WO2021099504A1 - An intravaginal device for a cow - Google Patents

Abstract

An intravaginal device (200, 300, 400) for a cow, comprises a core (100) made of a plastic material and a membrane (202, 302, 402) that at least partially encases the core. The membrane comprises a therapeutically active agent, and is able to release the therapeutically active agent within a period of 6-10 days. The core is in the form of a closed continuous structure formed of a rod comprising a first part (102), a second part (104), a third part (106), and a fourth part (108), which are connected via their ends such that they form an X-shape. Each of the parts of the core comprises a first curved portion (114), a second straight portion (116), a third curved portion (118), a fourth straight portion (120), and a fifth curved portion (122).

Description

AN INTRAVAGINAL DEVICE FOR A COW

TECHNICAL FIELD

The present disclosure relates generally to an intravaginal device; and more specifically, to an intravaginal device for a cow.

BACKGROUND

Intravaginal devices are widely used for cattle for controlled release of a drug in both estrus synchronization (zootechnical use) and anoestrus cow (therapeutic use) programs. In order to produce milk, dairy cow usually need to regularly give birth to a calf. Thus, the fertility of dairy cows has an immense effect on the productivity of a dairy farm. Traditionally, the farmers observe a cow's behaviour during daily routine activities to assess the correct time for artificial insemination. For example, cows in heat (i.e. in sexually receptive period) exhibit restless behaviour such as tendency to mount other animals, allowing themselves to be mounted, bellowing etc. However, in recent years the herd size in commercial dairy farms has grown rapidly, making visual observation of cow's behaviour and heat a challenging, time consuming task. This has led to the development of different hormonal programs aiming for estrus synchronization, which in turn allows for a timed artificial insemination of larger groups of animals, and thus reduce the time and labour used for estrus detection etc. Current synchronization programs require manifold handling of cows, are time-consuming and complex, thereby increasing the chances of treatment errors. It has been proven in literature, that the inclusion of a progesterone releasing, intravaginal device in these synchronization programs will increase the conception rate. Currently, there are many technical problems associated with conventional intravaginal devices. Some of the major technical problems include inadequate drug release characteristics. Furthermore, the conventional devices typically contain too much of the drug, and are thus not optimised properly. Often the conventional intravaginal devices are not disposed of properly. They usually contain a residual amount of the drug leading to a wastage of drug (e.g. existing commercial devices may have even up to 50 % of the initial load after use) and a potential hazard for the environment. It is well known that for that reason existing intravaginal devices are sometimes used off-label repeatedly with still satisfying results. Other problems include low cow-comfort during the use of the conventional intravaginal devices.

Recent studies have shown that the existing intravaginal devices, which often have been launched decades ago (30 - 40 years ago), do no longer meet the demands of modern, high yielding dairy cows. High producing dairy cows metabolize progesterone much faster than e.g. non-lactating heifers or cows of beef breeds. Indeed, a higher milk yield comes along with a higher feed intake and thus a higher blood flow though the intestine and the portal vein of the liver. In the latter the steroid hormones are metabolized. Furthermore, steroid hormones are lipophilic and therefore accumulate in milk. With a higher milk yield more steroid hormones are lost in the milk (Sangsritavong et al., 2004; Sartori et al., 2005; Wolfenson et al., 2005).

Therefore, some veterinarians and dairy producers tend to (off-labelly) use two devices at the same time, which restores the pharmaceutical effect in these high yielding animals (Bisinotto et al., 2013; Bisinotto et al, 2015a; Bisionotto et al., 2015b). Therefore, in light of the foregoing discussion, there exists a need to overcome the aforementioned drawbacks associated with conventional intravaginal devices used for cows.

SUMMARY The present disclosure seeks to provide an intravaginal device for a cow. The present disclosure seeks to provide a solution to the existing problem of inadequate drug release characteristics resulting in a need of larger amount of drug load in a conventional intravaginal device.

An aim of the present disclosure is to provide a solution that overcomes at least partially the problems encountered in prior art, and provides an improved intravaginal device that increases drug release characteristics resulting in increased absorption of progesterone with relatively smaller amount of drug load as compared to existing intravaginal devices, and ensures adequate retention of the conventional intravaginal device while maintaining local tolerance in the insertion state.

In one aspect, an embodiment of the present disclosure provides an intravaginal device for a cow, comprising

- a core made of a plastic material;

- a membrane at least partially encasing said core, the membrane comprising a therapeutically active agent and being able to release the therapeutically active agent within a period of 6-10 days; wherein

- the core is in the form of a closed continuous structure formed of a rod comprising - a first part having a first end and a second end;

- a second part having a first end and a second end;

- a third part having a first end and a second end;

- a fourth part having a first end and a second end; - the second part being a mirror image of the first part with respect to a first plane;

- the third part being a mirror image of the second part with respect to a second plane, the second plane being perpendicular to the first plane;

- the fourth part being a mirror image of the third part with respect to the first plane;

- the first part being a mirror image of the fourth part with respect to the second plane; - the first, second, third and fourth parts being connected via their ends such that they form an X-shape on a third plane, wherein the third plane is perpendicular to the first plane and to the second plane;

- the first and second plane intersecting at a centre point of the X- shape; and each of the parts of the core comprising

- a first curved portion having a radius of curvature R1 of 40-60 mm;

- a second straight portion;

- a third curved portion having a radius of curvature R3 of 2-9 mm; - a fourth straight portion; and

- a fifth curved portion having a radius of curvature R4 of 10-30 mm; and wherein a compression strength of the intravaginal device, when compressing at constant rate of 600 mm/min with a Universal Mechanical Testing apparatus, in a direction perpendicular to the first plane is - 10-40 N when the device is compressed to 25 % of its width in the direction of compression;

- 25-50 N when the device is compressed to 50 % of its width in the direction of compression, provided it is higher than the compression strength at 25 % of its width in the direction of compression. Embodiments of the present disclosure substantially eliminate or at least partially address the aforementioned problems in the prior art, and enable the disclosed intravaginal device to have adequate surface contact with the vaginal walls of a cow that allows increased absorption of the drug (i.e. the therapeutically active agent) even with relatively smaller amount of drug load present in the intravaginal device, and almost all drug content is released within the time of use, so that a minimum amount of the therapeutically active agent is discarded after use, and thus much less residues are released and the environmental safety pattern is improved.

