The present invention relates to an intravaginal ring, a method of manufacturing said ring and the use of 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 are 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 an 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 an intravaginal ring that reduces the variability of the release rate of steroids over time.

In a third aspect according to the present invention a provided an intravaginal ring in which the known problems relating to complicated and expensive manufacturing processes, dose dumping and initial drug burst 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 an intravaginal ring which is stable at room temperature.

The novel and unique features whereby these and further aspects are achieved according to the present invention is by providing intravaginal ring comprising

— a core comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content from 26 to 40 wt%, and an estrogenic steroid, 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.

The intravaginal ring according to the invention relates to a system that comprises a core surrounded, at least partly but preferably completely, by a sheath. However contrary to the conventional systems of this kind, the sheath of the present invention also comprises a high concentration of an active ingredient, whereby simultaneous release of two steroids is provided.

Dual administration of two steroids finds application in a number of different areas, e.g. in contraceptive rings and in 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 and without the need to use sophisticated multi-layer extrusion technology.

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 the core are observed for a longer period of time. In addition such high concentrations of the active ingredient are associated with good physical stability of the progestational 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 the release rate of the active ingredient in the core decreases as active ingredient (s) that is deeper inside the core/reservoir must diffuse to the surface. However loading the sheath with a high concentration of a progestational steroid, the inventors of the present invention has found that the release rate of the estrogenic steroid in the core slightly increases over time, thereby compensating for the further distance said steroid must travel to the surface of the intravaginal ring for being released to the surroundings, thereby providing a substantially zero-order relate rate of the estrogenic steroid during the desired treatment period. It is important 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. 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 that 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 ethylenevinyl 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. The presence of the progestational steroid in the relatively high concentrations 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. This will provide a reliable release rate and a lower initial burst of the estrogenic steroid. 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. 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 dissolved in the first ethylene-vinyl acetate copolymer and in these embodiments the estrogenic steroid is preferably present in the first ethylenevinyl acetate copolymer at concentration at or below the saturation concentration of said estrogenic steroid at 25°C.

Since it is expected that some of the estrogenic steroid will redistribute throughout the intravaginal ring upon storage, i.e. the concentration of steroid in the core will drop as a part of the steroid will diffuse into the sheath, the term "below the saturation concentration" refers to the concentration of the estrogenic steroid in the core measured in an equilibrated intravaginal ring, i.e. when an equilibrium of the estrogenic steroid has been reached in the intravaginal ring.

Alternatively, the estrogenic steroid may be present in the core in the form of particles, preferably crystals, for the same reasons 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 the core, it is preferred that said estrogenic steroid is dispersed and/or incorporated in the first ethylene-vinyl acetate copolymer of the core in a concentration of at least 10 wt% of the total weight of the core, preferably at least 15 wt%, and even more preferred at least 20 wt%.

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, it is not known to have a progestational steroid in the sheath in the high concentrations claimed in the present invention. Small concentrations of active ingredient i.e. concentrations well below 10 wt%, will have no or only a very limited effect on the release rate of the active ingredient in the core, and are accordingly not relevant for the present invention.

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.

It is however preferred that the particles/crystals of the progestational steroid and optionally the estrogenic steroid have a mean particle size of between 3 |lm and 40 |lm, preferably between 8 p.m and 24 pm, and even more preferred between 10 and 24 pm 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.

As used herein, the term "crystals" refers to particles of the active ingredient arranged in a 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 skill in the art can also be used, e.g. dynamic light scattering, or a sieve analysis. 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 D90 means that 90% of the particles have a diameter below the given value when measured using e.g. laser diffraction, dynamic light scattering, or a sieve analysis.

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.

The second ethylene-vinyl acetate copolymer 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.

In order to provide the desired zero order release profile of the estrogenic steroid it is preferred that the core comprises an ethylene-vinyl acetate copolymer with a vinyl acetate content from 26 to 40 wt%, preferably 26 wt%, 33 wt% or 40 wt%.

