Vaginal ring

Abstract

The present invention relates to an intravaginal ring (1) comprising a core (2) and a sheath (5), the core (2) containing a first ethylene-vinyl acetate copolymer (3) with a vinyl acetate content of 28-40% by weight and at least 10% by weight of an estrogen steroid (4) based on the weight of the core, and the sheath (5) containing a second ethylene-vinyl acetate copolymer (6) with a vinyl acetate content of 18-28% by weight and at least 10% by weight of a progesterone steroid (7) based on the weight of the sheath. The inventors have found that by using the intravaginal ring according to the invention it is possible to achieve an optimal independent release of the two active ingredients, i.e. estrogen steroid and progesterone steroid, without a complex assembly of components and without the use of sophisticated multi-layer extrusion techniques.

Description

[Technical field]

[0001] The present invention relates to an intravaginal ring, a method for making the ring, and uses of the ring.

[0002] Various types of (IVR) have been developed to provide a controlled, sustained release of the active ingredient, preferably by diffusion through the surface of the ring.

[0003] Examples of such devices are Estring®, Femring®, and Nuvaring®, all of which provide a controlled, sustained release of steroid molecules over an extended period of time, e.g., weeks / months. In addition to preventing unwanted pregnancy, the devices have several advantages: their use is controlled by the woman; the dosage of the drug can be better regulated without the user's attention; compared to their orally administered counterparts, the destruction of a significant portion of the daily dose of the drug (by the intestine and by passing through the liver first) can be avoided.

[0004] These known vaginal rings have proven particularly useful for the delivery of steroids, whose relatively small molecular size and substantially water-insoluble nature allows for effective penetration through the hydrophobic elastomer / polymer so that therapeutic concentrations can be rapidly achieved in the body.

[0005] However, it is known that diffusion in polymers is complex and depends on several different factors, such as temperature, manufacturing process, solubility and diffusibility of drug in polymer, surface area of ​​drug reservoir, distance that drug diffuses through device to reach device surface, and molecular weight of drug.Therefore, it is still difficult to understand, predict, and control the diffusion of small and large molecules into polymer systems.In this regard, the use of intravaginal rings to deliver drugs requires a design that controls the release rate so that the user can reliably receive an appropriate daily dose throughout the life of the device.

[0006] In a reservoir system, i.e., a drug-loaded core surrounded by a non-medicated membrane / sheath, the drug first distributes from the reservoir into the sheath 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 within the membrane, the rate of drug flux is constant, and zero-order release is achieved. However, as the drug concentration in the reservoir decreases, so does the gradient across the membrane and the rate of drug release.

[0007] 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.

[0008] Simultaneous delivery / release of drugs has found applications in a variety of different areas. However, placing a blend of drugs in one intravaginal ring in a ratio equal to the desired delivery rate ratio rarely produces the desired results. In many cases, drugs are present in a blend, so they do not diffuse together at the same rate through a surface or membrane. Instead, this rate will depend on the intrinsic rate of the normalized permeation rate of the drug through, for example, a rate-controlling membrane. Thus, flexibility is limited to the selection of suitable polymer candidates for the sheath. Thus, the range of delivery rate ratios and the degree of control over delivery rate ratios are very limited.

[0009] Of course, the need to maintain a certain delivery rate ratio can be met by using a separate intravaginal ring for each drug.However, this is obviously undesirable.Even one intravaginal ring can cause disruption to the normal physiological activity of animals or humans, and the presence of two or more intravaginal rings compounds this disruption.In addition, the failure of one intravaginal ring will result in the loss of the desired delivery ratio.In addition, the complete treatment with one intravaginal ring is more acceptable to patients and more efficient to insert and remove.

[0010] Specific delivery rate adjustments can also be met by two or multiple compartment intravaginal rings and ring bodies containing drug-releasing capsules, however, manufacturing such rings on an industrial scale is complex and expensive.

[0011] A further problem with known intravaginal rings configured to release multiple drugs is that such rings typically exhibit less than optimal release patterns for the different drugs, while it is generally preferable for all drugs to be released at a controlled rate over a particular duration.

[0012] Thus, there is a need for a novel intravaginal ring configured for controlled release of two active ingredients / drugs at precise rates, and a simple, inexpensive method for manufacturing the intravaginal ring.

[0013] Thus, in a first aspect of the invention there is provided an intravaginal ring which can be loaded with both an oestrogen steroid and a progesterone steroid, each steroid being released at a controlled rate independent of the other steroid.

[0014] In a second aspect of the present invention, an intravaginal ring is provided that reduces the variability in release rate over time for a steroid.

[0015] In a third aspect of the present invention, an intravaginal ring is provided which provides a substantially zero order release rate for estrogenic steroids while eliminating known problems associated with complex and expensive manufacturing processes, dose dumping, and initial burst of drug.

[0016] In a fourth aspect of the invention, an intravaginal ring is provided that is stable at room temperature.

[0017] The novel and unique features which achieve these and further aspects of the present invention include: a core containing a first ethylene-vinyl acetate copolymer having a vinyl acetate content of 26 to 40% by weight and an estrogenic steroid; and A sheath containing a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 20-40% by weight and at least 10% by weight of a progesterone steroid based on the weight of the sheath. The vaginal ring is provided by

[0018] The intravaginal ring according to the present invention relates to a system comprising a core at least partially, but preferably completely, surrounded by a sheath. However, in contrast to conventional systems of this type, the sheath according to the present invention also contains a high concentration of the active ingredient, which allows the simultaneous release of two steroids.

