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 a vaginal ring, a method for manufacturing the ring, and use of the ring.

[0002] Various types of intravaginal rings (IVRs) have been developed to control and sustain the release of active ingredients, preferably by diffusion through the surface of the ring.

[0003] Examples of such devices are Estring®, Femring®, and Nuvaring®, all of which continuously release steroid molecules while controlling them over a long period, for example, for several weeks / months. In addition to preventing unwanted pregnancy, this device has several advantages: its use is controlled by the woman; the drug dosage can be better adjusted without the user having to pay attention; and substantial destruction (by the intestine and by first passing through the liver) of a significant portion of the daily drug dose can be avoided compared to orally administered counterparts.

[0004] These known vaginal rings have been found to be particularly useful for the release of steroids, and their relatively small molecular size and substantially water-insoluble nature allow for effective penetration through hydrophobic elastomers / polymers, and therapeutic concentrations can be achieved immediately in the body.

[0005] However, diffusion within the polymer is complex and is known to depend on multiple different factors, which are, for example, temperature, the manufacturing process, the solubility and diffusibility of the drug in the polymer, the surface area of the drug reservoir, the distance the drug diffuses through the device to reach the surface of the device, and the molecular weight of the drug. Therefore, it is still difficult to understand, predict, and control the diffusion of low and high molecular weight drugs into polymer systems. In this regard, the use of vaginal rings for drug delivery requires a design that can control the release rate so as to reliably provide the user with an appropriate daily dose throughout the life of the device.

[0006] In reservoir-based systems, i.e., drug-filled cores surrounded by non-medicinal membranes / sheaths, the drug is first dispensed 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 drug concentration gradient is maintained within the membrane and the rate of drug flux is constant, achieving zero-order release. However, as the drug concentration in the reservoir decreases, the gradient across the membrane and the drug release rate also decrease.

[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.

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

[0009] Of course, the need to maintain a specific delivery rate ratio can be met by using separate vaginal rings for each drug. However, this is clearly undesirable. This is because even one vaginal ring can disrupt normal physiological activity in animals or humans, and the presence of two or more vaginal rings will compound this disruption. In addition, if there is a defect in one vaginal ring, the desired delivery ratio will be lost. Furthermore, complete treatment with one vaginal ring is more acceptable to the patient and more efficient in terms of insertion and removal.

[0010] Adjustment of a specific delivery rate can also be achieved by a two- or multi-compartment vaginal ring and a ring body containing a drug release capsule. However, manufacturing such a ring on an industrial scale is complex and expensive.

[0011] A further problem with known vaginal rings configured for delivering multiple drugs is that such rings typically exhibit release patterns that are not optimal for different drugs, while in general, it is preferred that all drugs are released at a controlled rate over a specific duration.

[0012] Therefore, there is a need for a novel vaginal ring configured to release two active ingredients / drugs at an accurate rate while controlling them, and a method for simply and inexpensively manufacturing such a vaginal ring.

[0013] Thus, in a first aspect of the present invention, there is provided a vaginal ring capable of loading both an estrogen steroid and a progesterone steroid, wherein each steroid is released at a controlled rate independent of the other steroid.

[0014] In a second aspect of the present invention, there is provided a vaginal ring that reduces the variation in the release rate of a steroid over time.

[0015] In a third aspect of the present invention, there is provided a vaginal ring that eliminates the known problems associated with complex and expensive manufacturing processes, dose dumping, and initial drug bursts, and at the same time provides a substantially zero-order release rate for an estrogen steroid.

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

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

[0018] The vaginal 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 this type of conventional system, the sheath according to the present invention also contains a high concentration of the active ingredient, whereby the two steroids are released simultaneously.

[0019] The dual administration of the two steroids has found uses in various areas (e.g., contraceptive rings and rings providing hormonal replacement).

[0020] For such vaginal rings, it is necessary to release the two steroids simultaneously and at the same timing. Therefore, it is necessary to independently adjust the release rates of these steroids to the physiologically optimal rate (mg / day). By using the vaginal ring according to the present invention, the inventors have found that the two steroids (estrogen steroid and progesterone steroid) can be released optimally independently without the need for complex assembly of the members or the use of sophisticated multi-layer extrusion techniques.