Additional aspects, advantages, features and objects of the present disclosure would be made apparent from the drawings and the detailed description of the illustrative embodiments construed in conjunction with the appended claims that follow. It will be appreciated that features of the present disclosure are susceptible to being combined in various combinations without departing from the scope of the present disclosure as defined by the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS The summary above, as well as the following detailed description of illustrative embodiments, is better understood when read in conjunction with the appended drawings. For the purpose of illustrating the present disclosure, exemplary constructions of the disclosure are shown in the drawings. However, the present disclosure is not limited to specific methods and instrumentalities disclosed herein. Moreover, those skilled in the art will understand that the drawings are not to scale. Wherever possible, like elements have been indicated by identical numbers. Embodiments of the present disclosure will now be described, by way of example only, with reference to the following diagrams wherein:

FIG. 1A is a schematic view of a core of an intravaginal device, in accordance with an embodiment of the present disclosure; FIG. IB is a perspective view of the core of FIG. 1A of an intravaginal device, in accordance with an embodiment of the present disclosure;

FIG. 2 is a schematic view of an intravaginal device, in accordance with an embodiment of the present disclosure; FIG. 3 is a schematic view of an intravaginal device, in accordance with another embodiment of the present disclosure;

FIG. 4A is a schematic view of an intravaginal device, in accordance with yet another embodiment of the present disclosure;

FIG. 4B illustrates the intravaginal device of FIG. 4A in a folded state, in accordance with an embodiment of the present disclosure; and

FIGs. 5A, 5B and 5C are schematic views that illustrate various comparative forms of intravaginal devices used in tests.

FIGs. 6 and 7 illustrate some results of the Experiments.

In the accompanying drawings, a number relates to an item identified by a line linking the number to the item. When a number is accompanied by an associated arrow, the number is used to identify a general item at which the arrow is pointing. DETAILED DESCRIPTION OF EMBODIMENTS

The following detailed description illustrates embodiments of the present disclosure and ways in which they can be implemented. Although some modes of carrying out the present disclosure have been disclosed, those skilled in the art would recognize that other embodiments for carrying out or practising the present disclosure are also possible.

In one aspect, an embodiment of the present disclosure provides an intravaginal device for a cow, comprising

- a core made of a plastic material; - a membrane at least partially encasing said core, the membrane comprising a therapeutically active agent and being able to release the therapeutically active agent within a period of 6-10 days; wherein

- the core is in the form of a closed continuous structure formed of a rod comprising

- a first part having a first end and a second end;

- a second part having a first end and a second end;

- a third part having a first end and a second end;

- a fourth part having a first end and a second end; - the second part being a mirror image of the first part with respect to a first plane;

- the third part being a mirror image of the second part with respect to a second plane, the second plane being perpendicular to the first plane; - the fourth part being a mirror image of the third part with respect to the first plane;

- the first part being a mirror image of the fourth part with respect to the second plane; - the first, second, third and fourth parts being connected via their ends such that they form an X-shape on a third plane, wherein the third plane is perpendicular to the first plane and to the second plane;

- the first and second plane intersecting at a centre point of the X- shape; and each of the parts of the core comprising

- a first curved portion having a radius of curvature R1 of 40-60 mm;

- a second straight portion;

- a third curved portion having a radius of curvature R3 of 2-9 mm;

- a fourth straight portion; and

- a fifth curved portion having a radius of curvature R4 of 10-30 mm; and wherein a compression strength of the intravaginal device, when compressing at constant rate of 600 mm/min with a Universal Mechanical Testing apparatus, in a direction perpendicular to the first plane is

- 10-40 N when the device is compressed to 25 % of its width in the direction of compression;

- 25-50 N when the device is compressed to 50 % of its width in the direction of compression, provided it is higher than the compression strength at 25 % of its width in the direction of compression.

The present disclosure thus provides the aforementioned intravaginal device that is easy-to-use, reliable and better tolerated for a cow. The core is in the form of a closed continuous structure and the first, second, third and fourth parts of the core are connected via their ends such that they form an X-shape, where the membrane comprising the therapeutically active agent at least partially encases the core. This X- shape of the core ensures that the intravaginal device is in sufficient surface contact with the vaginal walls of cow to allow maximum absorption of progesterone while maintaining comfort (or at least a minimum discomfort) for the cow as well as excellent retention for a given time period, for example, about 6-10 days. The adequate surface contact with the vaginal walls of cow allows release of more progesterone while having a smaller relative drug load (e.g. progesterone content of the device is relatively reduced). The use of the intravaginal device increases conception rate of timed artificial insemination (TAI) protocols, when compared to synchronization programmes including injections.

The membrane at least partially encases said core and the membrane comprises the therapeutically active agent. The membrane may encase the core entirely. In an alternative embodiment disclosed below, the membrane may cover the area left inside the closed continuous structure in X-shape of the core, either from one side or from both sides of the X- shape. In this embodiment, the surface area of the membrane is significantly increased, which may influence the release of the drug (depending on the drug load in the membrane). Other alternatives for the membrane are also discussed below, all aiming at giving more options on the drug release profile and release speed.

The intravaginal device enables at least almost all drug content to be released within the time of use, so that a minimum amount of the therapeutically active agent is discarded. In other words, the intravaginal device thus prevents wastage of drug and avoids the risk of any potential harm to environment at disposal of the intravaginal device after use. Moreover, the intravaginal device is cost-effective, as the number of work steps, injections and treatments typically required for successful artificial insemination thereafter are reduced by use of the intravaginal device. Furthermore, the intravaginal device enables a desired progesterone release for 6-10 days, may maintain a target progesterone plasma level of approximately 5 nanogram per millilitre (ng/mL) or more, and may ensure rapid decrease in progesterone plasma levels at the end of the release period. Indeed, the present device allows tailoring of the release profile, for example with a significant burst right after insertion and either a constant or decreasing release thereafter.

The X-shaped structure of the intravaginal device not only improves cow comfort but also reduces accumulation of pus or other discharge and inflammation in response to the use of the disclosed intravaginal device. Furthermore, the use of the present intravaginal device increases the overall conception rates in cows and also reduces the calving interval.

The aforementioned intravaginal device is a single use device, and ensures no re-use of the intravaginal device in another animal as almost all drug content is released within the time of use. The intravaginal device is designed for easy handling even with a single hand. The intravaginal device works equally when held either with a right hand or a left hand. It is to be understood by a person of ordinary skill in the art that although the term "cow" is used throughout the present disclosure, the term "cow" covers both cow and heifer. Moreover, optionally, by a suitable modification in the size (i.e. cross-sectional dimensions) of the intravaginal device, the intravaginal device may be used for female buffalo or other dairy animals.

The intravaginal device has a compression strength, measured by compressing at constant rate of 600 mm/min with a Universal Mechanical Testing apparatus, in a direction perpendicular to the first plane, that is

- 10-40 N when the device is compressed to 25 % of its width in the direction of compression;

- 25-50 N when the device is compressed to 50 % of its width in the direction of compression, provided it is higher than the compression strength at 25 % of its width in the direction of compression.

The compression strength required to compress the device in the direction it is compressed when inserted into the cow's vagina thus follows a certain function, which is close to linear (as shown below in connection with the Experimental part). Indeed, it was found out that the compression strength in this given direction of other forms as well as of commercial devices follows a different curve, and typically follows a logarithmic growth. It is believed that the particular compression behaviour makes the present device better tolerated by the cows, as the device, once released in the vagina, does not return to its original shape in any sharp manner. For the measurement of the required strength, the device is arranged in the Universal Mechanical Testing apparatus by using suitable sized plates and arranged the device in between two plates, with a very small initial compression strength, which is sufficient to hold the device in place before the actual testing.