[0019] Dual administration of two steroids has found applications in various areas, such as contraceptive rings and rings providing hormone replacement.

[0020] For such an intravaginal ring, it is necessary to release the two steroids simultaneously and at the same time. Therefore, the release rates of these steroids must be independently adjusted to the physiological optimum (mg / day). The inventors have found that by using the intravaginal ring of the present invention, it is possible to achieve an independent and optimal release of two steroids (estrogen steroid and progesterone steroid) without the need for complex assembly of components or the need for sophisticated multi-layer extrusion techniques.

[0021] The use of an intravaginal ring with a concentration of at least 10% by weight of progesterone steroid in the sheath ensures that the desired near zero order release behavior for the estrogen steroid in the core is observed over a longer period of time. In addition, such a high concentration of active ingredient is coupled with good physical stability of the progesterone steroid.

[0022] Substantially zero order release means that the estrogenic steroid is released in a substantially constant amount over a given period of time. In some embodiments, the system exhibits a substantially zero order release profile for the estrogenic steroid over a treatment period of at least 14 days, preferably at least 28 days, and even more preferably about 2-3 months.

[0023] As mentioned above, the problem of the release rate of the active ingredient in the core decreasing because the active ingredient or ingredients deeper in the core / reservoir have to diffuse to the surface is well known.However, the inventors have found that by loading the progesterone steroid in the sheath at a high concentration, the release rate of the estrogen steroid in the core increases slightly over time, thereby compensating for the additional distance the steroid must travel to the surface of the intravaginal ring for release to the environment, thereby providing a substantially zero-order release rate for the estrogen steroid over the desired treatment period.

[0024] It is important that the progesterone steroid be dispersed and / or incorporated into the second ethylene-vinyl acetate copolymer sufficiently to control the rate of diffusion of the estrogen steroid through the sheath.

[0025] Without being bound by theory, it is believed that the progesterone steroid in the sheath acts as a filler and controls the release rate of the estrogen steroid. When the progesterone steroid present in the sheath is released to the surroundings, the concentration of the progesterone steroid decreases, facilitating the diffusion of water into the sheath, leaving an empty porous matrix and / or empty pockets / holes, and / or the sheath collapses, thereby ensuring the desired zero-order release characteristics for the estrogen steroid. Thus, it is believed that the space initially occupied by the progesterone steroid may leave an empty porous matrix (which may be filled with water due to water intrusion) and / or leave an empty pocket / hole. This contradicts the conventional knowledge that the release rate of the active ingredient in the core surrounded by the non-medicated sheath decreases slightly over time (i.e., the desired zero-order release rate cannot be maintained for the desired treatment period for such conventional vaginal rings).

[0026] In some embodiments, the progestational steroid is dispersed in the second ethylene-vinyl acetate copolymer preferably at least 15% by weight, even more preferably at least 20% by weight, and even more preferably at least 25% by weight.

[0027] To ensure that the oestrogen steroid is releasable throughout the sheath, it is preferred that the sheath contain a progesterone steroid at a concentration of no more than 40% by weight, preferably no more than 35% by weight, based on the weight of the sheath.

[0028] The presence of progesterone steroid in the sheath at a relatively high concentration not only leads to an increase in the average path length that the estrogen steroid molecule must travel between two points in the sheath, but also reduces the amount of estrogen steroid that can be dissolved in the second ethylene-vinyl acetate copolymer of the sheath, thus reducing the release rate of estrogen steroid through the sheath.This provides a reliable release rate and a lower initial burst of estrogen steroid.Therefore, the sheath can be made smaller, providing a smaller product with a significantly lower burst of estrogen steroid.

[0029] In this respect, it is preferred that the progesterone 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 reservoir of undissolved solid crystals, which act as seed crystals, i.e., as a sustained release reservoir. Over time, as the progesterone steroid is delivered to the surroundings, some of the crystals will be released into the second ethylene-vinyl acetate copolymer, which will release the progesterone steroid for a long period of time. Furthermore, the stability of the progesterone steroid in the intravaginal ring is improved when the progesterone steroid is incorporated in the sheath as undissolved particles / crystals.

[0030] Without being bound by theory, it is believed that by maintaining a high concentration of progesterone steroid in the sheath, the crystals create a porous network pathway that leaves many sites / openings / pores open in the matrix of the second ethylene-vinyl acetate copolymer, ensuring that the estrogen steroid can only be released through a tortuous pathway within the sheath, thereby increasing the diffusion length and controlling the release rate.

[0031] To obtain the desired zero order release of the estrogen steroid during the treatment period, it is preferred that the estrogen steroid is dissolved in the first ethylene-vinyl acetate copolymer, and in these embodiments, the estrogen steroid is preferably present in the first ethylene-vinyl acetate copolymer at a concentration that is equal to or less than the saturation concentration of the estrogen steroid at 25°C.

[0032] Because it is expected that some of the estrogenic steroids will redistribute throughout the intravaginal ring upon storage (i.e., the concentration of steroids in the core will decrease as some of the steroids diffuse into the sheath), the term "below saturation concentration" refers to the concentration of estrogenic steroids in the core as measured in an equilibrated intravaginal ring (i.e., when equilibration of the estrogenic steroids in the intravaginal ring has been achieved).

[0033] Alternatively, the estrogen steroid may be present in the core in particulate, preferably crystalline, form for the same reasons as disclosed for the progesterone steroid, thus improving the stability of both the estrogen and progesterone steroids and thus the stability of the intravaginal ring according to the invention.

