intermediate layer loaded with 5 wt% of estradiol (5 mm fiber diameter), all three-layers of the rings are made of EVA28, Fig. 5 shows simulated estradiol release rates from rings BE1, BE2, BE3 having an inactive core, and an intermediate layer having different thicknesses, all three-layers of the rings are made of EVA28, Fig. 6 shows simulated estradiol average daily release from ring BE1 having an inactive core and a 100 µm e intermediate layer, all three-layers of the ring are made of EVA28, Fig. 7 shows simulated estradiol average daily release from ring BE4 having an inactive core and a 100 µm intermediate layer, all three-layers of the ring are made of EVA28, Fig. 8 shows simulated estradiol release rate from rings BE4, BE5, BE6 having an inactive core and different thicknesses of the intermediate layer, all three-layers of the ring are made of EVA28, Fig. 9 shows simulated estradiol average daily release from rings CE1, CE2, and CE3 each having an inactive intermediate layer. The core and sheath are made from EVA 28 and the inactive intermediate layer is made of EVA 15, Fig. 10 shows simulated estradiol average daily release from ring CE1 having an inactive intermediate layer made of EVA 15, Fig. 11 shows progesterone release from two IVRs comprising 33.9 wt% progesterone in the sheath and with 0.39 wt % and 10 wt% in the ring, Fig. 12a,b,c are microscopy pictures showing layer thicknesses of sheath and intermediate for K1 – K8, Fig 13a shows the average daily release of progesterone for the IVRs K1 - K8 for 28 days, Fig. 13b shows a zoom of the daily release of progesterone for the IVRs K1 - K8 for days 1 – 5, Fig. 14a shows simulated average daily release of estradiol for the IVRs K1, K2 and K3 for 28 days, Fig. 14b shows measured average daily release of estradiol for the IVRs K1, K2 and K3 for 28 days, Fig. 15 shows estradiol release on day 1 (burst) from K1, K2, and K3, Fig. 16a shows simulated average daily estradiol release for the IVRs K2, K4 and K5 for 60 days, Fig. 16b shows measured average daily estradiol release for the IVRs K2, K4 and K5 for 28 days, Fig. 17 shows measured average daily estradiol release for the IVRs K4, K5 and K6 for 28 days, Fig. 18a shows simulated daily estradiol release for the IVRs K7, and D8 for 60 days, and Fig. 18b shows measured average daily estradiol release for the IVRs K3, K7 and K8 for 28 day. Figure 1 shows a preferred first embodiment of a three-layered intravaginal ring (IVR) 1 according to the invention. In said embodiment the IVR comprises an inactive core 2, an intermediate layer 3 made of a first ethylene-vinyl acetate copolymer 4 and an estrogenic steroid 5, and a sheath 6 made of a second ethylene-vinyl acetate copolymer 7 and comprising a progestational steroid 8. As is evident from the drawings, the three-layers of the intravaginal ring are co-axially arranged, i.e. the core, intermediate layer and sheath share a common axis. Figure 2 shows a second embodiment of the three-layered intravaginal ring (IVR) 1’ according to the invention. Said IVR corresponds to the first embodiment and for like parts the same reference numbers are used. In the second embodiment the core 9 is made of a first ethylene-vinyl acetate copolymer 4 and comprises the estrogenic steroid 5, and the intermediate layer 10 is the inactive layer. The sheath 6 is the same as for the first embodiment. Example 1: Effect of sheath thickness on the release of Estradiol (E2) from IVRs in which estradiol is present in the intermediate layer. To evaluate the effect of the concentration of Estradiol in the intermediate layer and thickness of the sheath the release rate of a series of intra-vaginal rings having an inactive core has been evaluated using computational modeling. The model considers the diffusion of the Estradiol (E2) which is driven by the concentration gradient in the system and the dissolution of Estradiol crystals dispersed in the intermediate layer and it assumes the receiving medium to be a perfect sink. The release rate of Estradiol is affected by the Sheath thickness, and the concentration of Estradiol in the intermediate layer should be enough to provide a sustained release rate during 28 days of considered treatment. Experimentally when rings are tested for in-vitro release, the medium is refreshed daily. Hence, the experimentally determined release rate is in fact the release rate that is averaged over 24 hours. For this reason, the simulated results have also been averaging over the period of one day. The three layers of the tested vaginal rings are all made of EVA28, i.e. an ethylene-vinyl acetate copolymer having a vinyl acetate content of 28 wt%. The average release rate of estradiol is provided in Table 1, and are shown in Fig. 3 and Fig. 4