In one embodiment of the present invention the first and second ethylene-vinyl acetate copolymer have the same vinyl acetate content, i.e. the first and second ethylene-vinyl acetate copolymer are the same. When a specific vinyl acetate 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 of 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 ethylenevinyl 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 ring i.e. it comprises both an estrogenic steroid and a progestational steroid. In a preferred embodiment the estrogenic steroid is estradiol and the progestational steroid is selected from the group consisting of a progestogen, etonogestrel, levonorgestrel, d-l-norestrel 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 preferably is the outer layer of the intravaginal ring according to the present invention, can be varied to further control the release rate of the estrogenic steroid and the progestational steroid. Thus, the drug delivery system according to the invention does preferably not contain/comprise any sheath/membrane (e.g. a rate-controlling sheath) without an active ingredients.

In one embodiment the thickness of the sheath is between 0.05 mm and 3 mm. Said thickness can preferably be between 0.05 mm and 2 mm, more preferably between 0.1 mm and 2 mm and even more preferably between 0.2 mm and 0.6 mm. In certain embodiments the thickness of the sheath is 100 |lm, 200 [Im, 300 |lm, 400 |lm, 500 |lm, or 600 |lm.

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.

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 around 4 mm.

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.

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 preferred embodiment the intravaginal ring comprises

— a core comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content of 28 wt% or 33 wt%, and a concentration of an estrogenic steroid below the saturation concentration at 25°C, and

— a sheath comprising a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 24 wt%, 28 wt%, 33 wt% or 40 wt%, and 30 wt% of an progestational steroid based on the weight of the sheath.

The core of said preferred embodiment has a cross-sectional diameter of 4 mm and the sheath a thickness of 600 |lm. The diameter of the ring is 54 mm.

In a preferred embodiment the average release rate of estradiol is from 80 |lg/day to 160 |lg/day during a treatment period of 28 days, and preferably a near zero order release rate is provided. However said average release rate may be higher e.g. up to 200 |lg/day, e.g. up to as 180 |lg/day or about 165 |lg/day. In additional or alternatively, the average release rate of progestogen is from 5 mg/day to 10 mg/day for a treatment period of 28 days. 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 |J.g/day and the average release rate of progestogen is 10 mg/day, in a different embodiment the average release rate of estradiol is 100 |lg/day and the average release rate of progestogen is 5 mg/day, in a third embodiment the average release rate of estradiol is 160 |lg/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 the 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 and a single sheath completely surrounding said core, and wherein the estrogenic steroid in the core and the a progestational steroid in the sheath.

The present invention also relates to a method of manufacturing the intravaginal ring according to the present invention.

Said method comprises a. providing a core comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content from 26 to 40 wt%, and an estrogenic steroid, b. providing a sheath of 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, and c. co-extruding the core and sheath into a fiber, and d. cutting the fiber into an appropriate length thereby providing a fiber element, and e. combining the ends of fiber element to form the intravaginal ring.

As the core and sheath are co-extruded a very simple and inexpensive embodiment according to the invention is provided, however the cores and sheath can be formed in separate injection molding or extrusion steps if preferred. Injection molding and extrusion are well known in the art and will not be discussed further in this application.

It is preferred that the method further comprises a cooling step in which the provided fiber or fiber element is cooled to a temperature of 20°C or below for providing the crystals of the steroid in the sheath and optionally the core. This may e.g. be obtained by placing the fiber into a cooling water bath.

Without being bound by theory, the inventors believe that the crystals formed in the sheath and optionally the core is caused by the kinetics of re-crystallization. The relatively high concentrations of active ingredient in the sheath and optionally the core, will result in a higher concentration of "seed"' crystals, upon which recrystallization can occur when the fiber is cooled after co-extrusion.