The compression strength or strength required to compress the device to 25 % of its width can be for example from 10, 15, 20, 25, 30 or 35 N up to 15, 20, 25, 30, 35 or 40 N. The respective strength to compress the device to 50 % of its width can be for example from 25, 30, 35, 40 or 45 N up to 30, 35, 40, 45 or 50 N, provided it is higher than the strength required to compress the device to 25 % of its width.

The aforementioned intravaginal device comprises a core made of a plastic material. The plastic material may for example have a tensile strength of 35-55 N/mrn^ measured according to ISO 527-1:2012 and a flexural modulus of 900-1700 N/mrn^ measured according to DIN EN ISO 178:2019. A typical flexural strength is 30-180 MPa, as measured according to ASTM D790-17. The core acts as a supporting frame structure to provide a sufficient strength to the intravaginal device so that the intravaginal device is stable in the vagina of a cow when in use. According to an embodiment, the plastic material from which the core is fabricated is a medical-grade plastic material and is employable for a single use for hygienic purpose. Optionally, the core is fabricated from a combination of the plastic material and a filler, such as silica or short glass fibres.

The material of the core is selected such that the core is pliable, for example by hand. The core provides flexibility to the intravaginal device so that the intravaginal device is easily foldable for simple insertion purpose. The intravaginal device is easy-to-use and inserted in the vagina of a cow optionally by one hand (e.g. by a farmer himself or a veterinary professional). Alternatively, for reasons of convenience, an inserter, such as a simple syringe-type inserter, is optionally used to insert the intravaginal device. The core returns to its original shape once inserted to the vagina of the cow.

According to an embodiment, the core is made of a material selected from a group consisting of polyethylene, polypropylene, polyamide, polyether ether ketone, ethyl vinyl acetate, polycarbonate and thermoplastic polyurethane. Optionally, the core may partially comprise glass fibre or silica. In an example, the core is a drug-free elastomer core (e.g. made of silicone elastomer). The fabrication material of the core provides the required resilience to the intravaginal device while maintaining comfort in the insertion state and during removal. The resilience of the frame prevents expulsion of the intravaginal device out of the vagina and displacement inside the vagina due to contractions, as the flexible core balances out the stress caused by the contractions. In an example, the core may be fabricated using a three-dimensional printing process (i.e. a process in which a 3D object is built from a computer-aided design model) or injection moulding.

The core is in the form of a closed continuous structure formed of a rod. The closed continuous structure of the core represents a four-armed starfish in shape. Specifically, the core has an X-shaped structure. The extremities (e.g. end of arms of the branches towards the centre point of the X-shape) of the core are curved inwards towards the centre of the core (e.g. like an inverted "U"). Preferably, the rod forming the core has a smooth structure. Beneficially, the X-shaped core facilitates easy insertion and ensures adequate retention of the intravaginal device inside the vagina of the cow.

The core comprises a first part having a first end and a second end, a second part having a first end and a second end, a third part having a first end and a second end, and a fourth part having a first end and a second end. Optionally, each of the first, second, third, and fourth parts of the core has a bell-curve like shape with the peak of the curve represented as inverted "U". The first end and the second end are opposite ends of each of the first, second, third and fourth parts of the X-shaped core. The second part is a mirror image of the first part with respect to a first plane. In an example, the first plane may be an imaginary vertical plane that bisects the first part and the fourth part from the second part and the third part. The third part is a mirror image of the second part with respect to a second plane, the second plane being perpendicular to the first plane. The fourth part is a mirror image of the third part with respect to the first plane. The first part is a mirror image of the fourth part with respect to the second plane. In an example, the second plane may be an imaginary horizontal plane that is perpendicular to the imaginary vertical plane (i.e. the first plane). The second plane bisects the first part and the second part from the third part and the fourth part. The first, second, third and fourth parts are connected via their ends such that they form an X-shape on a third plane, wherein the third plane is perpendicular to the first plane and to the second plane. The first and second plane intersect at a centre point of the X-shape. The first ends and the second ends of the first, second, third and fourth parts are directed inwards towards the centre point of the X-shaped core. The second end of the first part is connected (or conjoined) to the first end of the second part, the second end of second part is connected to the first end of the third part, the second end of third part is connected to the first end of the fourth part, and the second end of fourth part is connected to the first end of the first part. In an example, the third plane may be perpendicular to the imaginary vertical plane and the imaginary horizontal plane. For example, when the intravaginal device is placed on a flat table, the X-shape is clearly visible when viewing from above the table.

Furthermore, each of the parts of the core comprises:

- a first curved portion having a radius of curvature R1 of 40-60 mm;

- a second straight portion;

- a third curved portion having a radius of curvature R3 of 2-9 mm; - a fourth straight portion; and

- a fifth curved portion having a radius of curvature R4 of 10-30 mm.

Each of the first, second, third and fourth parts of the X-shaped core is a continuous and smooth structure formed of multiple curved and straight portions. The curved portions, such as the first, third and fifth curved portions and the straight portions, such as the second and fourth straight portions enable each of the first, second, third and fourth parts of the core to bend at specific points (or regions) and straighten at other points respectively to result in a defined shape of the first, second, third and fourth parts that are connected to form the continuous X-shaped core. According to an embodiment, the radius of curvature R1 is 45-55 mm. In an example, the radius of curvature R1 may be from 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58 or 59 mm up to 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 mm. According to an embodiment, the radius of curvature R3 is 3- 7 mm. In an example, the radius of curvature R3 may be from 2, 3, 4, 5, 6, 7 or 8 mm up to 3, 4, 5, 6, 7, 8 or 9 mm. According to an embodiment, the radius of curvature R4 is 15-25 mm. In an example, the radius of curvature R4 may be from 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 28 or 29 mm up to 11, 12, 13, 14, 15, 16, 17,

18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 28, 29 or 30 mm.

According to an embodiment, a distance between the third curved portion of the first part and the third curved portion of the second part is 80-120 mm, and a distance between the third curved portion of the first part and the third curved portion of the fourth part is 100-140 mm. In an example, the distance between the third curved portion of the first part and the third curved portion of the second part may be from 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118 or 119 mm up to 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,

93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 or 120 mm. The distance between the third curved portion of the first part and the third curved portion of the fourth part may be from 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118,

119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,

133, 134, 135, 136, 137, 138 or 139 mm up to 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119,

120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139 or 140 mm.

According to an embodiment, the rod forming the core has a largest cross-sectional dimension of 6-12 mm. In an example, the cross-sectional dimension may be from 6, 7, 8, 9, 10 or 11 mm up to 7, 8, 9, 10, 11 or 12 mm. The outside of the core between the third curved portions of two successive parts (of the first, second, third, and fourth parts) forms a concave structure. Similarly, inside of the core between the third curved portions of two successive parts (of the first, second, third, and fourth parts) forms a convex structure. In an example, specifically, the outside of the core from the second straight portion of the first part to the second straight portion of the fourth part forms a concave structure. The outside of the core from the second straight portion of the second part to the second straight portion of the third part forms a concave structure.