[0034] When the estrogenic steroid is present as particles in the core, it is preferred that the estrogenic steroid is dispersed and / or incorporated in the first ethylene-vinyl acetate copolymer of the core at a concentration of at least 10% by weight, preferably at least 15% by weight, and even more preferably at least 20% by weight of the total weight of the core.

[0035] It should be noted that although the sheath surrounding the drug-loaded core is known to contain low concentrations of active ingredient (see, for example, WO2013 / 120888), it is not known to have the sheath contain high concentrations of progesterone steroid as claimed in the present invention. Low concentrations of active ingredient, i.e., well below 10% by weight, have no or only a very limited effect on the release rate of the active ingredient in the core and are therefore not critical to the present invention.

[0036] Based on the context of the present invention, one skilled in the art will understand that the diffusion rate through the sheath can be controlled and / or tailored by varying the amount / concentration of the progesterone steroid in the sheath, by using different grades of the second ethylene-vinyl acetate copolymer, and / or by using different particle sizes or blends of different particle sizes for the progesterone steroid.

[0037] However, the particles / crystals of the progestational steroid, and optionally the estrogenic steroid, preferably have an average particle size of from 3 μm to 40 μm, preferably from 8 μm to 24 μm, even more preferably from 10 μm to 24 μm, as such particle sizes have been found to provide the desired near zero order release rate over an extended period of time, i.e. over the desired treatment period of at least 14 days, preferably at least 28 days.

[0038] As used herein, the term "crystal" refers to particles of active ingredient arranged in an ordered microscopic structure to form a crystal lattice. The term "crystal size" or "particle size" refers to the average particle diameter of the crystal or particle. Particle size, crystal size and / or particle size distribution are preferably measured using laser diffraction, for example, using a Malvern laser scattering particle size analyzer. However, other particle measurement devices or techniques known to those skilled in the art can also be used, such as dynamic light scattering or sieve analysis. As used herein, the term "crystal size" or "particle size" refers to the particle distribution diameter of the particle / crystal. In one example, D90 means that 90% of the particles have a diameter below a given value, for example, as measured by laser diffraction, dynamic light scattering, or sieve analysis.

[0039] 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 canal, i.e., the materials are believed to be non-toxic and non-absorbable to the patient or animal, and to have excellent mechanical and physical properties.

[0040] The vinyl acetate concentration of the EVA copolymer determines the rate at which the active ingredient diffuses generally through the system; the lower the vinyl acetate concentration, the slower the rate at which the active ingredient is released from or migrates through the copolymer.

[0041] The second ethylene-vinyl acetate copolymer has a vinyl acetate content of 20-40% by weight, for example 24%, 28%, 33% or 40% by weight, as these materials provide the desired release characteristics through the sheath, for example by ensuring that the progesterone steroid release rate is at an optimal level.

[0042] To provide the desired zero order release profile for the oestrogen steroid, the core preferably contains an ethylene-vinyl acetate copolymer having a vinyl acetate content of 26-40% by weight, preferably 26%, 33% or 40% by weight.

[0043] In one embodiment of the invention, the first and second ethylene-vinyl acetate copolymers have the same vinyl acetate content (ie, the first and second ethylene-vinyl acetate copolymers are the same).

[0044] When a specific vinyl acetate content, e.g. 20 wt%, is mentioned, this refers to the wt% content provided by the manufacturer. However, because manufacturers may use different internal analytical methods to determine the vinyl acetate content, the actual vinyl acetate content may vary from 1-2% depending on the manufacturer. Thus, in the present invention, vinyl acetate content refers to the vinyl acetate content in an ethylene-vinyl acetate copolymer, as determined by high-resolution NMR according to standard procedures. The wt% of vinyl acetate content in an ethylene-vinyl acetate copolymer is based on the weight of the ethylene-vinyl acetate copolymer.

[0045] The intravaginal ring according to the present invention is a dual drug delivery ring, i.e., the ring contains both an estrogen steroid and a progesterone steroid. In a preferred embodiment, the estrogen steroid is estradiol, and the progesterone steroid is selected from the group consisting of progestogen, etonogestrel, levonorgestrel, D-1-norestrel, and norethindrone, preferably levonorgestrel. These steroids may be selected for preventing contraception, or for treating certain conditions (e.g., vaginal atrophy), or for hormone replacement therapy, such as symptoms associated with menopause (e.g., hot flashes).

[0046] The intravaginal ring of the present invention is adapted to deliver a pharmacologic effective amount of the steroid. By "pharmacologic effective" is meant an amount sufficient to affect a desired physiological or pharmacological change in a subject. This amount will vary depending on the potency of the steroid, the desired physiological or pharmacological effect, and the intended duration of treatment, etc. One skilled in the art will be able to determine the pharmacologic effective amount for a given steroid according to standard procedures.

[0047] The thickness of the sheath (which is preferably the outer layer of the intravaginal ring according to the present invention) can be varied to further control the release rate of the estrogen and progesterone steroids.Thus, the drug delivery system according to the present invention preferably does not include / comprise a sheath / membrane that does not have an active ingredient (e.g. a rate-controlling sheath).

[0048] In one embodiment, the thickness of the sheath is between 0.05 mm and 3 mm. This thickness may be preferably 0.05 to 2 mm, more preferably 0.1 mm to 2 mm, and even more preferably 0.2 mm to 0.6 mm. In a particular embodiment, the thickness of the sheath is 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, or 600 μm.