[0021] By using a vaginal ring in which the concentration of the progesterone steroid in the sheath is at least 10% by weight, it is guaranteed that the desired substantially zero-order release behavior of the estrogen steroid in the core is observed over a longer period. In addition, such a high concentration of the active ingredient is associated with good physical stability of the progesterone steroid.

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

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

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

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

[0026] In some embodiments, the progesterone steroids are dispersed in a second ethylene-vinyl acetate copolymer, preferably at least 15 wt%, more preferably at least 20 wt%, even more preferably at least 25 wt%.

[0027] To ensure that the estrogen steroids can be released throughout the sheath, it is preferred that the sheath contains the progesterone steroids at a concentration of 40 wt% or less, preferably 35 wt% or less, 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 estrogen steroid molecules must travel between two points in the sheath, but also decreases the amount of estrogen steroid that can be dissolved in the second ethylene-vinyl acetate copolymer of the sheath, and thus reduces the release rate of estrogen steroid through the sheath. This results in a more reliable release rate and a lower initial burst of estrogen steroid. Therefore, the sheath can be made smaller, and a smaller product with a significantly lower burst of estrogen steroid can be provided.

[0029] In this regard, 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 storage site for undissolved solid crystals, which act as seed crystals, i.e., sustained-release reservoirs. As time passes and the progesterone steroid is delivered to the surroundings, a portion of the crystals is released into the second ethylene-vinyl acetate copolymer, thereby enabling the progesterone steroid to be released over a long period. Furthermore, the stability of the progesterone steroid in the vaginal ring is improved when the progesterone steroid is incorporated into the sheath as undissolved particles / crystals.

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

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

[0032] Since a portion of the estrogen steroid is expected to redistribute throughout the vaginal ring during storage (i.e., the concentration of the steroid in the core decreases as a portion of the steroid diffuses into the sheath), the term "below the saturation concentration" refers to the concentration of the estrogen steroid in the core measured in an equilibrated vaginal ring (i.e., when equilibrium of the estrogen steroid is achieved in the vaginal ring).

[0033] Alternatively, the estrogen steroid may be present in the core in particulate form, preferably crystalline form, for the same reasons disclosed for the progesterone steroid. In this way, the stability of both the estrogen steroid and the progesterone steroid is improved, and thus the stability of the vaginal ring according to the present invention is improved.

[0034] When the estrogen steroid is present as particles in the core, the estrogen steroid is preferably 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] Although it is known that the sheath surrounding the drug-loaded core contains the active ingredient at a low concentration (see, for example, WO2013 / 120888), it should be noted that, as claimed in the present invention, it is not known to contain progesterone steroid at a high concentration in the sheath. At a low concentration of the active ingredient, i.e., a concentration well below 10% by weight, it has no effect or only a very limited effect on the release rate of the active ingredient in the core and is therefore not important for the present invention.

[0036] Based on the context of the present invention, a person skilled in the art will understand that by changing the amount / concentration of progesterone steroid in the sheath, by using different grades for the second ethylene-vinyl acetate copolymer, and / or by using different particle sizes or blends of different particle sizes for the progesterone steroid, it is possible to control and / or adjust the diffusion rate through the sheath.

[0037] However, the particles / crystals of progesterone steroid and optionally estrogen steroid preferably have an average particle size of 3 μm to 40 μm, preferably 8 μm to 24 μm, and even more preferably 10 μm to 24 μm. Such particle sizes have been found to provide the desired substantially zero-order release rate over a long period, i.e., for a desired treatment period of at least 14 days, preferably at least 28 days.

[0038] As used herein, the term "crystal" refers to the particles of the active ingredient being arranged in a regular 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. The 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 measuring devices or techniques known to those skilled in the art can also be used, such as, for example, 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. For example, D90 means that when measured by, for example, laser diffraction, dynamic light scattering or sieve analysis, 90% of the particles have a diameter below a given value.