[0002] Dimensions Drug loading Estradiol release Delivery Diameter Length Sheath Inter- Intermediate Sheath Burst Average Average system (mm) (mm) (µm) mediate layer wt% PNG (µg / day) daily daily release layer EVA wt% E2 release (2- (1-28) 28 EVA28 28) (µg / day) (µm) (µg / day) AE1 5 157 200 300 10.1 33.9 831.84 447.67 461.39 AE2 5 157 40030010.07 33.9 782.50 234.12 253.70AE3 5 157 70030010.18 33.9782.30 139.98 162.92 AE4 5 157 2003005.00 33.9829.92 402.26 417.53 AE5 5 157 4003005.06 33.9782.46 226.22 246.08 AE6 5 157 7003005.18 33.9782.27 138.75 161.73 Table 1: Simulated release rates of Estradiol (E2) The simulation shows that the average daily release from a ring having 33.9 wt% progesterone (PGN) crystals in the sheath act like a release rate-limiting membrane, i.e. it reduces the release rate of Estradiol from the ring. The presence of progesterone crystals increases the diffusion length and reduces the amount of available EVA. It should be noted that the drug is homogeneously distributed after equilibration and no partitioning between core, intermediate layer and sheath will take place as all are made of EVA28. Example 2: Effect of the intermediate layer thickness and its Estradiol concentration on the release rate from IVRs in which Estradiol is present in the intermediate layer. A parametric study is conducted to demonstrate the release rate regarding the thickness of the intermediate layer and its Estradiol concentration from an intravaginal ring comprising an inactive core. The results are shown in Table 2 and in Fig. 5 to Fig. 8. Dimensions Drug loading Estradiol release Delivery Diameter Length Sheath Inter- Intermediate Sheath Burst Average Average system (mm) (mm) (µm) Mediate layer wt% PNG (µg / day) daily release on EVA28 layer wt% E2 release (2- day 28) (µm) 28) (µg / day) EVA28 (µg / day) BE1 5 157 40010012.17 33.9 782.51 234.14 224.73 BE2 5 157 400 200 10.60 33.9 782.50 234.14 224.73 BE3 5 157 400 300 10.07 33.9 782.50 234.14 224.73 BE4 5 157 400 100 6.28 33.9 782.44 220.80 187.53 BE5 5 157 400 200 4.58 33.9 782.44 221.40 200.84 Fig. 5 and 6 shows the release rate of estradiol and the a BvEe6rage 5 dai 1l5y7 re 40l0ease 300for 4d.0i4fferen 33t.9 in 7t8e2r.4m4edi 2a2t1.e41 la 2y0e0.r85 Table 2: Simulated release rates of Estradiol. thicknesses and for an Estradiol concentration around 10 wt%. Said results shows that for a concentration of about 10 wt% estradiol, no visible impact can be observed on the release rate of Estradiol during the treatment period. The release rate is mainly governed by the Sheath thickness loaded with progesterone crystals, as dissolved Estradiol can be maintained at saturation during the treatment period (i.e., enough Estradiol is present in the intermediate layer even for the 100 µm). For a concentration of estradiol around 5 wt% the release rate is comparable to 10 wt% Estradiol for all the rings, however for ring BE4 (intermediate 100 µm) a depletion can be seen around day 27 as shown in Fig. 7 and Fig. 8. Example 3: Effect on release rate of estradiol (E2) present in the core and the thickness of an inactive intermediate layer. To evaluate the effect of the thickness of an inactive intermediate layer, different intra-vaginal rings have been evaluated using computational modeling. Increasing the sheath thickness to reduce the release of Estradiol could be used to a certain level to tailor the release rate of Estradiol. However, achieving a low release of Estradiol e.g. 80 µg / day may lead to a very thick sheath which might require longer maturation time for the equilibration of Estradiol in the intravaginal rings. In this example the IVRs comprise Estradiol in the core (of EVA 28), a rate-limiting intermediate layer made of EVA 15, and a sheath made of EVA2 8 and comprising 33.9wt% progesterone. The results of the release rate for estradiol is provided in Table 3 and shown in Fig. 9 and Fig. 10. Dimensions Drug loading Estradiol release Delivery Diameter Length Sheath Inter- Core Sheath Burst Average Average Day 28 system (mm) (mm) (µm) Mediate wt% E2 wt% PGN (µg / day) daily daily release EVA28 layer release release (µg / day) (µm) (2-28) (1-28) EVA15 (µg / day) (µg / day) 791.36 128.64 152.31 115.15 CE1 5 157 4008010 33.9 791.36 117.17 141.24 101.75 CE2 5 157 400 100 10 33.9 791.36 85.994 111.19 63.606 CE3 5 157 400 200 10 33.9 Table 3: Simulated release rates of estradiol for IVRs having an core made of EVA28, an inactive intermediate layer made of EVA15, and a sheath made of EVA28. As is evident from said results incorporation of an inactive intermediate layer of EVA 15, lead to a substantial reduction in the release rate of Estradiol. The reduction is dependent also on the thickness of the intermediate layer; thus the release rate can be tailored to meet a desired release rate of Estradiol, even for an average release rate lower than 80 µg / day, independently of the release