[0049] Those skilled in the art will understand that a thinner sheath may have less active ingredient than a thicker sheath, and that the concentration of progesterone steroid in the sheath should be sufficient to maintain the release of the associated active ingredient at the desired rate over the desired treatment period. By using a grade of ethylene-vinyl acetate copolymer with a higher or lower vinyl acetate content, the thickness of the sheath can be changed while maintaining substantially the same average release rate for the estrogen steroid. For example, if a thicker sheath is desired because more progesterone steroid needs to be accommodated in the sheath, a grade of ethylene-vinyl acetate copolymer with a higher vinyl acetate content can be selected.

[0050] The core preferably has a circular cross-section with a cross-sectional diameter of 2 to 8 mm, more preferably 3 to 6 mm, even more preferably approximately 4 mm.

[0051] The dimensions of the intravaginal ring may vary depending on the subject's anatomy, the amount of active ingredient to be delivered to the patient, the period of time the active ingredient is to be delivered, the diffusion characteristics of the active ingredient, and other manufacturing considerations. The only requirement is that the intravaginal ring be flexible enough to be bent and inserted into 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 an intravaginal ring may, for example, range from about 45 mm to about 65 mm, and / or the length of the fibrous elements forming the intravaginal ring may be 150-170 mm, preferably 154-160 mm, for example about 157 mm.

[0052] In the context of the present invention, the term intravaginal ring also contemplates ring designs or configurations having other shapes, for example polygonal and / or wavy shapes, or where the configuration is not a complete and / or closed circle / shape.

[0053] In a preferred embodiment, the intravaginal ring comprises: a core having a first ethylene-vinyl acetate copolymer with a vinyl acetate content of 28% by weight to 33% by weight and an estrogen steroid concentration below its saturation concentration at 25° C.; and a sheath containing a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 24%, 28%, 33%, or 40% by weight and 30% by weight of a progesterone steroid based on the weight of the sheath; Equipped with.

[0054] The core in the preferred embodiment has a cross-sectional diameter of 4 mm and a sheath thickness of 600 μm. The ring diameter is 54 mm.

[0055] In a preferred embodiment, the average release rate of estradiol is between 80 μg / day and 160 μg / day during a 28 day treatment period, preferably resulting in a near zero order release rate, however the average release rate may be higher, for example up to 200 μg / day, such as 180 μg / day, or about 165 μg / day.

[0056] Additionally, or alternatively, the average release rate of the progestogen is 5 mg / day to 10 mg / day over a treatment period of 28 days. As the progestogen content in the sheath becomes depleted, the release rate of the progestogen is expected to decrease over the treatment period.

[0057] Based on this application, one skilled in the art will understand that combinations of average release rates of estradiol and progestogen are contemplated within the scope of the present invention, for example, in one intravaginal ring, the average release rate of estradiol is 80 μg / day and the average release rate of progestogen is 0 mg / day, in another 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.

[0058] In a preferred embodiment according to the invention, the intravaginal ring does not contain any steroids other than the two steroids (i.e., an estrogen steroid and a progesterone steroid) and / or does not comprise any additional core and / or layers (e.g., a sheath and a membrane), i.e., the intravaginal ring according to the invention consists of a core and a sheath completely surrounding said core, with the estrogen steroid in the core and the progesterone steroid in the sheath.

[0059] The present invention also relates to a method for producing an intravaginal ring according to the present invention.

[0060] The method comprises: a. providing a core containing a first ethylene-vinyl acetate copolymer having a vinyl acetate content of 26-40% by weight and an estrogenic steroid; b. providing a sheath containing a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 20-40% by weight and at least 10% by weight of a progestogen steroid based on the weight of the sheath; c. co-extruding the core and sheath into a fiber; d. Producing fiber elements by cutting the fibers to an appropriate length; and e. Combining the ends of the fibrous elements to form an intravaginal ring. Includes.

[0061] Because the core and sheath are co-extruded, the present invention provides a very simple and inexpensive implementation, although if preferred, the core and sheath can be formed in separate injection molding or extrusion processes. Injection molding and extrusion are well known to those skilled in the art and will not be discussed further herein.

[0062] The method preferably further comprises a cooling step in which the provided fiber or fiber element is cooled to a temperature below 20° C. to effect crystallization of the steroid in the sheath and optionally the core. This can be achieved, for example, by placing the fiber in a chilled water bath.

[0063] Without being bound by theory, the inventors believe that the crystals that form in the sheath and optionally the core are caused by recrystallization kinetics: a relatively high concentration of active ingredient in the sheath and optionally the core results in a relatively high concentration of "seed" crystals that can cause recrystallization when the fiber is cooled after co-extrusion.

[0064] Said cooling step is preferably carried out immediately after step c, ie as soon as practically possible from a manufacturing point of view, ie preferably within 30 minutes of completion of the fibre in step c.

[0065] The ring is preferably manufactured by heat welding the fiber ends together without the addition of any additional EVA or adhesive material.