[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, that is, the material is considered to be non-toxic and non-absorbable to patients or animals, and has 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, and the lower the vinyl acetate concentration, the slower the rate at which the active ingredient is released from the copolymer or the rate at which the active ingredient moves through the copolymer.

[0041] The second ethylene-vinyl acetate copolymer has a vinyl acetate content of 20 to 40% by weight, for example 24% by weight, 28% by weight, 33% by weight or 40% by weight. 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 characteristics for the estrogen steroid, the core preferably contains an ethylene-vinyl acetate copolymer having a vinyl acetate content of 26 to 40% by weight, preferably 26% by weight, 33% by weight or 40% by weight.

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

[0044] When a specific vinyl acetate content, for example 20% by weight, is mentioned, this refers to the weight % content provided by the manufacturer. However, since the manufacturer may use different internal analytical methods to determine the vinyl acetate content, the actual vinyl acetate content may vary within a range of 1-2% by the manufacturer. Thus, in the present invention, the vinyl acetate content refers to the vinyl acetate content in the ethylene-vinyl acetate copolymer determined by high-resolution NMR according to standard procedures. The weight % of the vinyl acetate content in the 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. That is, 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 progesterone, etonogestrel, levonorgestrel, D-1-norethindrel, and norethynodrel, preferably levonorgestrel. These steroids can be selected for preventing contraception, or treating some condition (such as vaginal atrophy), or for hormone replacement therapy, such as for symptoms associated with menopause (such as hot flashes).

[0046] The intravaginal ring according to the present invention is adapted to deliver a pharmaceutically effective amount of the steroid. "Pharmaceutically effective" means an amount sufficient to affect the desired physiological or pharmacological change in the subject. This amount varies depending on factors such as the potency of the steroid, the desired physiological or pharmaceutical effect, and the intended duration of treatment. One of ordinary skill in the art would be able to determine a pharmaceutically 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 steroid and the progesterone steroid. Thus, the drug delivery system according to the present invention preferably does not include / is not provided with a sheath / membrane without 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 can preferably be 0.05 - 2 mm, more preferably 0.1 mm - 2 mm, and even more preferably 0.2 mm - 0.6 mm. In certain embodiments, the thickness of the sheath is 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, or 600 μm.

[0049] One of ordinary skill in the art in contact with the present invention would understand that a thinner sheath may have less active ingredient than a thicker sheath, and that the concentration of the progesterone steroid in the sheath should be sufficient to maintain the release of the relevant active ingredient at the desired rate over the desired treatment period. By using grades of ethylene-vinyl acetate copolymer with a higher or lower vinyl acetate content, the thickness of the sheath can be varied while substantially maintaining the same average release rate for the estrogen steroid. For example, if a thicker sheath is desired because it is necessary to accommodate more progesterone steroid 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 mm to 6 mm, and even more preferably approximately 4 mm.

[0051] The dimensions of the vaginal ring can vary depending on the target anatomical structure, the amount of active ingredient to be delivered to the patient, the period over which the active ingredient is to be delivered, the diffusion characteristics of the active ingredient, and other manufacturing considerations. The only requirements are that the vaginal ring be flexible enough to be bent and inserted into the vaginal cavity and rigid enough to withstand the expulsive forces of the vaginal muscle tissue without causing abrasion to the vaginal epithelium. The outer diameter of such a vaginal ring can be, for example, in the range of about 45 mm to about 65 mm, and / or the length of the fiber elements forming the vaginal ring can be 150 to 170 mm, preferably 154 to 160 mm, and can be, for example, about 157 mm.

[0052] In the context of the present invention, the term "vaginal ring" also contemplates ring designs or structures having other shapes, such as polygonal shapes and / or wavy shapes, or structures that are not a complete and / or closed circle / shape.

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

[0054] The core of the preferred embodiment has a cross-sectional diameter of 4 mm and the sheath has a thickness of 600 μm. The diameter of the ring 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, and preferably, a substantially zero-order release rate is achieved. However, the average release rate may be higher than this, for example, up to 200 μg / day, such as 180 μg / day, or about 165 μg / day.