of progesterone from the sheath. Example 4: Release of progesterone (PGN). In order to compare the release rate of progesterone in the dependence of concentration of estradiol in an intravaginal ring, the following IVRs were tested: AC400: An IVR with a sheath made of EVA28 and comprising 33.9 wt% progesterone, said ring contains 0.39 wt% estradiol in a layer made of EVA28. Cross-sectional fiber diameter: 5.00 mm. DC400: An IVR with a sheath made of EVA28 and comprising 33.9 wt% progesterone, said ring contains 10 wt% estradiol in a layer made of EVA28. Cross-sectional fiber diameter: 5.00 mm. The progesterone release rates are shown in table 4 and Fig. 11 Time (days): 0-6 h 6-24 h 1.00 2.00 3.00 4.00 7.00 8.00 9.00 10.00 11.00 14.00 AC400 Mean (mg) 34.84 32.02 66.85 25.66 19.22 16.02 12.38 10.79 9.82 9.19 8.64 7.71 DC400 Mean (mg) 35.84 32.49 68.32 25.88 19.32 16.09 12.56 10.79 9.96 9.29 8.67 7.82 Time (days): 15.00 16.00 17.00 18.00 21.00 22.00 23.00 24.00 25.00 28.00 29.00 30.00 AC400 Mean (mg) 7.24 6.81 6.61 6.28 5.87 5.63 5.26 4.94 4.66 4.01 3.56 3.22 DC400 Mean (mg) 7.33 6.92 6.66 6.31 5.92 5.55 5.23 4.81 4.45 3.70 3.16 2.79 Table 4: Mass of Progesterone released during each sampling interval (mg) It can be seen from said results that the concentration of estradiol in the ring does not affect the release of progesterone, as both IVRs AC400 (0.39 wt% estradiol) and DC400 (10 wt% estradiol) have substantially identical release profiles of progesterone. Thus, it can be concluded from said data that the release rate of progesterone is independent of the concentration of estradiol in the ring. Example 5: In-vitro release of estradiol (E2) and progesterone (PGN) from different manufactured three-layered intra-vaginal rings. To evaluate the theoretical data from the computational modeling examples, eight batches of intra-vaginal rings were produced, K1 – K8. The targeted length of the fiber that forms the intra-vaginal rings (IVRs) is 163.5 mm, and the fiber diameter is 5 mm for all the IVRs. The produced batches of IVRs, K1 – K8, are summarized in table 5. Delivery Sheath Intermediate Sheath Intermediate Core Theoretical target Theoretical system (µm) layer composition layer composition content target content (µm) composition of E2 in mg of PGN in mg K1 200 300 27 wt% PGN 10 wt% E2 64.102 132.901 EVA28 EVA28 EVA28 K2 530 300 27 wt% PGN 10 wt% E2 54.263 327.975 EVA28 EVA28 EVA28 K3 650 300 27 wt% PGN 10 wt% E2 50.686 391.436 EVA28 EVA28 EVA28 K4 530 130 27 wt% PGN 10 wt% E2 24.612 327.975 EVA28 EVA28 EVA28 K5 530 200 27 wt% PGN 10 wt% E2 37.169 327.975 EVA28 EVA28 EVA28 K6 530 200 27 wt% PGN 10 wt% E2 37.169 327.975 EVA28 EVA28 EVA28 K7 550 80 27 wt% PGN 10 wt% E2 173.767 338.829 EVA28 EVA16 EVA28 K8 550 160 27 wt% PGN 10 wt% E2 159.218 338.829 EVA28 EVA16 EVA28 Table 5: Manufactured IVR batches having a target diameter of 5 mm, and a target length of 163.5 mm. The IVR batches were manufactured using the method according to the invention, with the specific follows consecutive steps: 1. Weighing of milled EVA and relevant steroid (estradiol and progesterone) according to the details in table 5 and table 7: a) weighing of EVA for the inactive layer b) weighing of milled EVA and estradiol for either the core or intermediate layer c) weighing of milled EVA and progesterone for the sheath 2. Mixing the respective EVAs and relevant steroid for each layer, i.e. core, intermediate layer and sheath 3. Compounding and pelletizing said mix for each layer, 4. Mixing the provided pelletized mix with magnesium stearate (mgst), 5. Trico-extruding the core, intermediate layer and sheath into a fiber, 6. Cutting the fiber into an appropriate length thereby providing a fiber element, and 7. Combining the ends of fiber element to form IVRs of the batches K1 – K8. The following raw materials were used for the manufacture of the IVRs K1 – K8: Material Supplier Comments Micronized Progesterone Pfizer (PGN) Micronized Estradiol Aspen Oss Particle size, average ≤ 7 µm hemihydrate (E2) Particle size, standard deviation ≤ 1.9 µm Particle size, LT 20 µm ≥ 95% Magnesium stearate Peter Greven (Mgst) Milled EVA 28 Celanese Melt flow index: 22.10 g / 10 min Vinyl acetate content: 28.5 % ATEVA® 2820A 21021503 EVA 40 pellet Celanese ATEVA® 4030ACG EVA 28 pellet Celanese ATEVA® 2820-AG EVA 16 pellet Celanese ATEVA® 1608 Table 6: Raw materials Step 2 was obtained by transferring the milled EVA and steroids to a mixing bag in the proportions specified in table 7. Formulations E2 wt% PGN wt% EVA wt% 27 wt% PGN N / A 73 10 wt% E2 10 N / A 90 EVA 16 N / A N / A 99.9* EVA 28 N / A N / A 99.9* EVA 40 N / A N / A 99.9* Table 7: Formulations for preparing the layers of the IVR batches K1 –K8 * 0.1 % of Magnesium stearate Mgst Note: API load in the pellet is defined as the weight fraction of API in the pellet mAPI / (mAPI+mEVA28)x100 The batches containing progesterone