[0066] The invention will now be described in further detail by describing exemplary embodiments of an intravaginal ring according to the invention. [Brief description of the drawings]

[0067] [Figure 1] 1 shows a perspective view of a preferred embodiment of a vaginal ring according to the present invention; [Diagram 2] 4 shows the average simulated release of progesterone for ring AE3. [Diagram 3] 1 shows the average simulated release of estradiol for ring AE3. [Figure 4] 1 shows the effect of sheath thickness on simulated progesterone release and early depletion. [Diagram 5] 1 shows the effect of cross-sectional diameter on estradiol release profile. [Figure 6] The average simulated release of estradiol for ring BF1 is shown. [Figure 7] 1 shows the average simulated release of progesterone for ring BF1. [Figure 8] 1 shows simulated estradiol release and the effect of sheath thickness on the release rate (rings BF1, BF2 and BF3). [Figure 9] Figure 2 shows simulated progesterone release in ring BF1. [Figure 10] Photographs showing cross-sections of fibers having a core loaded with 0.39 wt% estradiol and a sheath loaded with 5 wt% progesterone, with sheath thicknesses of (a) 200 μm, (b) 300 μm, and (c) 400 μm. [Figure 11]Photographs showing cross-sections of fibers having a core loaded with 0.39 wt% estradiol and a sheath loaded with 33.9 wt% progesterone, with sheath thicknesses of (a) 200 μm, (b) 300 μm, and (c) 400 μm. [Figure 12] Photographs showing cross-sections of fibers having a core loaded with 10 wt% estradiol and a sheath loaded with 33.9 wt% progesterone, with sheath thicknesses of (a) 200 μm, (b) 300 μm, and (c) 400 μm. [Figure 13A] 1 shows the release of progesterone and estradiol for an IVR with 0.39% w / w estradiol in the core and 5% w / w progesterone in the sheath. [Figure 13B] 1 shows the release of progesterone and estradiol for an IVR with 0.39% w / w estradiol in the core and 5% w / w progesterone in the sheath. [Figure 14A] 1 shows progesterone release from various IVRs. [Figure 14B] 1 shows progesterone release from various IVRs. [Figure 14C] 1 shows progesterone release from various IVRs. [Figure 15] Progesterone release is shown for various IVRs with 10% estradiol w / w in the core and 33.9% progesterone w / w in the sheath. [Figure 16A] Estradiol release is shown for different IVRs with different estradiol and progesterone concentrations in the core and sheath. [Figure 16B] Estradiol release is shown for different IVRs with different estradiol and progesterone concentrations in the core and sheath. [Figure 16C] Estradiol release is shown for different IVRs with different estradiol and progesterone concentrations in the core and sheath. [Figure 17A] Figure 2 shows estradiol release for various IVRs. [Figure 17B] Figure 2 shows estradiol release for various IVRs.

[0068] 1 shows a preferred embodiment of an intravaginal ring (IVR) 1 according to the present invention. In this embodiment, the IVR comprises a core 2 made of a first ethylene-vinyl acetate copolymer 3 containing an estrogenic steroid 4, and a sheath 5 made of a second ethylene-vinyl acetate copolymer 6 containing a progesterone steroid 7.

[0069] 2-17 are discussed in further detail below with reference to the Examples below.

[0070] Example 1 To assess the effect of external diameter and sheath thickness, the release kinetics of a series of intravaginal rings were evaluated by computer modeling. The model takes into account drug diffusion (driven by the concentration gradient within the system and the slow dissolution of progesterone (P4) dispersed in the sheath) and assumes that the receiving medium is a perfect sink. Since the cross-sectional diameter of the ring determines the surface area of ​​the system, it is hypothesized that rings with larger diameters will exhibit proportionally more drug release.

[0071] The thickness of the sheath determines the amount of progesterone present in the ring (assuming the concentration of progesterone is uniform / unchanging). The amount of drug substance loaded into the delivery system is an important design parameter, as progesterone release should be sustained over the intended period of use, while significant exceedance should be avoided for economic and environmental reasons.

[0072] The rings evaluated are made of EVA28, used for both the core and the sheath. During storage, redistribution of dissolved progesterone and estradiol occurs by an internal diffusion process. A fraction of the drug initially loaded in the core (i.e., estradiol (dissolved)) diffuses into the sheath, and this process will continue until the ring is equilibrated, which may last several weeks depending on the sheath thickness and storage conditions. The estradiol loadings listed in Table 1 are obtained after equilibration at a uniform concentration of 0.27% by weight in the ring (including sheath and core), which corresponds to the estradiol saturation concentration of EVA28 at 37° C. Thermodynamic equilibration of the sheath with progesterone loaded in the ring (see Table 1) results in a progesterone concentration of 30% by weight in the sheath and 1.7% by weight in the core.

[0073] This simulation confirms the prediction of those skilled in the art that in this particular case, the thickness of the sheath does not affect estradiol release, since the drug is uniformly distributed after equilibration and no partitioning occurs between the core and the sheath, since both are made of EVA28.

[0074] The release rates for a series of nine rings (varying sheath thickness and cross-sectional diameter) are listed in Table 1. The table reveals that the release rates of progesterone (P4) and estradiol (E2) scale with cross-sectional diameter.

[0075] TIFF2025503105000002.tif243170

[0076] Figures 2 and 3 show the simulated mean release of progesterone and estradiol, respectively, for ring AE3. As can be seen from the figures, the release rate of the steroids decreases over the 28 day treatment period.

[0077] 4 shows a simulation of progesterone release from rings A1 and A3, illustrating premature depletion that occurs when the sheath thickness is insufficient and the progesterone content is insufficient to sustain progesterone release over the intended 28 day period of use.

[0078] The effect of cross-sectional diameter on the release profile of E2 is shown in Figure 5. It should be noted that the release rates visualized in Figures 4 and 5 are the actual release rates, so the burst appears much higher since the release at the very beginning of the dissolution is of course much higher than the first day average.

[0079] Example 2 A series of intravaginal rings were evaluated by computer modeling to assess the effect of estradiol E2 dispersed in the core and sheath thickness on release rate.

[0080] The release rates for a series of three rings with different sheath thicknesses are listed in Table 2. From this table, it is clear 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 rate of estradiol even at 28 days. Varying the sheath thickness did not have a significant effect on the release rate of progesterone.