According to an embodiment, a form of the cross-section of the rod forming the core is selected from a group consisting of a circle, an ellipse and a stadium. Beneficially, a smooth cross-section and small diameter of the rod facilitate frictionless and nearly painless insertion of the intravaginal device into and out of the vagina, and minimises any risk of perforation of the vaginal walls of the cow. The aforementioned intravaginal device further comprises a membrane at least partially encasing said core, the membrane comprising a therapeutically active agent and being able to release the therapeutically active agent within a period of 6-10 days. The membrane provides the intravaginal device with a capability of controlled and constant release of the therapeutically active agent for 6-10 days. Optionally, the intravaginal device releases of the therapeutically active agent via the membrane leading to a target plasma levels of the therapeutically active agent (e.g. progesterone) of approximately 5 ng/ml. In an example, beneficially, the plasma concentration of the therapeutically active agent in the initial 1-4 days of the 6-10 days period may be highest (e.g. in the range of ³ 5 ng/ml, such as 5-7 ng/ml) and then gradually decline slightly to approximately ³ 2 ng/ml, such as 2-5 ng/ml, for the remaining period of up to maximum 10 days. The membrane is uniform and essentially non-porous (i.e. no through-holes). In other words, the membrane is semi-permeable to allow release of the therapeutically active agent via the membrane. In an embodiment, the membrane completely encases the core as a coating film formed around the rod that forms the core of the intravaginal device. In this embodiment, the membrane may be arranged on the core before the core is formed into the closed X-shape. The cross-sectional dimension of the intravaginal device is slightly larger than the cross-sectional dimension of the core as the membrane surrounds the core.

According to an embodiment, the membrane has a thickness of 0.5-2 mm. In an example, the thickness of the membrane may be from 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7 or 1.9 mm up to 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9 or 2 mm. In an example, if the diameter (or cross-sectional dimension) of the core is dl, and the diameter of the intravaginal device having both the core and the membrane surrounding the core is d2, then the thickness of the membrane is typically (d2-dl)/2.

According to an embodiment, the membrane is prepared by mixing the therapeutically active agent (e.g. progesterone) in a silicone elastomer (e.g. poly(dimethylsiloxane)) and pressing this mixture in a thin sheet. The thin sheet is then rolled on top of the core to as a coating film to encase the core and subsequently cured in an oven. In an example, the curing is performed for 2 hours at 115 °C. It is to be understood by a person of ordinary skill in the art that the curing duration and temperate is exemplary and different curing duration and temperature may be used without limiting the scope of the disclosure. For example, depending on material used to fabricate the core and the membrane, the curing duration and temperature may vary accordingly.

In an example, the membrane with the therapeutically active agent is injection moulded, dip coated or extruded so as to encase the core. Injection moulding process manufactures the membrane with the therapeutically active agent by injecting molten materials into a mould subjected to high heat and pressure conditions. The dip coating method includes any of an immersion, deposition or evaporation techniques to coat the core with the membrane. Beneficially, dip coating techniques do not result in altering the therapeutically active agent's properties or functions. In yet another embodiment, the membrane may be allowed to swell in a solvent, pulled over the core, wherein it tightens when the solvent evaporates.

According to an embodiment, the membrane is made of a material selected from a group consisting of poly(dimethyl silicone), siloxane based elastomer, a thermoplastic polyurethane, a thermoplastic polyurethane elastomer, ethyl vinyl acetate, a polyolefin-based elastomer, a silicone containing thermoplastic, polyurethane, polylactic acid and polycaprolactone. Optionally, the membrane is made of ethylene-vinyl acetate.

According to an embodiment, the therapeutically active agent is progesterone. Optionally, the therapeutically active agent is selected from a group consisting of progesterone, gonadotropin-releasing hormones, prostaglandine-F2a and nonsteroidal anti-inflammatory drugs. Also, analogues of gonadotropin-releasing hormones and prostaglandine-F2a may be used.

According to an embodiment, the membrane is arranged to extend outside the X-shape of the core to a distance of up to 60 mm. In an example, the membrane may be arranged to extend outside the X-shape of the core from 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 mm up to 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60 mm. According to another embodiment, the membrane is additionally or alternatively arranged over a surface formed by the X-shape of the core. Indeed, a closed area is formed by the X-shape of the core. The membrane may extend over the closed area when arranged over the rod forming the X-shaped core. These embodiments increase the surface area of the membrane significantly, which may allow more precise tailoring of the release profile of the therapeutically active agent. According to an embodiment, the intravaginal device is a hairy X-shaped device. This means that in either of the above embodiments (the membrane covers the inner area of the X-shape and/or extends outside the X-shape), the membrane free from contact with the core comprises slits and/or fringes. Thus, in addition to the coating film formed around the rod, a portion of the membrane is free from contact with the core and comprises slits and/and fringes. By slits are meant typically rectilinear openings where both ends of the slit are closed, i.e. the membrane is uniform at both ends of the slits. The fringes are formed when the portion of the membrane is cut to slits at defined intervals, i.e. at one end of the slit, the membrane is not uniform. In an example, in addition to the coating film formed around the rod, a first portion of the membrane extends inwards within a closed area formed by the X-shape of the core and a second portion of the membrane extends from outside the X-shape of the core. In such embodiment, the first portion and the second portion of the membrane is free from contact from the core but is attached to the coating film formed around the rod. Both the first portion and the second portion of the membrane may be in the form of fringes to increase the surface contact of the membrane to vaginal walls of the cow and reduce the accumulation of puss on the intravaginal device. The length of the fringes is less at the extremities and highest at the first end and the second end of each part of the first, second, third, and fourth parts. Optionally, the fringes are formed when the membrane is cut to slits at defined intervals, for example, at 5 mm intervals (or width). The fringes that results from such slits are strong enough so that no material is left behind when the intravaginal device is removed. The membrane in the above embodiments may be made as one layer, or it may comprise two or more layers. For example, the rod may be first coated with the membrane, and thereafter a second layer of the membrane is arranged on the device. Alternatively, two layers of membrane may be arranged on two sides of the device, and be in contact in the middle.

Optionally, a removal string is attached at one or more points of the intravaginal device such that the device folds at the time of removal from the vagina of the cow. The removal string is used to remove the intravaginal device after use, i.e. at the end of a wearing period (typically about 6-10 days after insertion). In an implementation, the removal strings are attached at three points (or four points) on the intravaginal device for easy folding at the time of removal from the vagina of the cow.

According to another embodiment, the intravaginal device is devoid of fringes and slits. In this embodiment, the intravaginal device comprises the membrane that encases the core as a coating film formed around the rod that forms the core. In addition to the coating film formed around the rod that forms the core, a portion of the membrane is extended inwards within a closed area formed by the X-shape of the core. Optionally, this portion of the membrane within the closed area (e.g. middle portion of the core) formed by the X-shape of the core is devoid of fringes and slits and is provided to increase rigidity as well as increase the surface area of the membrane containing the therapeutically active agent.