It is preferred that said cooling step is performed immediately after step c., 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 c. 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 an exemplary embodiment of the intravaginal ring according to the invention

Fig. 1 shows a perspective view of a preferred embodiment of a vaginal ring according to the invention,

Fig. 2 shows the simulated average release of progesterone for ring AE3,

Fig. 3 shows the simulated average release of estradiol for ring AE3,

Fig. 4 shows the simulated progesterone release and the impact of sheath thickness on early depletion,

Fig. 5 shows the influence of cross-sectional diameter on the release profile of estradiol,

Fig. 6 shows the simulated average release of estradiol for ring BF1,

Fig. 7 shows the simulated average release of progesterone for ring BF1,

Fig. 8 shows the simulated estradiol release and the impact of sheath thickness on release rate (rings BF1, BF2 and BF3),

Fig. 9 shows the simulated progesterone release in ring BF1, Fig. 10 shows photos of a cross-section of the fibers with a 0.39 wt% estradiol loaded core and 5 wt% progesterone loaded sheath with a sheath thickness of (a) 200 pm; (b) 300 pm, and (c) 400 pm,

Fig. 11 shows photos of a cross-section of the fibers with a 0.39 wt% estradiol loaded core and 33.9 wt% progesterone loaded sheath with a sheath thickness of (a) 200 pm; (b) 300 pm and (c) 400 pm,

Fig. 12 shows photos a cross-section of the fibers with a 10 wt% estradiol loaded core and 33.9 wt% progesterone loaded sheath with a sheath thickness of (a) 200 pm; (b) 300 pm and (c) 400 pm,

Fig. 13A and B shows progesterone and estradiol release of IVRs with 0.39 w/w % estradiol in the core and 5 w/w% progesterone in the sheath,

Fig. 14A, B and C shows progesterone release of different IVRs

Fig. 15 shows progesterone release of different IVRs with 10 w/w % estradiol in the core and 33.9 w/w% progesterone in the sheath,

Fig. 16 shows estradiol release of different IVRs with different estradiol and progesterone concentrations in core and sheath, and

Fig. 17 shows estradiol release of different IVRs.

Figure 1 shows a preferred embodiment of an intravaginal ring (IVR) 1 according to the invention. In said embodiment the IVR comprises a core 2 made of a first ethylene-vinyl acetate copolymer 3 and comprising an estrogenic steroid 4, and a sheath 5 made of a second ethylene-vinyl acetate copolymer 6 and comprising a progestational steroid 7.

Figs. 2 - 17 are discussed in further details below with reference to the following examples.

Example 1

In order to evaluate the effect of outer diameter and sheath thickness the release rate of a series of intra-vaginal rings has been evaluated using computational modeling. The model takes into account diffusion of the drug which is driven by the concentration gradient in the system and the slow dissolution of progesterone (P4) crystals dispersed in the sheath and it assumes the receiving medium to be a perfect sink. The cross- sectional diameter of the ring determines the surface area of the systems and hence larger diameter rings are assumed to display proportionally higher drug release.

The thickness of the sheath determines the amount of progesterone present in the ring, assuming progesterone concentration is uniform/not varied. The amount of drug substance loaded in the delivery system 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.

The evaluated rings are made from EVA28 which is used for both core and sheath. During storage redistribution of dissolved progesterone and estradiol, due to internal diffusion processes, will take place. A fraction of the drug initially loaded in the core (i.e., estradiol (dissolved)) will diffuse into the sheath, and this process will continue until the ring is equilibrated, a process that can take several weeks depending on sheath thickness and storage conditions. The estradiol loading listed in table 1 will result after equilibration in a uniform concentration in the ring, including sheath and core, of 0.27 wt%, which corresponds with the estradiol saturation concentration in EVA28 at 37°C. The thermodynamic equilibrium of the progesterone-loaded sheath (see Table 1) in the ring will result in a progesterone concentration of 30 wt% in the sheath and 1.7 wt% in the core.

The simulations confirm the expectation of the skilled person that in this specific case sheath thickness does not affects estradiol release because the drug is homogeneously distributed after equilibration and no partitioning between core and sheath will take place as both are made of EVA28.