[0081] TIFF2025503105000003.tif237170

[0082] Figure 6 shows the average daily release from BF1. The rings provide sufficient estradiol over the entire period of use (28 days). Increasing the sheath thickness from 400 μm (ring BF1) to 600 μm (ring BF3) reduces the average daily release by approximately 30% (see Figures 2 and 8).

[0083] 7 and 9 show simulated progesterone release from ring BF1, showing that even at a drug loading as high as 35% by weight, premature depletion occurs and there is insufficient progesterone in the ring to sustain sufficient release over the intended 28 day use period.

[0084] Example 3 To evaluate the effect of estradiol (E2) concentration in the core, progesterone (P4) concentration in the sheath, and the effect of sheath thickness on the release rates of estradiol and progesterone, respectively, a series of intravaginal rings (IVR) were prepared as follows.

[0085] TIFF2025503105000004.tif78170

[0086] Process Scheme and Manufacturing Core / sheath fibers containing the APIs estradiol and progesterone were produced as shown in the following process flow for fiber production.

[0087] TIFF2025503105000005.tif60170

[0088] Milled EVA and API were weighed according to the proportions detailed in Table 3. All four batches were mixed using the same mixing protocol. Compounding was done using a tight intermeshing 11 mm twin screw extruder (Thermo scientific twin screw extruder Pharma 11). In summary, the four batches were compounded according to Table 3 to produce active granules / pellets. The compounding set temperature for all batches is 90°C.

[0089] TIFF2025503105000006.tif52170

[0090] Magnesium stearate (MgSt) was added to all batches to enhance the processing properties of the pellets in the co-extrusion process: 0.1 wt% MgSt was first added to the mixing bag containing the active pellets, which were then mixed by hand for approximately 3 minutes.

[0091] A co-extrusion line with a 5 mm die was used to produce 5 mm sheath / core fibers, comprising a single screw extruder 16 / 25 (D / L) (i.e., 16 is the diameter and 25 is the length, the diameter ratio is D / L) for the sheath and a single screw 25 / 25 (D / L) for the core.

[0092] The fibers produced contained the active ingredient in both the core and the sheath; furthermore, the sheath thickness was varied for each formulation, resulting in sheath thicknesses of 200 μm, 300 μm, and 400 μm for a fiber diameter of 5 mm (see Table 5).

[0093] Fiber properties (diameter and sheath thickness) were controlled by the melt pump speeds of Extruder 1 (sheath) and Extruder 2 (core) to produce 5 mm diameter fibers with the required sheath thickness. All fibers were extruded at 90°C-100°C. Melt pump speeds were calculated based on the pump capacity. The sheath thickness compared to the core can be seen in Figure 11 (AC batch) and Figure 12 (DC batch). For the AB batch (Figure 10), no boundary was visible. The melt pump speeds 1 and 2 for each batch are listed in Table 4.

[0094] TIFF2025503105000007.tif82170 The melt pump volume for the sheath is 0.6 cm 3 and for the core it is 2.4 cm 3 It is.

[0095] After co-extrusion, the fibers are cut to lengths of 157 mm and then welded to form intravaginal rings (IVRs). The IVRs produced (for each batch) are listed in Table 5.

[0096] For the AB batch, the progesterone concentration loaded in the sheath is 5 wt %, and during extrusion the progesterone is completely dissolved, as expected. As a result of internal diffusion, the progesterone redistributes throughout the ring, and if no premature crystallization occurs, the progesterone concentration in the ring will be completely uniform once the ring is at equilibrium.

[0097] TIFF2025503105000008.tif76170*The numbers 200, 300 and 400 represent sheath thicknesses of 200 μm, 300 μm and 400 μm, respectively.

[0098] Optical observation of fibers For each of batches AB200, AB300 and AB400, i.e., 0.39 wt% estradiol and 5 wt% progesterone, no clear boundary was observed between the core and the sheath (see FIG. 10), whereas for the other batches, a clear boundary was observed (see FIGS. 11 and 12), because estradiol and progesterone were dissolved in EVA28 in the sheath and core, respectively.

[0099] The contrast (i.e., boundary) between the core and sheath is greatest for batches AC200, AC300, and AC400, which are loaded with dissolved estradiol (0.39 wt%) and crystalline progesterone (33.9 wt%) (compare with FIG. 11).

[0100] The contrast (i.e., boundary) is lower when both APIs are present in crystalline form, i.e., for IVR containing 10 wt. % estradiol and 33.9 wt. % progesterone (in addition to the dissolved API fraction) (as seen in Figure 12 for DC200, DC300, and DC400).

[0101] The sheath / core systems observed generally exhibited a centered / concentrated geometry (see Figures 11 and 12).

[0102] The release rates of estradiol and progesterone for the prepared IVRs are shown in Table 6 (estradiol data shown), Table 7 (progesterone data shown), and corresponding Figures 13-17.

[0103] TIFF2025503105000009.tif243170TIFF2025503105000010.tif243170TIFF2025503105000011.tif243170 TIFF2025503105000012.tif243170TIFF2025503105000013.tif243170TIFF2025503105000014.tif243170

[0104] TIFF2025503105000015.tif245170TIFF2025503105000016.tif245170TIFF2025503105000017.tif245170TIFF2025503105000018.tif245170 TIFF2025503105000019.tif245170TIFF2025503105000020.tif245170TIFF2025503105000021.tif245170TIFF2025503105000022.tif245170

[0105] The results from Tables 6 and 7 are discussed in more detail below.

