EP-4739292-A1 - A THREE-LAYERED INTRAVAGINAL RING

EP4739292A1EP 4739292 A1EP4739292 A1EP 4739292A1EP-4739292-A1

Abstract

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

Inventors

DE GRAAFF, WOUTER
Refaa, Zakariaa

Assignees

Sever Pharma Solutions

Dates

Publication Date: 20260513
Application Date: 20240704

Claims (1)

Claims 1. An three-layered intravaginal ring (1;1’) comprising - a core (2;9) - an intermediate layer (3;10), and - a sheath (6) comprising a second ethylene-vinyl acetate copolymer (7) having a vinyl acetate content from 20 to 40 wt%, and at least 10 wt% of a progestational steroid (8) based on the weight of the sheath, wherein one of the core (9) and intermediate layer (3) comprises a first ethylene-vinyl acetate copolymer (4) having a vinyl acetate content from 26 to 40 wt% and an estrogenic steroid (5), and the other one of the core (2) and intermediate layer (10) is an inactive layer (2;10). 2. A three-layered intravaginal ring according to claim 1, wherein the sheath (6) comprises at least 15 wt% of the progestational steroid (8) based on the weight of the sheath (6), preferably at least 20 wt%, and even more preferred at least 30 wt% and/or wherein the sheath comprises 40 wt% or less of the progestational steroid (8) based on the weight of the sheath, preferably 35 wt% or less. 3. A three-layered intravaginal ring according to claim 1 or 2, wherein the progestational steroid (8) is dispersed and/or incorporated in the second ethylene-vinyl acetate copolymer (7) in the form of particles, such as crystals. 4. A three-layered intravaginal ring according to according to any of the preceding claims, wherein the estrogenic steroid (5) is dispersed and/or incorporated in the first ethylene-vinyl acetate copolymer (4) in the form of particles, e.g. crystals. 5. A three-layered intravaginal ring according to any of the preceding claims, wherein the core (9) or intermediate layer (3) comprises at least 5 wt% of the estrogenic steroid (5) based on the weight of the core or intermediate layer, preferably at least 10 wt%, and even more preferred at least 15 wt%. 6. A three-layered intravaginal ring according to any of the claims 3, 4 or 5 wherein the particles of the progestational steroid (8) and the estrogenic steroid in the second and the first ethylene-vinyl acetate copolymer (7,4), have a particle size of between 1 µm and 40 µm, preferably between 2 µm and 24 µm, and even more preferred between 3 and 10 µm, and even more preferred around 5µm as determined by laser diffraction. 7. A three-layered intravaginal ring according to any of the preceding claims, wherein the estrogenic steroid (5) is estradiol or estriol. 8. A three-layered intravaginal ring according to any of the preceding claims, wherein the progestational steroid (8) is selected from a group consisting of progestogen, progesterone, etonogestrel, levonorgestrel, d-1-norestrel, segesterone, segesteronacetat and norethindrone. 9. A three-layered intravaginal ring according to any of the preceding claims, wherein said intravaginal ring only comprises one estrogenic steroid (5) and one progestational steroid (8). 10. An intravaginal ring according to any of the preceding claims, wherein said intravaginal ring only comprises a single core, a single intermediate layer completely surrounding said core and a single outer sheath completely surrounding said intermediate layer. 11. A three-layered intravaginal ring according to any of the preceding claims, wherein when the intermediate layer (3) comprises the estrogenic steroid (5), said intermediate layer (3) preferably has a thickness from 50 µm to 500 µm, preferably from 80 µm to 400 µm, and even more preferred from 100 µm to 300 µm. 12. A three-layered intravaginal ring according to any of the preceding claims 1 - 10, wherein when the intermediate layer (10) is the inactive layer, said intermediate layer (10) preferably has a thickness from 50 µm to 300 µm, preferably from 50 µm to 200 µm, and even more preferred from 80 µm to 200 µm. 13. A three-layered intravaginal ring according to any of the preceding claims, wherein the cross-sectional diameter of the core (2;9) is from between 2 and 8 mm, more preferably between 3 mm and 6 mm and even more preferably from 4 mm to 5 mm. 14. A three-layered intravaginal ring according to any of the preceding claims, wherein the thickness of the sheath (6) is between 0.05 mm and 1 mm, preferably between 50 µm and 600 µm, more preferred between 100 µm and 500 µm, and even more preferred between 200 µm and 500 µm. 15. A method of manufacturing the three-layered intravaginal ring (1) according to any of the claims 1 – 14, said method comprises a. providing an inactive core (2), b. providing an intermediate layer (3) comprising a first ethylene-vinyl acetate copolymer (4) having a vinyl acetate content from 26 to 40 wt%, and at least 5wt%, preferably at least 10 wt% estrogenic steroid (5) based on the weight of the intermediate layer, and wherein said estrogenic steroid is incorporated into the first ethylene-vinyl acetate copolymer (4) in the form of particles, c. providing a sheath (6) comprising a second ethylene- vinyl acetate copolymer (7) having a vinyl acetate content from 20 to 40 wt%, and at least 10 wt% of an progestational steroid (8) based on the weight of the sheath, wherein said progestational steroid is incorporated into the second ethylene-vinyl acetate copolymer (4) in the form of particles, d. co-extruding the core (2;9), intermediate layer (3;10) and sheath (6) into a fiber, and e. cutting the fiber into an appropriate length thereby providing a fiber element, and f. combining the ends of fiber element to form the three-layered intravaginal ring. 16.A method according to claim 15, wherein step a and b of the method of claim 15 are modified as a’ and b’ respectively: a’. providing an core (9) comprising a first ethylene- vinyl acetate copolymer (4) having a vinyl acetate content from 26 to 40 wt%, and at least 5wt%, preferably at least 10 wt% estrogenic steroid (5) based on the weight of the core, and wherein said estrogenic steroid is incorporated into the first ethylene-vinyl acetate copolymer in the form of particles, and b’. providing an inactive intermediate layer (10). 17.A method according to claim 15 or 16, wherein said method further comprises a cooling step in which the provided fiber from step d. is cooled to a temperature of about 20C in order to provide crystals of the progestational steroid (8) and the estrogenic steroid (5). 18.A method according to claim 17, wherein said cooling step is completed within a period of less than 10 minutes from completion of the fiber in step d, and even more preferred not more than about 2 minutes from completion of the fiber in step d.