were mixed using a blender and the estradiol batches were mixed manually for 3 min. The compounding in step 3 was conducted using an 11 mm closely intermeshing twin screw extruder (Pharma 11 twin screw extruder from Thermo Scientific). The compounding set temperature of all batches is 90 °C in order to produce the relevant pellets with the respective steroids. To enhance the processing properties of the pellets in the tri-extrusion process, Magnesium stearate (Mgst) was added to all batches in step 4. First, 0.1 wt% of Mgst was added to the mixing bags with the relevant pellets and then manually mixed for around 3 minutes. Mgst is also added to the EVA pellet for the inactive layer (core or intermediate) in the same portion. In step 5 a tri-extruder with a 6 mm die was used to produce the tri-layer fibers with a diameter of 5 mm. The tri-extruder line comprises a single screw extruder 16 / 25 (D / L) (i.e. 16 is the diameter and 25 is the length) for the core, and a single screw extruder 12 / 33.3 for the sheath and intermediate layers. The volume of the melt pumps is 0.6 cm for the core and 0.3 cm for the sheath and intermediate. The production speed was set to around to 1 m / min, see also table 8. The fiber characteristics (e.g., diameter and layer thicknesses) were controlled by the melt pump speed for the three extruders to produce a fiber of 5 mm diameter with the required layers thickness. All the fibers were extruded using extrusion temperature between 90°C and 100 °C, except for EVA 16, where the layer extruder temperature was raised up to 120 °C, and for EVA 40, where the temperature of the core extruder decreased to 70 °C. The die temperature was set to 90 °C except for K7 and K8 where one temperature zone in the die increased to 115 °C. Melt pump speed (rpm) Delivery Haul-off Fiber diameter system Sheath Intermediate Core Extruder speed (mm) Extruder layer Extruder (m / min) K1 13.1 16.9 25.1 1.07 5.004 K2 35.8 14.0 17.0 1.07 5.010 K3 44.6 12.8 14.0 ≈ 1.04 4.998 K4 35.8 4.7 21.5 ≈ 1.08 4.998 K5 35.8 9.5 19.2 1.07 4.984 K6 35.8 9.5 19.2 1.07 4.999 K7 35.8 3.8 21.9 1.07 5.032 K8 35.8 9.5 19.2 1.06 4.971 Table 8: Melt pump speed of the three extruders The melt pump speed was calculated based on the capacity of the pumps, with some adjustments to reach the target. The melt pump values are shown in table 8. After co-extrusion, the fibers are cut into a length of 163.5 mm in step 6 and then welded together to form the intra- vaginal rings (IVRs) in step 7. For each batch 20 IVRs were produced. For all IVR-batches, K1 – K8, the sheath is made of EVA 28 with 27 wt% progesterone. For batch K1 to K6, the 10 wt% estradiol material is located in the intermediate layer (intermediate) and the core is inactive and made of EVA 28 except for K6, where EVA 40 is used. For K7 and K8, the 10 wt% estradiol material is located in the core and EVA 16 is used for the inactive intermediate layer. In order to evaluate the thickness of the sheath and intermediate layer the respective IVRs were observed under a SMZ Microscope with zoom 2.00x, exposure time 70 ms, using a camera DFK 33UX264 Three distinct layers were observed in the microscope, and the sheath and intermediate thicknesses are measured for three samples from each batch. The results are shown in fig. 12a,b and c and summarized in table 9. Delivery Sheath Sheath Intermediate layer Intermediate layer system Target thickness (µm) Measured Target thickness Measured thickness thickness (µm) (µm) (µm) (SD (µm)) (SD (µm)) K1 200 200.6 300 291.3 (20.1) (27.7) K2 530 535.0 300 310.8 (29.3) (37.3) K3 650 650.2 300 317.5 (46.9) (41.4) K4 530 533.5 130 127.7 (28.4) (18.5) K5 530 523.8 200 200.6 (28.8) (36.7) K6 530 512.8 200 205.5 (25.3) (22.9) K7 550 550.7 80 83.1 (28.9) (21.1) K8 550 575.0 160 156.2 (40.7) (31.8) Table 9: Thickness of sheath and intermediate layer. target and measurement from microscopy pictures. Numbers in brackets are the measured standard deviation in µm. In order to investigate the release rate of estradiol and progesterone from the eight batches K1 – K8 the respective IVRs were tested in an in vitro dissolution test comprising a shaking incubator apparatus and a simple aqueous dissolution media (Water with SDS surfactant (1% wt.). The experiment was conducted at 37C, and the medium is refreshed daily during the 28 days test period. The IVR analysis started 23 days after the tri-extrusion. The samples were analyzed by HPLC. The average daily release rates for progesterone is shown in table 10, and fig. 13, and the average daily release rates for estradiol is shown in table 11. Table 10: Average Daily release of PGN for 28 days in K1 – K8 K1: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean PGN (mg) 64.5 24.1 15.1 8.8 3.0 1.5 1.2 1.0 0.8 0.7 0.6 0.5 0.4 0.3 0.3 0.2 SD (mg) 0.7 0.1 0.0 0.1 0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 % RSD 1.1 0.6 0.2 1.3 