The release rate of a series of nine rings with varying sheath thickness and cross-sectional diameters is given in table 1. From this table it becomes apparent that the release rate of progesterone (P4) and estradiol (E2) scales with crosssectional diameter.

Figure 2 and 3 shows the simulated average release for ring AE3 of progesterone and estradiol respectively. As can be seen from said figures that the release rate of the steroid decreases over the treatment period of 28 days.

Figure 4 displays the simulated release of progesterone from the rings Al and A3. This simulation illustrates early depletion, which occurs when the sheath thickness is insufficient and contains insufficient progesterone to sustain the release over the intended duration of use of 28 days.

The influence of cross-sectional diameter on the release profile of E2 is demonstrated in figure 5. It should be noted that the release rate visualized in figure 4 and 5 are the actual release rates. Hence the burst appears much higher as the release in the very early moments of eluting is of course much higher than the day one average.

Example 2

In order to evaluate the effect of the dispersed crystals of Estradiol E2 in the core and the sheath thickness on the release rate, a series of intra-vaginal rings has been evaluated using computational modeling.

The release rate of a series of three rings with varying sheath thickness is given in table 2. From this table, it becomes apparent that the release rate of Estradiol scales with the sheath thickness. Furthermore, the delivery systems (BF1, BF2, and BF3) provide a sustained and high release of Estradiol even at day 28. The change of sheath thickness has no significant effect on the release rate of progesterone. 5

15

Table 2

20

25

Figure 6 displays the average daily release from ring BF1. The ring provides sufficient estradiol during the whole period of use, 28 days. The increase of the sheath thickness from 400 pm (ring BF1) to 600 pm (ring BF3) reduces the average daily release by almost 30 %, as shown in Table 2 and Figure 8.

Figure 7 and 9 displays the simulated release of Progesterone from the ring BF1. Even at a high drug load of 35 % wt, the early depletion occurs, informing about the insufficient Progesterone inside the ring to sustain the release over the intended duration of use of 28 days.

Example 3

In order to evaluate the effect of estradiol (E2) concentration in the core; progesterone (P4) concentration in the sheath, and the effect of the sheath thickness on the release rate of estradiol and progesterone respectively, a series of intra-vaginal rings (IVRs) was prepared as follows.

Raw materials used in the production

Process schema and production

The core/sheath fibers containing the API's estradiol and progesterone were prepared as shown in the following process flow for fiber production.

The milled EVA and APIs were weighed according to the proportion detailed in table 3; all four batches are mixed using the same mixing protocol. The compounding is conducted using an 11 mm closely intermeshing twin screw extruder (Pharma 11 twin screw extruder from Thermo scientific). In summary, four batches were compounded according to table 3 to produce active granulate/pellets. The compounding set temperature of all batches is 90 °C.

To enhance the processing properties of the pellets in the coextrusion process, magnesium stearate (Mgst) was added to all batches. First, the 0.1 wt% of Mgst was added to the mixing bags with active pellets and then manually mixed for around 3 minutes. A co-extruder line with a 5 mm die was used to produce the 5 mm sheath/core fibers. The co-extruder line comprises a single screw extruder 16/25 (D/L) i.e. 16 is the diameter and 25 is the length over diameter ratio (D/L)) for the sheath and a single screw 25/25 (D/L) for the core.

Both the core and the sheath of the produced fibers contain active ingredients; in addition, the sheath thickness is varied for each formulation to obtain 200 pm, 300 pm, and 400 pm sheath thickness in 5 mm fiber diameter, as shown in Table 5.

The fiber characteristics (diameter and sheath thickness were controlled by the melt pump speed for extruder 1 (sheath) and extruder 2 (core) to produce a fiber of 5 mm diameter with the required sheath thickness. All the fibers were extruded between 90 °C and 100 °C. The melt pump speed was calculated based on the capacity of the pumps, and the sheath thickness compared to the core can be seen in Figure 11 (AC-batch) and 12 (DC-batch). No boundary could be seen for the AB-batch (Figure 10). The melt pump speed 1 and 2 for each batch are given in Table 4.