[0056] Furthermore, or alternatively, the average release rate of the progestogen is between 5 mg / day and 10 mg / day over a 28-day treatment period. Since the content of the progestogen in the sheath depletes, the release rate of the progestogen is expected to decrease over the treatment period.

[0057] Those skilled in the art based on this application will understand that combinations of the 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 release rate of the progestogen is 0 mg / day, and in different embodiments, the average release rate of estradiol is 100 μm / day and the average release rate of the progestogen is 5 mg / day, and in a third embodiment, the average release rate of estradiol is 160 μm / day and the average release rate of the progestogen is 8 mg / day, etc.

[0058] In a preferred embodiment according to the present invention, the intravaginal ring does not contain steroids other than the two steroids (i.e., the estrogen steroid and the progesterone steroid), and / or does not comprise additional cores and / or layers (such as a sheath and a membrane). That is, the intravaginal ring according to the present invention consists of one core and one sheath that completely surrounds the 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 manufacturing the intravaginal ring according to the present invention.

[0060] The method comprises a. Prepare a core containing a first ethylene-vinyl acetate copolymer having a vinyl acetate content of 26 to 40% by weight and an estrogen steroid. b. Prepare a sheath containing a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 20 to 40% by weight and at least 10% by weight of a progestogen steroid based on the weight of the sheath. c. Co-extrude the core and the sheath into fibers. d. Obtain fiber elements by cutting the fibers to an appropriate length, and e. Combine the ends of the fiber elements to form a vaginal ring. Including.

[0061] Since the core and the sheath are co-extruded, according to the present invention, a very simple and inexpensive embodiment is provided. However, preferably, the core and the sheath can be formed in another injection molding die or extrusion process. Injection molding dies and extrusion molding are well known to those skilled in the art and will not be discussed further in this application.

[0062] The method preferably further includes a cooling step, in which the prepared fibers or fiber elements are cooled to a temperature of 20°C or lower in order to produce crystals of the steroid in the sheath and optionally in the core. This can be achieved, for example, by placing the fibers in a cooling water bath.

[0063] Without being bound by theory, the inventors believe that the crystals formed by the sheath and optionally the core are caused by the kinetics of recrystallization. When the concentration of the active ingredient in the sheath and optionally the core is relatively high, the concentration of the "seed" crystals becomes relatively high, and thus recrystallization can occur when the fibers are cooled after co-extrusion.

[0064] The cooling step is preferably carried out immediately after step c, that is, as soon as possible from a manufacturing perspective, that is, preferably within 30 minutes from the completion of the fibers in step c.

[0065] The ring is preferably manufactured by welding the fiber ends together with heat without adding further EVA material or adhesive material.

[0066] The present invention will be described in more detail below by describing exemplary embodiments of the intravaginal ring according to the present invention.

Brief Description of the Drawings

[0067]

Figure 1

Figure 2

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Figure 13A

Figure 13B

Figure 14A

Figure 14B

Figure 14C

Figure 15

Figure 16A

Figure 16B

Figure 16C

Figure 17A

Figure 17B

[0068] Figure 1 shows a preferred embodiment of the 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 estrogen steroid 4 and a sheath 5 made of a second ethylene-vinyl acetate copolymer 6 containing a progesterone steroid 7.

[0069] Figures 2 to 17 will be discussed in more detail below with reference to the following examples.

[0070] Example 1 To evaluate the effects of the outer diameter and sheath thickness, the release rates of a series of intravaginal rings were evaluated by computer modeling. In this model, drug diffusion (driven by the concentration gradient within the system and the slow dissolution of progesterone (P4) dispersed in the sheath) is considered, and it is assumed that the receiving medium is a perfect sink. Since the surface area of the system is determined by the cross-sectional diameter of the ring, it is assumed that larger diameter rings will show proportionally more drug release.

[0071] The amount of progesterone present in the ring is determined by the sheath thickness (assuming a uniform / constant concentration of progesterone). The amount of drug substance loaded into the delivery system is an important design parameter. This is because progesterone release should be maintained over the intended period of use, while significant excess should be avoided for economic and environmental reasons.