2.9 2.3 3.0 0.6 1.2 2.8 1.0 1.3 2.7 1.8 8.2 0.9 K2: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean PGN (mg) 67.2 26.3 20.1 16.6 13.0 10.9 9.8 9.3 8.7 7.7 7.3 6.5 5.7 5.3 4.6 3.6 SD (mg) 0.3 0.2 0.1 0.2 0.1 0.0 0.1 0.1 0.2 0.0 0.1 0.0 0.0 0.0 0.2 0.0 % RSD 0.5 0.7 0.4 0.9 0.6 0.4 1.1 1.2 1.8 0.4 1.2 0.7 0.6 0.1 4.0 1.1 K3: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean PGN (mg) 67.3 26.1 19.9 16.5 13.0 11.0 10.0 9.4 8.6 7.9 7.3 6.7 6.1 5.7 5.2 4.9 SD (mg) 0.4 0.1 0.0 0.0 0.0 0.0 0.0 0.1 0.3 0.0 0.2 0.0 0.0 0.0 0.4 0.0 % RSD 0.5 0.5 0.1 0.1 0.2 0.2 0.2 0.6 3.4 0.1 2.4 0.2 0.1 0.4 7.3 0.1 K4: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean PGN (mg) 66.0 25.7 19.4 16.1 12.6 10.6 9.5 9.0 8.4 7.4 7.0 6.2 5.5 5.2 4.6 3.6 SD (mg) 1.4 0.6 0.5 0.3 0.2 0.2 0.2 0.2 0.3 0.1 0.2 0.1 0.1 0.0 0.2 0.0 % RSD 2.1 2.4 2.5 2.1 1.5 2.1 1.8 1.9 3.2 1.2 2.5 1.0 1.0 0.7 4.3 0.1 K5: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean PGN (mg) 66.8 25.5 19.3 16.0 12.5 10.6 9.5 8.9 8.3 7.4 7.1 6.3 5.5 5.1 4.4 3.4 SD (mg) 0.7 0.2 0.2 0.1 0.2 0.2 0.1 0.1 0.1 0.1 0.0 0.0 0.0 0.0 0.3 0.1 % RSD 1.0 0.9 0.9 0.8 1.4 1.4 0.7 1.0 0.9 0.8 0.4 0.5 0.7 0.3 6.6 2.2 K6: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean PGN (mg) 64.8 25.3 19.1 16.0 12.4 10.4 9.3 8.6 8.1 7.2 6.7 5.9 5.0 4.3 3.6 2.6 SD (mg) 0.6 0.0 0.1 0.1 0.0 0.1 0.1 0.0 0.0 0.1 0.0 0.0 0.2 0.2 0.5 0.1 % RSD 0.9 0.1 0.4 0.6 0.3 0.5 1.0 0.4 0.4 1.2 0.7 0.8 3.0 5.5 14.1 2.5 K7: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean PGN (mg) 66.6 26.1 19.8 16.3 12.8 10.9 9.7 9.1 8.6 7.7 7.3 6.5 5.7 5.2 4.8 4.1 SD (mg) 0.3 0.1 0.2 0.1 0.1 0.0 0.1 0.0 0.0 0.0 0.1 0.1 0.1 0.1 0.3 0.1 % RSD 0.5 0.3 0.8 0.6 0.5 0.3 0.8 0.3 0.2 0.2 1.8 0.9 1.0 1.0 5.3 1.9 K8: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean PGN (mg) 66.5 25.8 19.7 16.3 12.7 10.8 9.7 9.1 8.5 7.7 7.2 6.5 5.8 5.4 4.9 4.4 SD (mg) 0.1 0.1 0.1 0.1 0.1 0.1 0.0 0.0 0.1 0.1 0.2 0.1 0.1 0.0 0.1 0.0 % RSD 0.2 0.5 0.7 0.5 0.8 0.7 0.4 0.5 0.7 1.5 2.2 2.2 1.3 0.7 1.1 1.0 Table 11: Average Daily release of E2 for 28 days in K1 – K8 K1: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean E2 (mg) 2098.1 773.7 678.9 626.0 578.0 572.7 554.4 549.9 542.9 529.5 539.5 514.2 511.1 511.6 494.1 481.3 SD (mg) 8.1 4.9 5.3 6.9 3.8 3.7 7.6 5.1 10.5 3.1 9.4 3.2 2.2 5.6 31.3 3.9 % RSD 0.4 0.6 0.8 1.1 0.7 0.7 1.4 0.9 1.9 0.6 1.7 0.6 0.4 1.1 6.3 0.8 K2: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean E2 (mg) 1059.4 485.8 354.4 290.7 248.3 238.6 224.9 225.7 222.0 215.0 222.7 213.9 215.0 218.9 212.7 208.0 SD (mg) 2.2 3.7 1.2 2.6 2.0 2.2 3.0 3.5 4.7 2.1 3.9 3.1 3.5 2.9 12.7 1.9 % RSD 0.2 0.8 0.3 0.9 0.8 0.9 1.3 1.5 2.1 1.0 1.7 1.5 1.6 1.3 6.0 0.9 K3: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean E2 (mg) 710.5 399.4 311.0 258.8 209.4 192.1 181.2 177.8 172.2 168.7 171.8 166.0 166.6 168.8 162.1 164.9 SD (mg) 5.2 4.8 1.8 1.9 1.9 1.4 1.0 1.9 6.1 1.0 4.5 1.3 1.2 1.8 14.2 1.3 % RSD 0.7 1.2 0.6 0.7 0.9 0.7 0.6 1.0 3.5 0.6 2.6 0.8 0.7 1.1 8.8 0.8 K4: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean E2 (mg) 815.1 377.2 282.9 244.1 220.4 212.1 202.8 204.2 203.5 201.0 211.2 205.4 205.5 209.2 204.2 200.5 SD (mg) 47.4 22.2 14.4 8.8 4.5 3.1 2.3 2.3 4.4 1.3 3.8 2.0 2.3 1.4 8.9 1.1 % RSD 5.8 5.9 5.1 3.6 2.0 1.5 1.1 1.1 2.2 0.6 1.8 1.0 1.1 0.7 4.4 0.5 K5: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean E2 (mg) 795.4 432.2 317.9 268.1 237.0 230.1 216.5 215.7 211.2 207.9 220.0 212.2 211.0 212.6 206.4 205.0 SD (mg) 300.0 3.3 2.2 2.4 4.2 4.4 3.3 4.1 4.4 4.1 2.8 2.3 4.4 4.4 10.4 2.5 % RSD 37.7 0.8 0.7 0.9 1.8 1.9 1.5 1.9 2.1 2.0 1.3 1.1 2.1 2.1 5.0 1.2 K6: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean E2 (mg) 827.7 375.2 284.0 250.0 227.5 228.3 219.0 218.0 217.8 217.5 227.0 218.4 218.5 217.2 216.2 207.0 SD (mg) 1.2 3.5 3.4 4.7 4.7 5.3 6.9 5.7 6.0 7.9 6.3 7.5 5.8 4.0 33.7 2.9 % RSD 0.1 0.9 1.2 1.9 2.1 2.3 3.1 2.6 2.8 3.6 2.8 3.4 2.6 1.8 15.6 1.4 K7: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean E2 (mg) 318.3 210.7 187.3 168.6 146.3 137.7 128.2 125.6 122.8 119.7 122.9 116.9 114.6 114.1 110.5 109.8 SD (mg) 6.2 3.5 1.6 1.7 1.6 1.5 1.2 1.4 1.9 1.5 1.6 1.0 1.7 2.0 5.9 1.1 % RSD 1.9 1.7 0.9 1.0 1.1 1.1 1.0 1.1 1.5 1.2 1.3 0.9 1.5 1.7 5.3 1.0 K8: Day 1 2 3 4 7 8 9 10 11 14 15 18 21 22 25 28 Mean E2 (mg) 190.7 135.8 127.6 118.2 103.1 95.2 88.2 85.3 82.7 79.6 79.9 76.3 75.3 75.0 72.8 72.0 SD (mg) 6.0 3.5 3.0 1.8 1.7 0.9 0.8 1.6 1.1 1.4 1.5 1.7 1.0 1.1 2.8 0.5 % RSD 3.1 2.6 2.4 1.5 1.6 0.9 0.9 1.8 1.4 1.7 1.9 2.2 1.3 1.4 3.9 0.8 Example 6: Release of progesterone (PGN) from K1 – K8. The release rate of progesterone was evaluated to investigate if said release rate depended on the location of estradiol (core or intermediate layer) and / or the concentration of estradiol in the intravaginal ring. The average daily release rates for progesterone is shown in table 10, and fig. 13a, 13b, and the release characteristics of