Table4:Meltpumpspeedforeachformulation

Meltpumpvolumeforthesheathis0.6cm ³ and2.4cm ³ forthecore After co-extrusion, the fibers are cut into a length of 157 mm and then welded to form the intra-vaginal rings (IVRs). The produced IVRs (batches) are given in Table 5.

For the AB batch the progesterone concentration loaded in the sheath is 5wt%, and during extrusion the progesterone is as anticipated completely dissolved. As a consequence of internal diffusion progesterone will redistribute throughout the ring and in case no premature crystallization will take place the progesterone concentration in the ring will be fully homogeneous once the ring is in equilibrium.

Table5:ProducedbatchestogetherwiththeAPIcontent

*Thenumbers200,300,and400standfor200pm,300pm,and400pm sheaththickness,respectively.

Optical observation of fibers

For batches AB200, AB300, and AB400, i.e. 0.39 wt% estradiol and 5 wt% progesterone, no clear boundaries between the core and sheath could be observed as shown in Figure 10, contrary to the other batches, shown in Figure 11 and 12. This is because estradiol and progesterone were dissolved in EVA 28 in the sheath and core, respectively.

The contrast (i.e., boundary) between the core and sheath is maximal for dissolved estradiol (0.39 wt%) and crystal loaded progesterone (33.9 wt%) for batches AC200, AC300, and AC400, cf . Figure 11. The contrast (i.e., boundary) is low when both APIs are present in crystal form, i.e. for the IVRs comprising 10 wt% estradiol and 33.9 wt% progesterone (in addition to a dissolved fraction of API), as seen in the case of DC200, DC300, and DC400, see Figure 12.

The observed sheath/core system generally showed a centered/concentred geometry, as shown in Figure 11 and 12. The release rate of estradiol and progesterone of the prepared IVRs are given in table 6, which shows the estradiol data, table 7, which shows the progesterone data, and the corresponding figures 13 - 17.

The results from table 6 and 7 will be discussed in further details below.

Release of Estradiol and Progesterone in the provided IVRs

IVRs comprising 0.39 wt% estradiol and 5 wt% progesterone with different sheath thickness (AB-batch)

The release of estradiol and progesterone from IVRs obtained from batches containing 0.39 wt% estradiol and 5 wt% progesterone, i.e. the IVRs AB200, AB300 and AB400 are shown in Figure 13A and 13B.

As is evident from said figures the release of progesterone increases with increasing fiber sheath thickness; for all the cases, the daily release is less than 1 mg/day after day 10.

As estradiol is only present in the AB-batches in a low concentration (0.39 wt%) the estradiol is dissolved in the ring, and since the sheath and core are made from the same polymer (no partitioning) as for the AB200, AB300, and AB400 batch (see Figure 10), the estradiol concentration in equilibrium will be uniform and hence not affected by sheath thickness. However, a slight effect can be seen in Figure 13B and it is expected that this is attributed to the fact that small amounts of progesterone crystals are increasing the effective diffusion path, however only insignificantly.

Thus it is clear that small concentrations (5 wt%) of progesterone in the sheath have no or only a very limited effect on the release rate of the estradiol in the core.

Release of progesterone in dependence of estradiol concentration in the core

A comparison of the release rate of progesterone in the sheath in dependence of concentration of estradiol and sheath thickness is shown in Figure 14A, 14B and 14C. As is evident from said figures, the release of progesterone is much higher in the IVRs having 33.9 wt% progesterone in the sheath compared to the IVRs having 5 wt% progesterone in the sheath.