[0072] The evaluated ring is made of EVA28 and is used for both the core and the sheath. During storage, redistribution of dissolved progesterone and estradiol occurs by an internal diffusion process. The 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 for several weeks depending on the sheath thickness and storage conditions. The estradiol loading listed in Table 1 occurs after equilibration at a uniform concentration of 0.27 wt% within the ring (including sheath and core), which corresponds to the estradiol saturation concentration of EVA28 at 37°C. The thermodynamic equilibrium of the sheath loaded with progesterone in the ring (see Table 1) results in progesterone concentrations of 30 wt% in the sheath and 1.7 wt% in the core.

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

[0074] The release rates of a series of nine rings (with different sheath thicknesses and cross-sectional diameters) are listed in Table 1. It is clear from this table that the release rates of progesterone (P4) and estradiol (E2) scale with the cross-sectional diameter.

[0075] TIFF0007692537000001.tif243170

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

[0077] Figure 4 shows the progesterone release simulation from rings A1 and A3. This simulation explains the early depletion, which occurs when the sheath thickness is insufficient and the progesterone content is insufficient to maintain progesterone release over the intended 28-day use.

[0078] The influence of the cross-sectional diameter on the release characteristics of E2 is shown in Figure 5. Note that the release rates visualized in Figures 4 and 5 are the actual release rates. Therefore, the release at the very early stage of elution, of course, is much higher than the average on the first day, so the burst appears much higher.

[0079] Example 2 To evaluate the influence of estradiol E2 dispersed in the core and the sheath thickness on the release rate, a series of vaginal rings were evaluated by computer modeling.

[0080] The release rates for a series of three rings with different sheath thicknesses are listed in Table 2. It is clear from this table that the release rate of estradiol is scaled by the sheath thickness. Furthermore, the delivery systems (BF1, BF2, and BF3) provide a sustained and high release rate for estradiol even on the 28th day. Changing the sheath thickness had no significant effect on the progesterone release rate.

[0081] TIFF0007692537000002.tif237170

[0082] Figure 6 shows the average daily release from BF1. This ring provides sufficient estradiol over the entire use period (28 days). Increasing the sheath thickness from 400 μm (ring BF1) to 600 μm (ring BF3) results in an approximately 30% decrease in the average daily release (see Figures 2 and 8).

[0083] Figures 7 and 9 show the progesterone release simulation from ring BF1. Even when the drug loading is as high as 35 wt%, early depletion occurs, indicating that the progesterone in the ring is insufficient to maintain sufficient release over the intended 28-day usage period.

[0084] Example 3 To evaluate the effect of estradiol (E2) concentration in the core, the effect of progesterone (P4) concentration in the sheath, and the influence of sheath thickness on the release rate of each of estradiol and progesterone, a series of intravaginal rings (IVRs) were manufactured as follows.

[0085] TIFF0007692537000003.tif78170

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

[0087] TIFF0007692537000004.tif60170

[0088] The ground EVA and APIs were weighed according to the ratios detailed in Table 3. All four batches were mixed using the same mixing protocol. Compounding was carried out using a closely meshing 11 mm twin-screw extruder (Twin-screw extruder Pharma 11 from Thermo scientific). In summary, four batches were compounded according to Table 3 to produce active granules / pellets. For all batches, the compounding set temperature was 90 °C.

[0089] TIFF0007692537000005.tif52170

[0090] To enhance the processing characteristics of the pellets in the co-extrusion process, magnesium stearate (MgSt) was added to all batches. First, 0.1 wt% of MgSt was added to the mixing bag containing the active pellets, and then it was mixed by hand for approximately 3 minutes.

[0091] 5 mm sheath / core fibers were produced using a co-extrusion line equipped with a 5 mm die. The co-extrusion line consists of a single-screw extruder 16 / 25 (D / L) for the sheath (i.e., 16 is the diameter and 25 is the length, and the diameter ratio is D / L) and a single-screw 25 / 25 (D / L) for the core.