progesterone can be summarized as shown in table 12. IVRs Dimensions Experimental measurements of the PGN release Diameter Length Sheath Intermediate Burst (mg / day) Average daily Average daily (mm) (mm) (µm) (µm) release (2-28) release (1-28) (mg / day) (mg / day) K1 5 163.5 200 300 64.5 2.5 4.8 K2 5 163.5 530 300 67.2 8.8 10.9 K3 5 163.5 650 300 67.3 9.1 11.2 K4 5 163.5 530 130 66.6 8.6 10.6 K5 5 163.5 530 200 66.8 8.5 10.6 K6 5 163.5 530 200 64.8 8.1 10.1 K7 5 163.5 550 80 66.6 8.8 10.9 K8 5 163.5 550 160 66.5 8.8 10.9 Table 12: Release characteristics of progesterone (PGN) of the IVRs K1 – K8 As is evident from the data in table 10, table 12, and fig. 13 the progesterone release remains consistent across all batches K2 to K8 regardless of the location of estradiol, whether in the intermediate or the core. Additionally, it was shown that the PGN release is not dependent on the concentration of estradiol. As is evident from especially table 12 and fig. 13b, depletion of progesterone was observed from day 2 for batch K1; indicating that the sheath thickness (200 µm) is insufficient to sustain the release of progesterone for the 28 days. Example 7: Effect of sheath thickness on the release of Estradiol (E2) from IVRs in which estradiol is present in the intermediate layer. In order to investigate if the sheath thickness affects the release rate of estradiol, the release rate of estradiol for the IVRs K1, K2, and K3 were compared. Said rings have different sheath thicknesses, 200 µm, 530 µm and 650 µm, respectively, the same thickness of the intermediate layer (300 µm) containing 10 wt% estradiol; and an inactive core made of EVA 28. The simulation and experimental results for IVRs K1, K2 and K3 are shown in table 13, and fig. 14a, 14b respectively. Dimensions Simulation of the E2 release Experimental measurements of the E2 release IVRs Diameter Length Sheath Intermedia Burst Average daily Average daily Burst Average daily Average daily (mm) (mm) (µm) te (µg / day) release (2-28) release (1-28) (µg / day) release (2-28) release (1-28) (µm) (µg / day) (µg / day) (µg / day) (µg / day) K1 5 163.5 200 300 967.87 510.11 526.46 2098.1 543.5 599.0 K2 5 163.5 530 300 912.73 205.45 230.71 1059.4 237.9 267.2 K3 5 163.5 650 300 912.68 171.20 197.68 710.5 190.6 209.2 Table 13: Release characteristics of estradiol (E2) of the IVRs K1 – K3 As is evident from said data a good agreement between simulation and produced IVRs can be seen, especially where the zero-order release occurs. The burst region was not sufficiently captured by the simulations. However, the actual daily release was very close to the measured daily release as is also evident from table 13. The sheath thickness reduces the release of estradiol as e.g. can be seen in the 28 days in-vitro release analysis in fig. 14b. The release shows a burst followed by a zero-order release of estradiol over 28 days. Furthermore, as is evident from the results for K1, having a sheath thickness of 200 µm and where depletion of progesterone starts on day 2 of the in- vitro release analysis, as shown in fig. 13b, the release rate of estradiol is not only reduced even after full depletion of progesterone from the sheath, but the zero-order release of estradiol is maintained during the 28-days testing period. It should be noted that in the simulation data, see fig. 14a, the initial concentration of estradiol in the sheath, is the saturation level of the sheath, and that any supersaturation of estradiol in the IVR (i.e., sheath) is not considered. If supersaturation of estradiol in the sheath were taken into consideration, a higher burst would be expected. Furthermore, when comparing the release of estradiol on day 1 of the three IVRs, K1, K2 and K3, shown in fig. 15, it is clear that the release of estradiol is reduced with increased sheath thickness. Accordingly, the equilibration time for estradiol in the sheath increases with sheath thickness, leading to a lower burst compared to fully equilibrated rings (e.g., K3 compared to K2). Furthermore, when comparing the burst from the two IVRs AE1 (see table 1) and K1 (see table 13) it is clear that a reduced burst is observed with a higher concentration of progesterone in the sheath. AE1 and K1 are IVRs in which all layers are made of EVA28, having the same thickness of the sheath and intermediate layer (200 µm and 300 µm, respectively), same load of estradiol in the intermediate layer (10 wt%). The only differences being the fiber length and load of progesterone in the sheath, AE1 has 33.9 wt% progesterone in the sheath and K1 has 27 wt% progesterone, and the simulated burst of E2 is 831 µg / day for the AE1 ring (33.9 wt% progesterone) whereas the simulated burst of E2 in the K1 ring (27 wt% progesterone) is 968 µg / day. Thus, the difference between the burst of K1 and AE1 is higher than the impact of the length of the fiber on the burst about 4 %.