However as can be seen in Figure 14A, B and C data it can also be concluded that the presence of estradiol in either dissolved i.e. in a relatively low estradiol concentration (0.39 wt%), and/or in a crystal state i.e. a higher estradiol concentration (10 wt%), does not affect the release of progesterone. Note that as ring containing crystalline estradiol will also contain estradiol in a dissolved state and likely equal or close to the saturation concentration.

For instance in Figure 14A the IVRs AC200 (0.39 wt% estradiol) and DC200 (10 wt% estradiol) have substantially identical release profiles of progesterone, and the same can be seen for AC300 (0.39 wt% estradiol) and DC300 (10 wt% estradiol) in

Figure 14A and AC400 (0.39 wt% estradiol)and DC400 (10 wt% estradiol) in Figure 14C.

Effects of sheath thickness on the release of progesterone

As is shown in Figure 15 the increase in the sheath thickness allows sustained delivery of progesterone.

The daily release of progesterone from both AC and DC batches (for the same sheath thickness) is the same until the phenomenon of depletion is significant for each sheath thickness. Early on day 7, the impact of depletion on IVR is visible on DC200 (AC200), whereas DC300 (AC300) occurs on days 12-13. Even though only the data for the DC200 batches are shown in Figure 15, the data are identical for the AC batches. Effects of sheath thickness on the release of estradiol

As is evident from Figure 16A, B and C the presence of progesterone in the sheath, reduces the daily release of estradiol.

This effect is less pronounced with low sheath thickness e.g. 200 |lm between AB and AC IVRs, where estradiol (0.39 wt%) is mainly dissolved in the core, see Figure ISA.

When the estradiol exists in the core in crystal form (e.g. 10 wt%) estradiol as in the DC batches a maximum release threshold is defined by the sheath thickness loaded with progesterone crystals, as shown in Figure 16A, B and C.

In addition to the dissolved progesterone that hinders the release of estradiol, see Figure 13, the presence of the progesterone in crystal form also has an impact on the release of estradiol as shown in Figure 16.

As is evident from Figure 17A and B, the presence of the estradiol in crystal form i.e., the DC-batches with 10 wt% estradiol, allow sustained release of estradiol at zero order release rate of estradiol from the IVRs for 28 days.

There is a slight increase in the release of estradiol after day 14 can may be the result of two physical phenomena; the presence of progesterone crystal in the sheath which tends to increase the diffusion length (i.e., reducing the average release rate) and the depletion of crystals in the sheath which allows faster diffusion through the holes in the sheaths. It is in this respect believed that the space initially occupied by progesterone leaves behind an empty porous matrix (holes) which may be empty or become water- filled due to ingress of water. This means that the rings are in percolation or the crystals are dense near the outer surface of the IVRs. 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 holes thereby providing a free path for the estradiol, and accordingly the desired zero-order release profile..

The increase in the thickness of the sheath reduces the release rate of the estradiol embedded in the core. The increase of sheath thickness from 200 to 400 pm leads to a decrease in the average daily release of estradiol on day 24 from 409.14 pg to 226.64 p.g (for DC400 and DC200 respectively).

The experiments were perform using EVA28 (EVA 28 wt%), where it acted like a rate-controlling sheath. Similar results are expected with other preferred EVAs according to the present invention, e.g. ethylene-vinyl acetate polymer with a vinyl acetate content of 24 wt%, 33 wt% or 40 wt%.

The presence of progesterone limited/tailored the release rate of estradiol and provided a zero-order release of estradiol during the treatment period of 28 when the core is loaded at 10 wt% of estradiol.

Thus, based on the experimental data it can be concluded that the sheath-loaded progesterone crystals play the role of ratelimiting sheath with the tested VA-content. Without being bound by theory, it is in this respect believed that progesterone will function as a filler and control the release rate of estradiol in the core. When progesterone present in the sheath is steroid is reduced and it is believed that that 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. Such a zero order release was obtained with the DC-batch (10 wt% estradiol in the core and 33.9 wt% of progesterone in the sheath), see Figure 17B. 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.