[0092] Both the core and the sheath of the produced fibers contain the active ingredient: Furthermore, the sheath thickness was varied for each formulation, and the sheath thickness was set to 200 μm, 300 μm, and 400 μm at a fiber diameter of 5 mm (see Table 5).

[0093] The fiber properties (diameter and sheath thickness) were controlled by the melt pump speeds of extruder 1 (sheath) and extruder 2 (core), and fibers with a diameter of 5 mm were produced with the required sheath thickness. All fibers were extruded at 90 °C to 100 °C. The melt pump speeds were calculated based on the capacity of the pumps. 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] The melt pump volume for the TIFF0007692537000006.tif82170 sheath is 0.6 cm 3 and for the core is 2.4 cm 3 is.

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

[0096] In the case of the AB batch, the progesterone concentration loaded on the sheath is 5 wt%, and during extrusion molding, progesterone is completely dissolved as expected. As a result of internal diffusion, progesterone redistributes throughout the ring, and if early crystallization does not occur, the progesterone concentration in the ring becomes completely uniform when the ring reaches equilibrium.

[0097] For TIFF0007692537000007.tif, the numbers 76170*200, 300, and 400 represent sheath thicknesses of 200 μm, 300 μm, and 400 μm, respectively.

[0098] Optical observation of fibers For each batch AB200, AB300, and AB400, i.e., 0.39 wt% estradiol and 5 wt% progesterone, no distinct boundary was observed between the core and the sheath (see Figure 10), while for other batches, a distinct boundary was observed (see Figures 11 and 12). This is because estradiol and progesterone are dissolved in EVA28 in the sheath and the core, respectively.

[0099] The contrast (i.e., boundary) between the core and the sheath is greatest for each batch AC200, AC300, and AC400 in which estradiol (0.39 wt%) is dissolved and progesterone (33.9 wt%) is loaded as crystals (in contrast to Figure 11).

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

[0101] The observed sheath / core system generally showed a centered / concentred geometry (see Figures 11 and 12).

[0102] The release rates of estradiol and progesterone of the manufactured IVRs are shown in Table 6 (showing estradiol data), Table 7 (showing progesterone data), and the corresponding drawings 13 to 17.

[0103] TIFF0007692537000008.tif243170TIFF0007692537000009.tif243170TIFF0007692537000010.tif243170TIFF0007692537000011.tif243170TIFF0007692537000012.tif243170TIFF0007692537000013.tif243170

[0104] TIFF0007692537000014.tif245170TIFF0007692537000015.tif245170TIFF0007692537000016.tif245170TIFF0007692537000017.tif245170TIFF0007692537000018.tif245170TIFF0007692537000019.tif245170TIFF0007692537000020.tif245170TIFF0007692537000021.tif245170

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

[0106] Release of estradiol and progesterone in the prepared IVRs IVRs (AB batch) containing 0.39 wt% estradiol and 5 wt% progesterone with various sheath thicknesses The release of estradiol and progesterone from IVRs (i.e., AB200, AB300, and AB400) obtained from batches containing 0.39 wt% estradiol and 5 wt% progesterone is shown in FIGS. 13A and 13B.

[0107] As is apparent from the drawings, the release of progesterone increases as the thickness of the sheath increases: in all cases, the daily release is less than 1 mg per day after 10 days.

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

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

[0110] Release of progesterone dependent on the estradiol concentration within the core A comparison of the release rates of progesterone in the sheath, dependent on the concentration of estradiol and the thickness of the sheath, is shown in Figures 14A, 14B and 14C.

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

[0112] However, as can be seen from the data in FIGS. 14A, B, and C, it can also be concluded that progesterone release is not affected if estradiol is present in dissolved form, i.e., at a relatively low estradiol concentration (0.39 wt %), and / or in crystalline form, i.e., at a relatively high estradiol concentration (10 wt %). It should be noted that rings containing crystalline estradiol may also contain estradiol in dissolved form (likely at or near saturation concentration).

[0113] For example, in FIG. 14A, the IVR's AC200 (0.39 wt % estradiol) and DC200 (10 wt % estradiol) have substantially the same progesterone release characteristics, as do the AC300 (0.39 wt % estradiol) and DC300 (10 wt % estradiol) in FIG. 14A, and the AC400 (0.39 wt % estradiol) and DC400 (10 wt % estradiol) in FIG. 14C.