According to yet another embodiment, the intravaginal device is devoid of fringes and slits and comprises the membrane that only encases the core. For example, the membrane is formed as a coating film around the rod that forms the core and no other extension of the membrane in the form of fringes is provided. DETAILED DESCRIPTION OF THE DRAWINGS

Referring to FIG. 1A, there is shown a schematic view of a core 100 of an intravaginal device, in accordance with an embodiment of the present disclosure. The core 100 is in the form of a closed continuous structure formed of a rod. The core 100 comprises a first part 102 having a first end 102a and a second end 102b. The core 100 further comprises a second part 104 having a first end 104a and a second end 104b, a third part 106 having a first end 106a and a second end 106b, and a fourth part 108 having a first end 108a and a second end 108b. The second part 104 is a mirror image of the first part 102 with respect to a first plane 110A. The third part 106 is a mirror image of the second part 104 with respect to a second plane HOB, where the second plane is perpendicular to the first plane 110A. The fourth part 108 is a mirror image of the third part 106 with respect to the first plane 110A. Moreover, the first part 102 is a mirror image of the fourth part 108 with respect to the second plane HOB. The first part 102, the second part 104, the third part 106, and the fourth part 108 are connected via their ends such that they form an X-shape on a third plane (plane of the paper). The third plane is perpendicular to the first plane 110A and to the second plane HOB. The first plane 110A and the second plane HOB intersect at a centre point 112 of the X-shape of the core 100.

Furthermore, each of the parts of the core 100 comprises a first curved portion 114 having a radius of curvature Rl, a second straight portion 116, a third curved portion 118 having a radius of curvature R3, a fourth straight portion 120, and a fifth curved portion 122 having a radius of curvature R4. In this embodiment, a distance D1 between the third curved portion 118 of the first part 102 and the third curved portion of the second part 104 is approximately 106 mm and a distance D2 between the third curved portion of the first part 102 and the third curved portion of the fourth part 108 is approximately 116 mm.

Referring to FIG. IB, there is shown a perspective view of the core 100 of FIG. 1A of an intravaginal device, in accordance with an embodiment of the present disclosure. As shown, the core 100 is in the form of a closed continuous structure formed of a rod 124 and has an X-shape. Furthermore, the shape is essentially flat.

Referring to FIG. 2, there is shown a schematic view of an intravaginal device 200, in accordance with an embodiment of the present disclosure. The intravaginal device 200 comprises a membrane 202. The membrane 202 comprises a therapeutically active agent. In this embodiment, the membrane 202 encases the core 100 as a coating film formed around the rod that forms the core 100. In addition to the coating film formed around the rod, a portion of the membrane 202 is free from contact with the core 100 and comprises slits 206 and fringes 208 which are formed when the portion of the membrane 202 is cut to the slits 206 at defined intervals, as shown.

Referring to FIG. 3, there is shown a schematic view of an intravaginal device 300, in accordance with another embodiment of the present disclosure. The intravaginal device 300 comprises a membrane 302 that encases the core 100. In this embodiment, the intravaginal device 300 further comprises a portion 304 of the membrane 302 that is extended inwards within a closed area 306 formed by the X-shape of the core 100. The portion 304 of the membrane 302 is devoid of fringes and slits. Referring to FIG. 4A, there is shown a schematic view of an intravaginal device 400, in accordance with yet another embodiment of the present disclosure. In this embodiment, the intravaginal device 400 comprises a membrane 402 that only encases the core 100 and is devoid of fringes and slits.

Referring to FIG. 4B, there is shown the intravaginal device 400 in a folded state, in accordance with an embodiment of the present disclosure. As shown, the intravaginal device 400 is pliable and is folded by one hand for insertion purpose in the vagina of a cow. The direction of compression is also visible in this FIG.

FIGs. 5A, 5B and 5C illustrate various comparative forms of intravaginal devices used in tests, as explained below in the Experimental part, the arrows in FIGs. 5A and 5B showing the direction of compression. FIGs. 6 and 7 illustrate some results of the experiments, and are explained in more detail below in the Experimental part.

Modifications to embodiments of the present disclosure described in the foregoing are possible without departing from the scope of the present disclosure as defined by the accompanying claims. Expressions such as "including", "comprising", "incorporating", "have", "is" used to describe and claim the present disclosure are intended to be construed in a non^¬ exclusive manner, namely allowing for items, components or elements not explicitly described also to be present. Reference to the singular is also to be construed to relate to the plural.

EXPERIMENTAL PART

The present intravaginal device is the result of extensive studies with respect to the form of the device. Indeed, various forms of the device were tested with cows, i.e. in vivo. Furthermore, the release profile of the device was tested in vivo. Testing of the various forms for the device

Several different ring sizes were made from poly(dimethyl siloxane) (PDMS). The material used in the experiments was 70001 silicone elastomer filled with silica from Dow. The rings were made of a strand having a diameter of 8, 10 or 13 mm, and each strand was used to manufacture a ring of a diameter of 115 mm and of 140 mm.

The prepared rings were then tested in retention and local tolerance studies in cattle. First, the smallest and largest ring sizes were tested in heifers, and after that the 115 mm ring diameter samples were tested in dried-off dairy cows. The retention of the intravaginal rings was quite low while the local tolerability was good. Thus, the shape needed further studying.

A droplet shape (which was not a flat shape) as well as a "pink ribbon"- shape (flat) were also tested. They both showed better retention than the ring, but lower local tolerability than the ring. The local tolerability was on the same level as for commercial devices. However, as one sample of three was rejected of each of the designs, the shape was still further studied.

After these preliminary studies, four different shapes were selected for a larger study, one shape in two different hardness. These different forms are shown in Figures 5A, 5B, 5C and 1. The form in Figure 5A was named "Plow", the one in Figure 5B "Omega" and the one in Figure 5C "Ring". The fourth form tested is shown in Figure 1, and corresponds to the claimed device. The fourth form, which was named "X" was tested in two different hardness, named "X-hard" and "X-soft". The devices were made of a 3D-printed core made of polyamide (PA 2200, tensile strength 45 ±

3 N/mrn^, Shore D-hardness 75 ± 2), which was coated with the 70001 silicone elastomer filled with silica from Dow. The diameters varied as did the cross-sections of the rods forming the device, as indicated in Table 1.

Table 1

The compression strength of the samples was tested as follows. The samples were compressed at constant rate of 600 mm/min with a Universal Mechanical Testing apparatus, until the resisting force reached 40 N. For less rigid samples, the test was stopped before the jaws of the Universal Mechanical Testing apparatus crashed together. The direction of compression was for the X-shape the direction defining the smaller dimension of the shape when laid flat on a surface (i.e. direction perpendicular to the first plane), for the Omega-shape it was such that the ends of the shape were pressed towards one another (while avoiding the ends of the Omega to touch one another), and for the Plow-shape such that the opening inside the shape was compressed.