[0106] Estradiol and progesterone release during prepared IVR IVR containing 0.39% estradiol and 5% progesterone (AB batch) with various sheath thicknesses The release of estradiol and progesterone from IVRs obtained from batches containing 0.39% estradiol and 5% progesterone by weight (i.e., AB200, AB300, and AB400) is shown in Figures 13A and 13B.

[0107] As is evident from the figure, progesterone release increases with increasing sheath thickness: in all cases the daily release is less than 1 mg per day after 10 days.

[0108] Since estradiol is present in the AB batch at low concentration (0.39 wt%), estradiol dissolves in the ring. Since the sheath and core are made of the same polymer for the AB200, AB300 and AB400 batches (see FIG. 10) (no partitioning), the equilibrium estradiol concentration is uniform and therefore not affected by the sheath thickness. However, a slight effect is seen in FIG. 13B. This is expected due to the fact that a small amount of progesterone crystals increases the effective diffusion path, but only slightly.

[0109] Thus, it is clear that the low concentration (5% by weight) of progesterone in the sheath has no or only a very limited effect on the release rate of estradiol in the core.

[0110] Progesterone release depends on the concentration of estradiol in the core. A comparison of the release rate of progesterone in the sheath depending on the concentration of estradiol and the thickness of the sheath is shown in Figures 14A, 14B and 14C.

[0111] As is evident from the figure, the release of progesterone in the IVR with 33.9% by weight progesterone in the sheath is much higher compared to the IVR with 5% by weight progesterone in the sheath.

[0112] However, as can be seen from the data in Figures 14A, B, and C, it can also be concluded that estradiol does not affect progesterone release if it is present in a dissolved state, i.e., at a relatively low estradiol concentration (0.39% by weight), and / or in a crystalline state, i.e., at a relatively high estradiol concentration (10% by weight). Note that the rings containing crystalline estradiol also contain estradiol in a dissolved state, likely at or near saturation concentrations.

[0113] For example, in FIG. 14A, IVRs AC200 (0.39% estradiol by weight) and DC200 (10% estradiol by weight) have substantially identical progesterone release profiles, and the same is seen for AC300 (0.39% estradiol by weight) and DC300 (10% estradiol by weight) in FIG. 14A, and AC400 (0.39% estradiol by weight) and DC400 (10% estradiol by weight) in FIG. 14C.

[0114] Effect of sheath thickness on progesterone release As shown in FIG. 15, increasing the thickness of the sheath allows for sustained delivery of progesterone.

[0115] Daily progesterone release (for the same sheath thickness) from both AC and DC batches is the same until the depletion phenomenon becomes significant for each sheath thickness. The effect of depletion on IVR is seen as early as day 7 for DC200 (AC200), whereas for DC300 (AC300) this occurs on days 12-13. Although only data for the DC200 batch are shown in Figure 15, these data are identical for each AC batch.

[0116] Effect of sheath thickness on estradiol release As can be seen from Figures 16A, B and C, the presence of progesterone in the sheath reduces the daily release of estradiol.

[0117] This effect is less pronounced when the sheath is thin, e.g., 200 μm, as in the AB and AC IVRs, where estradiol (0.39 wt %) is primarily dissolved in the core (see FIG. 16A).

[0118] When estradiol is present in the core in crystalline form (eg, 10% by weight), as in the DC batches, the maximum release threshold is defined by the sheath thickness loaded with progesterone crystals (see Figures 16A, B and C).

[0119] In addition to dissolved progesterone preventing the release of estradiol (see FIG. 13), the presence of progesterone in crystalline form also affects the release of estradiol (see FIG. 16).

[0120] As can be seen from Figures 17A and B, the presence of estradiol in crystalline form, i.e., DC batches having 10% estradiol by weight, allows for sustained release of estradiol from the IVR at a zero order release rate for 28 days.

[0121] The slight increase in estradiol release after 14 days may be the result of two physical phenomena: the presence of progesterone in the sheath as crystals tends to increase the diffusion length (i.e., decrease the average release rate), and the depletion of crystals in the sheath allows faster diffusion through the holes in the sheath. At this point, the space originally occupied by progesterone is left with an empty porous matrix (holes), which may be empty or may be filled with water due to water ingress. This means that the ring is permeated or the crystals are dense near the outer surface of the IVR.

[0122] Thus, the space originally occupied by the progesterone steroid leaves an empty porous matrix which may fill with water upon ingress of water and / or leave empty holes, which is believed to provide the free passage of estradiol and thus the desired zero order release profile.

[0123] Increasing the sheath thickness decreases the release rate of estradiol embedded in the core: increasing the sheath thickness from 200 to 400 μm reduces the average daily release of estradiol on day 24 from 409.14 μg to 226.64 μg (for DC400 and DC200, respectively).

[0124] Experiments were performed with EVA28 (EVA 28% by weight), which acted like a rate-controlling sheath. Similar results are expected with other EVAs preferred according to the invention, such as ethylene-vinyl acetate polymers with vinyl acetate content of 24%, 33%, or 40% by weight.

[0125] When the cores are loaded with 10% estradiol by weight, the presence of progesterone limits / modulates the release rate of estradiol, resulting in a zero order release rate for estradiol over the 28 day treatment period.

[0126] Therefore, based on the experimental data, it can be concluded that the progesterone crystals loaded in the sheath play the role of a rate-controlling sheath at the VA content tested. Without being bound by theory, it is believed that in this regard, progesterone acts as a filler and controls the release of estradiol in the core. It is believed that the reduction in the presence of progesterone steroid in the sheath facilitates the diffusion of water into the sheath, leaving an empty porous matrix and / or empty pockets / holes and / or the sheath collapses, thereby ensuring the desired zero-order release profile for the estrogen steroid. Such a zero-order release was obtained with DC batch (10 wt.% estradiol in the core, 33.9 wt.% progesterone in the sheath) (see FIG. 17B).