[0003] Example 8: Effect of the intermediate layer thickness on the release rate from IVRs in which Estradiol (E2) is present in the intermediate layer. In order to investigate if the thickness of the intermediate affects the release rate of estradiol when estradiol is present in the intermediate layer, the release rate of estradiol from K2, K4, K5, were compared. Said IVRs have the same sheath thickness (530 µm) but different thicknesses of the intermediate layer, 310 µm, 130 µm, 200 µµ. The intermediate layer is loaded with 10 wt% estradiol (dissolved and crystal forms); and has an inactive core made of EVA 28. Furthermore, in order to evaluate if the material of the core influences the release rate of estradiol from the intermediate layer, the estradiol release from K6 (inactive core made of EVA 40). The simulation and experimental results for IVRs K2, K4, and K5 are shown in table 14, and fig. 16a, 16b respectively. The release of estradiol from K6 is shown in table 14, and fig. 17. Dimensions Simulation of the E2 release Experimental measurements of the E2 release IVRs Diameter Length Sheath Intermedia Burst Average daily Average daily Burst Average daily Average daily (mm) (mm) (µm) te (µg / day) release (2-28) release (1-28) (µg / day) release (2-28) release (1-28) (µm) (µg / day) (µg / day) (µg / day) (µg / day) K2 5 163.5 530 300 912.73 205.45 230.71 1059.4 237.9 267.2 K4 5 163.5 530 130 912.72 205.45 230.71 815.1 217.0 238.3 K5 5 163.5 530 200 912.71 205.45 230.71 795.4 228.2 248.5 K6 5 163.5 530 200 - - - 827.7 227.9 249.3 Table 14: Release characteristics of estradiol (E2) of the IVRs K2, K4, K5, K6 As is evident from table 14 and fig. 16a and 16b, the predicted steady-state average daily release of estradiol of around 200 µg / day in the simulations, was also observed by the experimental investigation of the IVRs. It is further expected that the IVRs can sustain the release of estradiol, not only for 28 days by at least 60 days as shown in fig. 16a. In the early period of release of estradiol (i.e., burst + few more days) from the IVRs, see fig. 16b, some differences in the release of estradiol can be shown in the three rings contrary to the simulations. The K2 IVR (300 µm thick intermediate layer) shows a higher burst and higher release during the first days of release compared to IVRs K4 and K5. The K5 IVR (130 µm thick intermediate layer) shows the lowest release. This can be ascribed to the amount of estradiol dissolved in the intermediate layer during tri-extrusion. The amount of dissolved estradiol increases with temperature. During extrusion, the estradiol crystals dissolve at high temperatures, upon cooling the estradiol molecules crystallize to reach thermodynamic equilibrium, this process is often too slow as it occurs at room temperature and depends on the crystallization kinetics of estradiol molecules in the polymer. For the thick intermediate layer (e.g. K2), the amount of estradiol dissolved in the intermediate is higher, some of the estradiol molecules are crystallizing and some diffuse to the core made of inactive EVA 28, which can be seen as a sink. For the thin intermediate layer i.e. K5, the excess of dissolved estradiol can be reduced faster whether by crystallization or by diffusion to the inactive core. It is worth mentioning, that the diffusion of estradiol to the core is a process that will continue until the equilibration of the core with estradiol. The presence of an inactive core allows for a reduced supersaturation in the intermediate (and the ring) as it acts like a sink for any excess of estradiol molecules. Thus, the inactive core in the three layer design contributes to the physical stability of the IVR, a stability feature that is not possible with a two-layer IVR without an inactive layer. In order to evaluate if VA content of the EVA of the core (permeability) influences the release rate of estradiol from the intermediate layer, the release of estradiol from K6 were compared with the release of estradiol from K4 and K5. The results are shown in fig. 17. K6 has an inactive core made of EVA 40, which due to its high VA content provides a high permeability of estradiol in said core. As is evident from table 14 and fig. 17 the release of estradiol from K6 was found to be similar both to K5, i.e. to an IVR with an identical thickness and composition of the sheath and intermediate layer but a different polymer, EVA28, in the inactive core, and to K4, i.e. a ring with a thinner intermediate layer of 130 µm loaded with estradiol. In addition, in the early days of the release, see fig. 17, the in-vitro release of estradiol is the same for K4 and K6. These results show the ability of the polymer EVA 40 to level out (suppress) the excess (i.e., supersaturation) of estradiol in the intermediate layer (and the ring) compared to EVA 28. Example 9: Effect on the release rate of estradiol present in the core and the thickness of an inactive intermediate layer. As shown previously in example 7 the release rate of estradiol from the IVR is reduced with increasing sheath thickness. However, as is evident from e.g. table 11 when estradiol is loaded in the intermediate layer, K1 – K6, the sheath thickness of K3 i.e. the IVRs with the largest sheath thickness (650 µm) of K1 – K6 was not sufficient to reach a release rate of about 80 µg / day, which is one preferred release rate of estradiol for an IVR according to the invention. However, providing an IVR with a thicker sheath than 650 µm might present technical difficulties since the extruders for the sheath are usually developed for thinner sheaths. Thus, in order to evaluate if it possible to obtain the desired release rate of about 80 µg / day by loading estradiol in the core and using a polymer with lower permeability in the intermediate layer e.g. EVA 16, the two IVRs K7 and K8 were produced. K7 and K8 have the same sheath thickness (550 µm) but different thicknesses of the intermediate layer, 80 µm and 160 µm , respectively. The intermediate layer is made of EVA16, and the core is loaded with 10 wt% estradiol (dissolved and crystal forms). The simulation and experimental results for IVRs K7, and K8 are shown in table 15, fig. 18a, and fig. 18b. Dimensions Simulation of the E2 release Experimental measurements of the E2 release IVRs Diameter Length Sheath Intermedia Burst Average daily Average daily Burst Average daily Average daily (mm) (mm) (µm) te (µg / day) release (2-28) release (1-28) (µg / day) release (2-28) release (1-28) (µm) (µg / day) (µg / day) (µg / day) (µg / day) K7 5 163.5 550 80 923.07 126.51 154.96 318.3 128.6 135.3 K8 5 163.5 550 160 923.07 105.18 134.39 190.7 86.1 89.8 Table 15: Release characteristics of estradiol (E2) of the IVRs K7, K8 EVA 16 has, due to a lower VA-content, a lower permeability than EVA 28, and as is evident from these results the use of an EVA 16 polymer in the intermediate layer had a dramatic effect on the release of estradiol from the core. Furthermore, a zero-order release is observed, as the release rate is almost constant in the release period of 28 days, see fig. 18b, even though a longer treatment period is possible as shown in the simulation in fig. 18a. Furthermore, as shown in fig. 18 and table 15, the average daily release in day 2 – 28 is reduced to 128.6 µg / day for K7 and to 86.1 µg / day for K8 showing that EVA16 acts like a rate- limiting membrane. In fig. 18b the release of estradiol from K7 and K8 was compared with the release of estradiol from K3, and as is evident from said figure, combining a progesterone-loaded sheath with an inactive EVA16 intermediate layer had more impact on the release of estradiol than a thicker sheath in which the estradiol was placed in the intermediate layer. For instance, the 650 µm thick sheath (K3) had a steady-state release of about 191 µg / day, whereas the K7 IVR showed a release of about 129 µg / day with a thickness of the intermediate layer of 83 µm and a sheath thickness of 550 µm, i.e. a combined thickness of 633 µm. Use of a 156 µm thick intermediate layer (K8) leads to an even lower average daily release rate of about 86 µg / day. Thus, a person skilled in the art will based on the present application understand that the release rate of estradiol can be tailored to any level independently from the progesterone release, just by changing the thickness of the intermediate thickness, the polymer of the layers etc. As an example can be mentioned that other polymers than EVA16 can be used to tailor the release of estradiol, e.g. an EVA28, however, in this specific case, the release rate reduction will not be the same as in the case of EVA16. Using the intravaginal ring according to the present invention the inventors have found that it is possible to attain independent and optimal release of the two active ingredients; an estrogenic steroid and a progestational steroid without the need for complex assembly of parts and without the need to use sophisticated multi-layer extrusion technology. The intravaginal ring has a simple and inexpensive design, and can therefore be used equally well both privately and in medical or hospital facilities. Modifications and combinations of the above principles and designs are foreseen within the scope of the present invention.