The objects of the study were to examine the retention rates of the devices, discharge and inflammation in response to the devices, cow comfort as measured by behavioural responses and ease of use of the devices.

The mechanical compression test results of the chosen four designs are given in FIG. 6, where the uppermost graph represents the results for the X-hard, the second from top those for Omega, the third from top the results for Plow and the lowermost graph illustrates the results for X-soft. Indeed, mechanical compression is an aspect relating to the ease of use, as the device is compressed for insertion. The Ring-shape could not be tested due to its floppiness. The abscissa on the graphs gives the compression extension in mm, and the ordinate the compressive load in N. As can be seen, the results for X-soft and X-hard are the most desirable, as the force required to compress increases almost linearly, without any sharp increase at the higher compression loads.

Each of these five device designs were tested in 40 animals, with the exception of the ring-shape, which was tested in 10 animals (as it was already shown that the retention is low using that design), as follows.

At the beginning of the study, on the first day (day 0), 180 cows underwent a metricheck procedure and were graded according to the guidelines presented in Parkinson (Parkinson et al., Diseases of Cattle in Australasia, New Zealand Veterinary Association Foundation for Continuing Education, 2010, chapter 11 : Reproduction and disorders of the reproductive system, pages 440-453). Only cows with a metricheck score of 0 were eligible for device insertion. All remaining eligible cows were then grouped by parity (2, 3, 4, 5, 6+) and the excess cows (over the required 170 cows) were randomly removed from the study with a random number generator in excel. The remaining 170 cows were assigned an intra-vaginal device by randomly allocating them. Before insertion of the device, the cows were milked in the morning and then were fed on the feed pad for approximately two hours.

The devices were inserted in groups of twelve (six cows per inserter). Once the group of twelve was completed, two observers who had been waiting in the office of the dairy shed, and therefore blinded to the treatments, came to observe the group of cows from the opposite side of the milking platform. Each observer monitored and recorded behavioural observations for six cows for ten continuous minutes (as determined by a stop watch). They recorded the start time for their observations and recorded their behavioural observations in one-minute long segments. Over ten one-minute-long periods, they observed and recorded what animals during that time period were straining, lifting their tail, stomping, defecating and urinating. Once the ten minutes of observations were completed, the cattle were released and the observers waited until the next twelve cows were ready for observations.

The cows were released from the milking platform to the race where they could not go any further in groups of twelve. Once there was a group of twenty-four ready, the cows were allowed to walk to the specified paddock for behavioural observations. A total of four staff were designated to paddock observations, operating in teams of two. At any one time, two staff were completing observations and two staff were retrieving the cattle from the race near the milking shed and taking them to the paddock and putting a temporary break fence behind them.

Once the break fence was in place for a group of twenty-four cows, all staff would walk to the observation area next to the paddock, strategically placed on a hill. Paddock observers worked as a team of two with one person observing and calling numbers and one person recording. They recorded behavioural observations in 9 x 5-minute long intervals. Over each 5- minute long period, they observed what animals were straining, lifting their tail, stomping, defecating/urinating or lying down.

Once the 45 minutes of observations were completed, they went and collected the next 24 cows for observation. Each team alternated observing and retrieving cattle until all observations have been completed. The break fencing was designed to ensure access to the trough.

At any point during the day, if the farmer or observation teams felt that a cow was in distress or extreme discomfort, they identified the cow for it to undergo a full veterinary examination.

After the first day, every morning, all cattle enrolled in the study were observed during milking by two observers. The observers would observe twelve cows each per row for the duration of the milking, up to ten minutes. They recorded the start time of observations and every minute following that start time that they were observed for. If the cattle were not observed for ten minutes, they would leave the space where the time was written on the record form blank so that the data entry team would enter that time period as not applicable, rather than an absence of behaviours. They recorded during the one-minute-long periods, what animals were straining, lifting their tail, stomping, defecating and urinating. If the observation team noticed that a device was sticking out to the point where it looked as though it was going to fall out, they removed the device and recorded the device and cow that it was removed from. If the observation team or farmer noticed any behaviour that indicated the cow was distressed and uncomfortable (e.g. constant straining), they alerted a veterinarian to provide a full examination and remove the device if considered necessary. The veterinary examinations were carried out by the same veterinarian for consistency.

If the farmer found any devices on the farm that had fallen out, he was instructed to keep them in the office and record on what day he found them.

On the last, seventh day of the study, all cows enrolled in the study were milked in the morning and observed for behavioural signs as explained for days 1-7. They then were place onto a feed pad for approximately 1.5 hours. At 9.30 am, approximately half of the cows were brought to the shed.

The veterinarian removing the devices held the cow tail aside with one hand while the assisting technician carefully cleaned the vulva with warm water and disinfectant and a cloth and then dried the vulva with a paper towel. The vagina was carefully examined by a veterinarian for the presence of a device and the device (if present) was carefully removed from the vagina. The device was visually assessed for the amount of pus and blood and graded :

0 - No pus or blood observed

1 - Small amount of pus and/or blood (flecks, small patches)

2 - Moderate amount of pus and/or blood (moderate patches and globs, light staining of blood over large areas, light amount of pus but over large areas of the device)

3 - Large amount of pus and/or blood covering the majority of the device ± pungent smell The presence or absence of a device, the device grade and any associated comments were recorded by a separate recorder. This process was repeated for all enrolled cattle.

After approximately 5-10 devices had been removed, one trained technician and one veterinarian cleaned the vulva again with warm water and disinfectant and then used a new disposable sterile speculum per cow to score the infection and inflammation. Although training was completed prior to this day, a further calibration was completed on the first 6 cows to ensure the grading was similar. The scoring system for vaginal discharge was:

Score 0 - No discharge or clear mucus Score 1 - Mucus and £50% pus Score 2 - Mucus and >50% pus Score 3 - Entirely pus The scoring system for inflammation was:

Score 0 - No red or swollen mucosa

Score 1 - Small focal area of red or swollen mucosa

Score 2 - Moderate sized area of red or swollen mucosa or a diffuse moderate swelling of the vagina Score 3 - Severe red and swollen mucosa in either a focal area or as a severe diffuse swelling of the majority of the vaginal mucosa.

Finally, the technician that was cleaning the vulvas for the device removal veterinarian then completed a metricheck procedure on all the cows grading them as per the grading system described in Parkinson (see above), scoring animals on a 0-3 scale. Statistical analysis of the results of testing of the various forms Retention of devices

Fisher's exact test was used to compare the difference in retention rates between devices; logistic regression could not be used as there were zero counts for one of the devices. Any devices that were actively removed by the staff were not included in the analysis for retention, as it was not known whether they would have been retained or not.

Discharge and inflammation

Only animals that had a device removed were included in the analysis of discharge and inflammation.