[0127] By using the intravaginal ring of the present invention, the inventors have found that it is possible to achieve independent and optimal release of the two active ingredients, i.e., estrogen steroid and progesterone steroid, without the need for complex assembly of components and without the need for sophisticated multi-layer extrusion techniques.

[0128] The intravaginal ring is simple in design and inexpensive, making it equally suitable for use in private and medical or hospital settings.

[0129] Modifications and combinations of the above principles and designs are contemplated as being within the scope of the present invention.

Claims

1. 1. An intravaginal ring comprising: a core (2) containing a first ethylene-vinyl acetate copolymer (3) having a vinyl acetate content of 26-40% by weight and an estrogenic steroid (4); A sheath (5) containing a second ethylene-vinyl acetate copolymer (6) having a vinyl acetate content of 20-40% by weight and at least 10% by weight of a progesterone steroid (7) based on the weight of the sheath. An intravaginal ring comprising:

2. 10. The intravaginal ring of claim 1, wherein the sheath contains at least 15%, preferably at least 20%, and even more preferably at least 30% progesterone steroid by weight based on the weight of the sheath.

3. 3. The intravaginal ring of claim 1 or 2, wherein the sheath contains no more than 40% by weight, preferably no more than 35% by weight, of a progesterone steroid based on the weight of the sheath.

4. 4. The intravaginal ring of any one of claims 1 to 3, wherein the progestational steroid is dispersed and / or incorporated in the second ethylene-vinyl acetate copolymer in particulate form, e.g., crystalline form.

5. 5. The intravaginal ring of any one of claims 1 to 4, wherein the estrogen steroid is dissolved in the first ethylene-vinyl acetate copolymer at up to its saturation concentration at 25°C.

6. 5. The intravaginal ring of any one of claims 1 to 4, wherein the estrogenic steroid is dispersed and / or incorporated in the first ethylene-vinyl acetate copolymer in particulate form, e.g., crystalline form.

7. 7. The intravaginal ring of claim 6, wherein the core contains at least 10%, preferably at least 15%, and even more preferably at least 20% estrogen steroid by weight based on the weight of the core.

8. 9. The intravaginal ring of claim 4, or any one of claims 6 to 8, wherein the particles of the progesterone steroid in the second ethylene-vinyl acetate copolymer, and optionally the particles of the estrogenic steroid in the first ethylene-vinyl acetate copolymer, have a particle size as determined by laser diffraction of from 3 μm to 40 μm, preferably between 8 μm and 24 μm, and even more preferably between 10 μm and 24 μm.

9. The intravaginal ring of any one of claims 1 to 8, wherein the first ethylene-vinyl acetate copolymer has a vinyl acetate content of 26%, 33%, or 40% by weight.

10. The intravaginal ring of any one of claims 1 to 9, wherein the second ethylene-vinyl acetate copolymer has a vinyl acetate content of 24%, 28%, 33%, or 40% by weight.

11. 11. The intravaginal ring of any one of claims 1-10, wherein the estrogenic steroid is estradiol.

12. 12. The intravaginal ring of any one of claims 1-11, wherein the progesterone steroid is selected from the group consisting of progestogen, etonogestrel, levonorgestrel, d-1-norestrel, and norethindrone.

13. 13. The intravaginal ring of any one of claims 1 to 12, wherein the sheath is the outer layer of the intravaginal ring.

14. 14. The intravaginal ring of any one of claims 1 to 13, wherein the thickness of the sheath is between 0.05 mm and 3 mm, preferably between 0.05 mm and 2 mm, more preferably between 0.1 mm and 2 mm, even more preferably between 0.1 mm and 0.6 mm.

15. The intravaginal ring of any one of claims 1 to 14, wherein the cross-sectional diameter of the core is between 2 and 8 mm, more preferably between 3 and 6 mm, and even more preferably between 4 and 5 mm.

16. The intravaginal ring of any one of claims 1 to 15, wherein the outer diameter of the intravaginal ring is in the range of 45mm to about 65mm, preferably approximately 54mm.

17. 17. A method of producing the intravaginal ring of any one of claims 1 to 16, comprising the steps of: a. providing a core containing a first ethylene-vinyl acetate copolymer having a vinyl acetate content of 26-40% by weight and an estrogenic steroid; b. Providing a sheath containing a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 20-40% by weight and at least 10% by weight of a progestogen steroid based on the weight of the sheath; c. co-extruding the core and sheath into a fiber; d. Producing fiber elements by cutting the fibers to an appropriate length; and e. combining the ends of the fibrous elements to form an intravaginal ring; A method comprising:

18. 18. The method of claim 17, further comprising a cooling step of cooling the fiber resulting from step c to a temperature of about 20°C to result in crystallization of at least the progesterone steroid in the sheath.

19. 17. Use of the intravaginal ring of any one of claims 1 to 16 to provide a substantially zero order release rate for an estrogen steroid for a treatment period of at least 28 days.

20. 20. The use according to claim 19, wherein the average release rate of estradiol is between 80 μg / day and 160 μg / day for a treatment period of at least 28 days.

21. 21. The use according to claim 19 or 20, wherein the average release rate of the progestogen is between 5 mg / day and 10 mg / day for a treatment period of at least 28 days.

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