[0114] Effect of Sheath Thickness on Progesterone Release As shown in FIG. 15, increasing the thickness of the sheath enables sustained delivery of progesterone.

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

[0116] Effect of Sheath Thickness on Estradiol Release As is clear from FIGS. 16A, B, and C, the presence of progesterone in the sheath decreases the daily release of estradiol.

[0117] This effect is not so remarkable when the thickness of the sheath is as thin as, for example, 200 μm, such as in the case of AB and AC IVRs where estradiol (0.39% by weight) is mainly dissolved in the core (see Fig. 16A).

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

[0119] In addition to the dissolved progesterone that hinders 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 is clear from Figs. 17A and B, the presence of estradiol in crystalline form, i.e., by the DC batch having 10% by weight of estradiol, enables the sustained release of estradiol from the IVR at a zero-order release rate for 28 days.

[0121] The slightly increased estradiol release after 14 days can be the result of two physical phenomena: the presence of progesterone as crystals in the sheath tends to increase the diffusion length (i.e., decrease the average release rate), and the depletion of crystals in the sheath enables faster diffusion through the holes in the sheath. In this regard, an empty porous matrix (holes) remains in the space that was initially occupied by progesterone, and this matrix can be empty or filled with water by the intrusion of water. This means that the ring is permeated or the crystals are dense near the outer surface of the IVR.

[0122] Therefore, in the space initially occupied by the progesterone steroid, an empty porous matrix remains, which can be filled with water by water intrusion and / or may leave empty holes, thereby providing a free passage for estradiol and thus the desired zero-order release characteristics.

[0123] The increase in the sheath thickness decreases the release rate of estradiol embedded in the core. When the sheath thickness increases to 200 - 400 μm, the average daily release of estradiol on the 24th day decreases from 409.14 μg to 226.64 μg (for DC400 and DC200 respectively).

[0124] When an experiment was conducted using EVA28 (EVA28 wt%), EVA28 acted like a rate-controlling sheath. Similar results are predicted for other preferred EVAs according to the present invention, which are, for example, ethylene-vinyl acetate polymers with a vinyl acetate content of 24 wt%, 33 wt%, or 40 wt%.

[0125] When the core is loaded with 10 wt% of estradiol, the presence of progesterone limits / regulates the release rate of estradiol, resulting in a zero-order release rate for estradiol during the 28-day treatment period.

[0126] Therefore, based on the experimental data, it can be concluded that progesterone crystals loaded in the sheath serve as a rate-controlling sheath for the VA contents tested. Without being bound by theory, it is believed that progesterone functions as a filler and controls the release of estradiol in the core. When the amount of progesterone steroid present in the sheath decreases, the diffusion of water into the sheath becomes easier, 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. Such zero-order release was obtained with the DC batch (10 wt% estradiol in the core, 33.9 wt% progesterone in the sheath) (see Figure 17B).

[0127] By using the intravaginal ring according to the present invention, the inventors have found that for two active ingredients, namely estrogen steroid and progesterone steroid, it is possible to release them independently and optimally without the need for complex assembly of the members and without the need for sophisticated multilayer extrusion techniques.

[0128] Since the design of this intravaginal ring is simple and inexpensive, it can be used equally well privately, as well as in medical or hospital facilities.

[0129] Modifications and combinations of the above principles and designs are pre-intended within the scope of the present invention.

Claims

1. A vaginal ring, wherein the vaginal ring comprises a core (2) containing a first ethylene-vinyl acetate copolymer (3) having a vinyl acetate content of 26 to 40% by weight and an estrogen steroid (4), and a sheath (5) containing a second ethylene-vinyl acetate copolymer (6) having a vinyl acetate content of 20 to 40% by weight and at least 10% by weight of a progesterone steroid (7) based on the weight of the sheath and the sheath is an outer layer of the vaginal ring, the vaginal ring.