There were four discharge and inflammation outcomes, namely device score when removed, speculum discharge score, speculum inflammation score and metricheck score. These were all scored on a 0-3 scale, but collapsed into scores 0-1 (no inflammation and/or discharge), and 2-3 (inflammation and/or discharge). Univariable logistic regression was undertaken for each of the outcomes, with device as the only predictor for device score and metricheck. There were two people involved with speculum examination, so speculum operator was also added as possible predictor for inflammation and discharge scores. Behaviour measurements

Eight days of behaviour measurements in the dairy shed and one day of behaviour measurements in the paddock/field were collected; these were analysed separately. Every animal was analysed for paddock and shed on day 0; however, if a device was lost from a cow, it was not known which day that occurred. As a result, every animal that did not have a device retained at the conclusion of the study was removed from the shed analysis after day 0. Each time period identified whether an animal elicited any of the stated behaviours during those time periods; these were not counts of behaviour so it was not appropriate to analyse them as counts per day. Data were analysed both at the one-minute level and also at the day level, where every behaviour event was collapsed to the presence or absence from an animal on a given day of recording.

Mixed multivariable logistic regression, with cow as a random effect, was used to identify associations between each of the five behavioural outcomes and device. Possible confounders and predictors included age, breed, recorder and day of insertion. Along with device description, these were all included in the initial mixed multivariable model. Fixed variables were removed from the model using backwards elimination if the log- likelihood ratio between two nested models had a significance of p>0.05, until all remaining fixed effects were significant at p£0.05. Device was retained in the model as the predictor of interest. The above methods were used when analysing all animals at day 0; however, as there was no clustering of the data within cow when analysed at the day level, a multivariable logistic regression was used.

The results on retention and tolerability are given below in Table 2.

Table 2: Retention and tolerability of device designs N(i): number of devices inserted

N(ar): number of devices actively removed by study staff N(ra): number of devices remaining for analysis N (I) : number of devices lost N(r): number of devices retained P: proportion of devices retained T: tolerability, 1 = best - 4 = worst n.a. = not applicable - all items lost early on in the study, no data with regards to tolerability available.

A total of 143 devices were removed from cattle at the conclusion of the study. There was a significant difference in the retention proportion of the five devices (p<0.001); retention percentage ranged from 100 for X- hard and X-soft, to 0% for Ring. There was a significant difference between Plow and Omega, and X-soft (p=0.012), and between Plow and Omega, and X-hard (p=0.026). It could be concluded that devices X-hard and X-soft had a greater proportion retained compared to Plow, Omega and Ring. There were 19 animals that had a comment made that the device was sticking out/coming out/sitting just back from vulva/loose. Ten of these comments were for the Omega, five for X-soft, three for X-hard and one for Plow. Out of these 19, only one animal with an Omega device had a comment that the device was half out, so it is not clear whether the majority of these were in any danger of actually falling out

There were 10 animals that had a comment that the device was nicely embedded into the vaginal tissue of the cow. Three of these were Plow, two were X-hard and five were X-soft.

In short, Omega was the best with regards to the tolerability (least amount of pus and irritation). The retention with the Omega design, however, was worse than for commercial CIDR devices, where a retention rate of 95 % is generally considered desired. Also, the results for the Ring design verified earlier results: although the tolerability seems to be good, the retention is quite low - in this study the retention was 0 %. The X- soft design had 100 % retention, and the tolerability was comparable to commercial CIDR devices. The Plow was on all accounts the worst design.

These studies thus show that the X-shape is the best for retention and tolerability.

Measurement of release rate

The release rate of progesterone was measured, using three commercial devices (CIDR®, PRID-Delta and Cue-Mate®) as well as the following materials. - Progesterone, purity of over 98 %

- unfilled polydimethylsiloxane elastomer with 15 ppm platinum catalyst (addition cure system) from NuSil (later referred to as PDMS/Pt)

- 70001 silicone elastomer (mostly PDMS) from Dow - ethylene vinyl acetate (EVA), Celanese Ateva 4030AC by Celanese

- 2-hydroxypropyl-6-cyclodextrin (2-HPBCD)

The development samples had the following structure: a drug-free elastomer core made of 70001 silicone elastomer and a membrane surrounding the core as a coating. The membrane was made by mixing progesterone in PDMS/Pt and pressing this mixture in a thin sheet. The diameter of the core was dl, and the diameter of the coated device was d2, i.e. the thickness of the membrane was (d2-dl)/2. Each sample had a length, and the length of the membrane was defined as I (i.e. the core was surrounded by the membrane over a length I of the core, the total length of the sample being slightly larger than length I). Sample preparation

The formulation development prototypes were prepared by mixing progesterone in silicone elastomer (PDMS/Pt, unfilled), and then pressing a thin sheet out of the elastomer/progesterone-mixture. The sheet was then rolled on top of a cylindrical silicone core (70001 containing 37 wt- % of silica) and subsequently cured in an oven (for 2 hours at 115 °C). EVA was also used in some samples as the progesterone matrix material, as explained above (the EVA was pressed to a sheet-form at 90 °C, as it does not need to be cross-linked, i.e. cured). In vitro dissolution

In vitro dissolution was determined with ultra-high-performance liquid chromatography (UHPLC). In the first in vitro dissolution tests, parameters were changed as part of the method development process. As the process advanced, the parameters evolved to the following set: - samples were held in flasks with a large opening and a volume of 1000 ml;

- dissolution medium: 1000 ml aqueous solution with 1 % of 2- hydroxypropyl-6-cyclodextrin; and

- samples were held in an incubator set at 37 °C, and stirred constantly ( 70 rpm).

Dissolution profile was determined from samples taken from each flask daily and new dissolution medium was changed every day.

First sets of exploratory samples were prepared in order to screen the release rate properties of progesterone from the silicone elastomer. Moreover, this sample set was planned so that it would also provide information regarding the effects of sample dimensions. Some properties for the exploratory samples are listed in Table 3 below, namely nominal sample dimensions, measured mass and progesterone concentration of the progesterone layer.

Table 3

^alue calculated on basis of mass, volume, and PDMS density Measurement of drug-free core mass missing

A second iteration round of samples was prepared from silicone elastomers with nominal properties (nominal sample dimensions, measured mass and progesterone concentration of the progesterone layer) according to Table 4. The cores were made of the 70001 silicone, and the membrane was made of the PDMS/Pt and progesterone (as listed above). These samples were used for verifying the predictive models created on basis of the first sample-set data.

Table 4

Formulation development was also conducted with alternative materials. For example, samples were prepared having a core made of the 70001 silicone elastomer and a membrane made of ethylene-vinyl acetate (EVA) according to Table 5. Moreover, the addition of formulation enhancing excipients to silicone elastomer was tested by adding 2-hydroxypropyl- b-cyclodextrin (2-FIPBCD) to the samples according to Table 6 (where m- % stands for mass percentage).