Claims

Claims 1. An three-layered intravaginal ring (1;1’) comprising - a core (2;9) - an intermediate layer (3;10), and - a sheath (6) comprising a second ethylene-vinyl acetate copolymer (7) having a vinyl acetate content from 20 to 40 wt%, and at least 10 wt% of a progestational steroid (8) based on the weight of the sheath, wherein one of the core (9) and intermediate layer (3) comprises a first ethylene-vinyl acetate copolymer (4) having a vinyl acetate content from 26 to 40 wt% and an estrogenic steroid (5), and the other one of the core (2) and intermediate layer (10) is an inactive layer (2;10).

2. A three-layered intravaginal ring according to claim 1, wherein the sheath (6) comprises at least 15 wt% of the progestational steroid (8) based on the weight of the sheath (6), preferably at least 20 wt%, and even more preferred at least 30 wt% and / or wherein the sheath comprises 40 wt% or less of the progestational steroid (8) based on the weight of the sheath, preferably 35 wt% or less.

3. A three-layered intravaginal ring according to claim 1 or 2, wherein the progestational steroid (8) is dispersed and / or incorporated in the second ethylene-vinyl acetate copolymer (7) in the form of particles, such as crystals.

4. A three-layered intravaginal ring according to according to any of the preceding claims, wherein the estrogenic steroid (5) is dispersed and / or incorporated in the first ethylene-vinyl acetate copolymer (4) in the form of particles, e.g. crystals.

5. A three-layered intravaginal ring according to any of the preceding claims, wherein the core (9) or intermediate layer (3) comprises at least 5 wt% of the estrogenic steroid (5) based on the weight of the core or intermediate layer, preferably at least 10 wt%, and even more preferred at least 15 wt%.

6. A three-layered intravaginal ring according to any of the claims 3, 4 or 5 wherein the particles of the progestational steroid (8) and the estrogenic steroid in the second and the first ethylene-vinyl acetate copolymer (7,4), have a particle size of between 1 µm and 40 µm, preferably between 2 µm and 24 µm, and even more preferred between 3 and 10 µm, and even more preferred around 5µm as determined by laser diffraction.

7. A three-layered intravaginal ring according to any of the preceding claims, wherein the estrogenic steroid (5) is estradiol or estriol.

8. A three-layered intravaginal ring according to any of the preceding claims, wherein the progestational steroid (8) is selected from a group consisting of progestogen, progesterone, etonogestrel, levonorgestrel, d-1-norestrel, segesterone, segesteronacetat and norethindrone.

9. A three-layered intravaginal ring according to any of the preceding claims, wherein said intravaginal ring only comprises one estrogenic steroid (5) and one progestational steroid (8).

10. An intravaginal ring according to any of the preceding claims, wherein said intravaginal ring only comprises a single core, a single intermediate layer completelysurrounding said core and a single outer sheath completely surrounding said intermediate layer.

11. A three-layered intravaginal ring according to any of the preceding claims, wherein when the intermediate layer (3) comprises the estrogenic steroid (5), said intermediate layer (3) preferably has a thickness from 50 µm to 500 µm, preferably from 80 µm to 400 µm, and even more preferred from 100 µm to 300 µm.

12. A three-layered intravaginal ring according to any of the preceding claims 1 - 10, wherein when the intermediate layer (10) is the inactive layer, said intermediate layer (10) preferably has a thickness from 50 µm to 300 µm, preferably from 50 µm to 200 µm, and even more preferred from 80 µm to 200 µm.

13. A three-layered intravaginal ring according to any of the preceding claims, wherein the cross-sectional diameter of the core (2;9) is from between 2 and 8 mm, more preferably between 3 mm and 6 mm and even more preferably from 4 mm to 5 mm.

14. A three-layered intravaginal ring according to any of the preceding claims, wherein the thickness of the sheath (6) is between 0.05 mm and 1 mm, preferably between 50 µm and 600 µm, more preferred between 100 µm and 500 µm, and even more preferred between 200 µm and 500 µm.

15. A method of manufacturing the three-layered intravaginal ring (1) according to any of the claims 1 – 14, said method comprises a. providing an inactive core (2),b. providing an intermediate layer (3) comprising a first ethylene-vinyl acetate copolymer (4) having a vinyl acetate content from 26 to 40 wt%, and at least 5wt%, preferably at least 10 wt% estrogenic steroid (5) based on the weight of the intermediate layer, and wherein said estrogenic steroid is incorporated into the first ethylene-vinyl acetate copolymer (4) in the form of particles, c. providing a sheath (6) comprising a second ethylene- vinyl acetate copolymer (7) having a vinyl acetate content from 20 to 40 wt%, and at least 10 wt% of an progestational steroid (8) based on the weight of the sheath, wherein said progestational steroid is incorporated into the second ethylene-vinyl acetate copolymer (4) in the form of particles, d. co-extruding the core (2;9), intermediate layer (3;10) and sheath (6) into a fiber, and e. cutting the fiber into an appropriate length thereby providing a fiber element, and f. combining the ends of fiber element to form the three-layered intravaginal ring. 16.A method according to claim 15, wherein step a and b of the method of claim 15 are modified as a’ and b’ respectively: a’. providing an core (9) comprising a first ethylene- vinyl acetate copolymer (4) having a vinyl acetate content from 26 to 40 wt%, and at least 5wt%, preferably at least 10 wt% estrogenic steroid (5) based on the weight of the core, and wherein said estrogenic steroid is incorporated into the first ethylene-vinyl acetate copolymer in the form of particles, and b’. providing an inactive intermediate layer (10).17.A method according to claim 15 or 16, wherein said method further comprises a cooling step in which the provided fiber from step d. is cooled to a temperature of about 20C in order to provide crystals of the progestational steroid (8) and the estrogenic steroid (5). 18.A method according to claim 17, wherein said cooling step is completed within a period of less than 10 minutes from completion of the fiber in step d, and even more preferred not more than about 2 minutes from completion of the fiber in step d.

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