2. The vaginal ring according to claim 1, wherein the sheath contains at least 15% by weight, at least 20% by weight, or at least 30% by weight of a progesterone steroid based on the weight of the sheath.

3. The vaginal ring according to claim 1, wherein the sheath contains 40% by weight or less, or 35% by weight or less of a progesterone steroid based on the weight of the sheath.

4. The vaginal ring according to claim 1, wherein the progesterone steroid is dispersed and / or incorporated in the form of particles, for example in the form of crystals, in the second ethylene-vinyl acetate copolymer.

5. The vaginal ring according to claim 1, wherein the estrogen steroid is dissolved in the first ethylene-vinyl acetate copolymer at a concentration not exceeding the saturation concentration of the estrogen steroid at 25°C.

6. The vaginal ring according to claim 1, wherein the estrogen steroid is dispersed and / or incorporated in the form of particles, for example in the form of crystals, in the first ethylene-vinyl acetate copolymer.

7. The vaginal ring according to claim 6, wherein the core contains at least 10% by weight, at least 15% by weight, or at least 20% by weight of an estrogen steroid based on the weight of the core.

8. The vaginal ring according to claim 4, wherein the particles of the progesterone steroid in the second ethylene-vinyl acetate copolymer have a particle size between 3 μm and 40 μm, between 8 μm and 24 μm, or between 10 μm and 24 μm as determined by laser diffraction.

9. The vaginal ring according to claim 6, wherein the particles of the estrogen steroid in the first ethylene-vinyl acetate copolymer have a particle size between 3 μm and 40 μm, between 8 μm and 24 μm, or between 10 μm and 24 μm as determined by laser diffraction.

10. The intravaginal ring according to claim 1, wherein the vinyl acetate content of the first ethylene-vinyl acetate copolymer is 26% by weight, 33% by weight, or 40% by weight.

11. The intravaginal ring according to claim 1, wherein the vinyl acetate content of the second ethylene-vinyl acetate copolymer is 24% by weight, 28% by weight, 33% by weight, or 40% by weight.

12. The intravaginal ring according to claim 1, wherein the estrogen steroid is estradiol.

13. The intravaginal ring according to claim 1, wherein the progesterone steroid is selected from the group consisting of progesterone, etonogestrel, levonorgestrel, d-1-norethindrel, and norethynodrel.

14. The intravaginal ring according to claim 1, wherein the thickness of the sheath is between 0.05 mm and 3 mm, between 0.05 mm and 2 mm, between 0.1 mm and 2 mm, or between 0.1 mm and 0.6 mm.

15. The intravaginal ring according to claim 1, wherein the cross-sectional diameter of the core is between 2 and 8 mm, between 3 mm and 6 mm, or 4 mm to 5 mm.

16. The intravaginal ring according to claim 1, wherein the outer diameter of the intravaginal ring is in the range of 45 mm to 65 mm or approximately 54 mm.

17. A method for manufacturing the intravaginal ring according to any one of claims 1 to 16, comprising: a. preparing a core containing a first ethylene-vinyl acetate copolymer having a vinyl acetate content of 26 to 40% by weight and an estrogen steroid; b. preparing a sheath containing a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 20 to 40% by weight and at least 10% by weight of a progesterone steroid based on the weight of the sheath; c. co-extruding the core and the sheath into fibers; d. obtaining fiber elements by cutting the fibers to an appropriate length; and e. combining the ends of the fiber elements to form an intravaginal ring. A method including the above steps.

18. The method according to claim 17, further comprising a cooling step of cooling the fibers obtained from step c to a temperature of about 20°C to produce at least crystals of the progesterone steroid in the sheath.

19. The intravaginal ring according to any one of claims 1 to 16 for providing a substantially zero-order release rate for the estrogen steroid during a treatment period of at least 28 days.

20. The intravaginal ring according to claim 19, wherein the average release rate of estradiol is from 80 μg / day to 160 μg / day during a treatment period of at least 28 days. **Claim 21** The intravaginal ring according to claim 19, wherein the average release rate of progesterone is from 5 mg / day to 10 mg / day during a treatment period of at least 28 days.

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