Table 5

Table 6 Release tests in vivo

Hairy-X samples were prepared for an in vivo study, where 12 cows were divided into three groups of four cows. Each group of cows was set to undergo three treatment cycles. During these cycles the cows would be treated with the hairy-X sample (test item), the CIDR (ref. item IX), and two CIDRs (ref. item 2X). The samples retrieved from the test were then analysed to measure the amount of progesterone released during the treatment cycle.

The hairy-X sample was prepared by 3D-printing a thermoplastic frame from polyamide, followed by coating the frame with the 70001 PDMS (the coating profile was extruded). The drug-containing layers (made of PDMS/Pt) were pressed a 1 mm thin films and cross-linked to the coated frame structure.

In order to gain some control over the reproducibility of sample manufacturing, process control limits were created based on weighing the progesterone containing portions of the samples. Additionally, process control samples were taken during the mixing process to ensure that the progesterone content of the elastomer mass was close to 10 m-%. For the outer rim filled with the progesterone / elastomer mixture, process control limits were: lower limit 5.90 g, target 6.60 g and upper limit 7.20 g. For the "hairy-X" samples, the limits were set as 17.3 g lower limit, 19.2 g target and 20.5 g upper limit.

Release results

A total of 49 samples were received back from the in vivo study. In total, 13 used and one unused hairy-X sample were received and 13 analysed

(including the unused sample). 12 used CIDR samples that were used alone were received, of which 10 were analysed. Of the CIDR samples that were used in pairs, 24 were received and 18 analysed. The progesterone content determined with an assay method (progesterone was extracted with 1000 ml of 1% dichloromethane, kept at an incubator at 37 °C and analysed with UHPLC) for the unused sample was 2.53 g, which was almost identical to the content estimate based on sample weights (2.54 g). The assay results for the used samples were determined, and the amount of progesterone released during the study was estimated based on the nominal progesterone contents of the samples. The results for estimated total amount of released progesterone in different cows (i.e. in vivo) are shown in FIG. 7. The spheres stand for the tests with CIDR, the triangles for the tests with two CIDR's, the squares for the tests with Hairy-X and the plus-signs denote the sum of two CIDR's. The cow ID number is given on the abscissa and the released progesterone on the ordinate. The results indicate that the amount of progesterone released from the hairy-X samples is at the same level or larger than the release from two CIDR products. The amount of progesterone released from a CIDR device was on average 0.50 grams for both 1 x CIDR and 2 x CIDR treatment periods.

Conclusions

Based on the retention study, the X-shaped frame design proved to be the best suited for vaginal device for cows. By utilizing the "hairy"-design on the X-frame, the available surface area on the design was sufficiently increased without considerably changing the mechanical properties. The hairy-X design provides an in vitro release rate which is equal to or larger than from two CIDR comparator products. Moreover, the nominal progesterone content of the hairy-X is lower than that of two CIDR products. Finally, analysis of the ex vivo samples confirmed that the amount of progesterone released under in vivo conditions equals or is larger than the release from two CIDR products.

Claims

1. An intravaginal device (200, 300, 400) for a cow, comprising

- a core (100) made of a plastic material;

- a membrane (202, 302, 402) at least partially encasing said core, the membrane comprising a therapeutically active agent and being able to release the therapeutically active agent within a period of 6-10 days; wherein

- the core is in the form of a closed continuous structure formed of a rod, comprising - a first part (102) having a first end (102a) and a second end

(102b);

- a second part (104) having a first end (104a) and a second end (104b);

- a third part (106) having a first end (106a) and a second end (106b);

- a fourth part (108) having a first end (108a) and a second end (108b);

- the second part being a mirror image of the first part with respect to a first plane (110A); - the third part being a mirror image of the second part with respect to a second plane (HOB), the second plane being perpendicular to the first plane;

- the fourth part being a mirror image of the third part with respect to the first plane; - the first part being a mirror image of the fourth part with respect to the second plane;

- the first, second, third and fourth parts being connected via their ends such that they form an X-shape on a third plane, wherein the third plane is perpendicular to the first plane and to the second plane; - the first and second plane intersecting at a centre point (112) of the X-shape; and each of the parts of the core comprising

- a first curved portion (114) having a radius of curvature R1 of 40- 60 mm;

- a second straight portion (116);

- a third curved portion (118) having a radius of curvature R3 of 2-9 mm;

- a fourth straight portion (120); - a fifth curved portion (122) having a radius of curvature R4 of 10-

30 mm; and wherein a compression strength of the intravaginal device, when compressing at constant rate of 600 mm/min with a Universal Mechanical Testing apparatus, in a direction perpendicular to the first plane is - 10-40 N when the device is compressed to 25 % of its width in the direction of compression;

- 25-50 N when the device is compressed to 50 % of its width in the direction of compression, provided it is higher than the compression strength at 25 % of its width in the direction of compression.

2. An intravaginal device (200, 300, 400) according to claim 1, wherein the therapeutically active agent is selected from a group consisting of progesterone, gonadotropin-releasing hormones, prostaglandine-F2a and nonsteroidal anti-inflammatory drugs.

3. An intravaginal device (200, 300, 400) according to claim 1 or 2, wherein the core (100) is made of a material selected from a group consisting of polyethylene, polypropylene, polyamide, polyether ether ketone, ethyl vinyl acetate and thermoplastic polyurethane.

4. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein the membrane (202, 302, 402) is made of a material selected from a group consisting of poly(dimethyl silicone), siloxane based elastomer, a thermoplastic polyurethane, a thermoplastic polyurethane elastomer, ethyl vinyl acetate, a polyolefin-based elastomer, a silicone containing thermoplastic, polyurethane, polylactic acid and polycaprolactone.

5. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein the radius of curvature R1 is 45-55 mm.

6. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein the radius of curvature R3 is 3-7 mm.

7. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein the radius of curvature R4 is 15-25 mm.

8. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein the membrane (202, 302, 402) is arranged over a surface formed by the X-shape of the core (100).

9. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein the membrane (202, 302, 402) is arranged to extend outside the X-shape of the core (100) to a distance up to 60 mm.

10. An intravaginal device (200, 300, 400) according to claim 8 or 9, wherein the membrane (202, 302, 402) free from contact with the core (100) comprises slits (206).

11. An intravaginal device (200, 300, 400) according to any of the claims 8-10, wherein the membrane (202, 302, 402) free from contact with the core (100) comprises fringes (208).

12. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein the rod forming the core (100) has a largest cross-sectional dimension of 6-12 mm.

13. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein a form of the cross-section of the rod forming the core (100) is selected from a group consisting of a circle, an ellipse and a stadium.

14. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein the membrane (202, 302, 402) has a thickness of 0.5-2 mm.

15. An intravaginal device (200, 300, 400) according to any of the preceding claims, wherein a distance between the third curved portion (118) of the first part (102) and the third curved portion (118) of the second part (104) is 80-120 mm, and a distance between the third curved portion of the first part and the third curved portion of the fourth part (108) is 100-140 mm.