Description

A three-layered intravaginal ring. The present invention relates to a three-layered intravaginal ring, and a method of manufacturing said ring. Various types of intravaginal rings (IVRs) have been developed for the controlled and sustained release of active ingredients preferably by diffusion through the surface of the ring. Examples of such devices are the Estring®, Femring®, and Nuvaring®, all of which provide controlled and sustained release of steroid molecules over a prolonged period, e.g. several weeks/months. In addition to preventing undesired pregnancies, the device provides several advantages: its use is controlled by the female; it allows for a better regulated dose of drug without attention by the user; and it avoids the destruction (by the intestine and by first pass through the liver) of an appreciable portion of the daily dosage of the drugs compared to their orally delivered counterparts. These known vaginal rings have been found particularly useful for the release of steroids, whose relatively small molecular size and substantially water-insoluble nature permit effective permeation through the hydrophobic elastomer/polymer, such that therapeutic concentrations may be readily achieved in the body. However, diffusion in polymers is complex and is known to depend on a number of different factors, e.g. temperature, the manufacturing process, the solubility and diffusivity of the drug in the polymer, the surface area of the drug reservoir, the distance the drug must diffuse through the device to reach its surface and the molecular weight of the drug. Consequently, it remains a challenge to understand, predict and control the diffusion of small and large molecules in polymer systems. In this respect, the use of intravaginal rings to deliver drugs requires a design that regulates the release rate so as to reliably provide the user with the appropriate daily dose throughout the lifetime of the device. In reservoir systems, i.e. a drug loaded core surrounded by a non-medicated membrane/sheath, the drug first partitions into the sheath from the reservoir and then diffuses to the other side of the sheath, where it is taken up by the receiving medium. While the reservoir is saturated, a constant concentration gradient of drug is maintained in the membrane, the rate of drug flux is constant, and zero order release is achieved. However, when drug concentration in the reservoir falls, the gradient across the membrane and the release rate of the drug also decreases. Furthermore, reservoir systems can be difficult to fabricate reliably, and pinhole defects and cracks in the sheath surrounding the reservoir, can lead to dose dumping, i.e. unintended, rapid drug release over a short period of time. Simultaneous drug delivery/release finds application in a number of different areas. However, the placement of a blend of drugs in a single intravaginal ring in a proportion equal to the desired delivery rate ratio will almost never achieve the desired result. In many cases, the drugs will not diffuse together through the surface or membrane at the same ratio, as they exist in the blend. The ratio would instead be dependent on the inherent ratio of the normalized permeation rates for the drugs through e.g. a rate-controlling membrane. Flexibility would therefore be limited to the selection of suitable polymer candidates for the sheath. Accordingly, the range of, and degree of control over, the delivery rate ratio, is extremely limited. Of course the need for maintaining a specified delivery rate ratio can be met by using a separate intravaginal ring for each drug. However, this is clearly undesirable, since the presence of two or more intravaginal rings will compound the disruption which even a single ring might create in the normal physiological activity of an animal or human. In addition, if one intravaginal ring malfunctions, the desired delivery ratio will be lost. Further, complete therapy in a single intravaginal ring is more acceptable to patients and more efficient to insert and remove. Adjustment of a specified delivery rate can also be met by two or multi-compartments intravaginal rings, and ring bodies containing drug release capsules. The industrial scale manufacturing of such rings is however complex and expensive. A further problem with the known intravaginal rings arranged for releasing more than one drug is that such rings usually show sub-optimum release patterns for the different drugs, whereas it is generally preferred that all drugs are released in a controlled rate during a specified duration of time. Thus, there is a demand for a novel intravaginal ring arranged for releasing two active ingredients/drugs in a controlled manner and in the correct ratio, and a method for manufacturing the system that is simple and inexpensive. Thus, it is a first aspect of the present invention to provide a three-layered intravaginal ring, which can be loaded with both an estrogenic steroid and a progestatio