A ready-to-use drug delivery system

Abstract

The present invention relates to a ready-to-use drug delivery system (1) which at the time of manufacturing comprises a first layer (2) comprising a first polymeric material (5) and a first active ingredient (6), a sheath (4) comprising a second polymeric material and (7) a second active ingredient (8), and wherein the sheath (4) further comprises the same first active ingredient (6) as loaded in the first layer (2). By loading both the first layer (2) and sheath with same first active ingredient (6) already during manufacturing of the drug delivery system, it is ensured that said drug delivery system is inherently ready-to-use, i.e. the need for a time-consuming equilibrium period is eliminated.

Description

[0001] A ready-to-use drug delivery system

[0002] The present invention relates to a drug delivery system, a method of manufacturing said system and the use of said system.

[0003] Various types of delivery systems, such as intravaginal rings, have been developed for the controlled and sustained release of active ingredients preferably by diffusion through the surface of the device.

[0004] One such device is the intrauterine device ( IUD); Mirena® which is considered one of the safest and most efficient contraception used worldwide. 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.

[0005] Other devices commercially available today are the intravaginal rings ( IVRs ), e. g. the Estring®, Femring®, and Nuvaring®, or subdermal contraceptive implants, e. g. the Implanon®, all of which provide controlled and sustained release of steroid molecules over a prolonged period, e. g. several weeks / months.

[0006] 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 polymer, such that therapeutic concentrations may be readily achieved in the body.

[0007] 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 drug delivery device 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.

[0008] 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 a substantial 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.

[0009] Furthermore, reservoir systems can be difficult to fabricate reliably, and pinhole defects and cracks in the membrane surrounding the reservoir, can lead to dose dumping, i. e. unintended, rapid drug release over a short period of time.

[0010] These problems are avoided in monolithic systems, in which drug is loaded directly into a polymer, which now acts as both a storage medium and a mediator of diffusion. Drug is typically loaded uniformly into monolithic devices, and the release is controlled by diffusion through the monolithic matrix material or through aqueous pores. However, with passing time, release rate decreases, as drug that is deeper inside the monolith device must diffuse to the surface, since it has farther to travel, and the quadratic relation between distance and time becomes important. Since the geometric factor is essential in this respect, the effects can be minimized by using other geometric shapes or hemisphere monoliths to provide near-zeroorder release, but such devices are neither easy nor inexpensive to fabricate.

[0011] Certain therapies or regimens require, or would benefit from, the administration of more than one active ingredient at the same time. This is true for the administration of a variety of medicaments extending from veterinary medicine to human drug administration. One example being in the field of contraception and hormone replacement therapy, another are in the field of multi prevention technology e. g. an intravaginal ring that release a contraceptive drug and an anti-retroviral drug simultaneously, in order to both prevent unplanned pregnancy and protect against a HIV infection.

[0012] In some cases, the two or more active ingredients are most effective when they are administered at specified rates relative to each another. Whether the ratio of these specified rates is 1. 0 (on a mole or weight basis ) or something other than 1. 0, deviations from the specified ratio can result in a loss of effectiveness, the inducement of undesirable side effects, or in some cases toxicity.

[0013] One problem with the known devices arranged for releasing more than one active ingredient, is that such devices usually show sub-optimum release patterns for the different active ingredients, whereas it is generally preferred that all active ingredients are released in a controlled rate during a specified duration of time.

[0014] One such drug delivery system is known from W091 / 04015. Said application describes a drug delivery system that can be administered in the evening, but where the main dose of active ingredient is delivered in the early morning, e. g. preventing pain upon awakening if the active ingredient is morphine. Said system comprises a burst layer with a high concentration of active ingredient and two end-layers with a lower amount of active ingredient. Said end-layers are placed at each end of the burst layer creating a sandwich like construction. The construction is coated with an insoluble coating, leaving the ends of the sandwich open thereby allowing the layers with active ingredient to be exposed to the aqueous surroundings after administration. The layers are made of a material that slowly dissolves during use, whereby the active ingredient is released through the open ends.

[0015] Another system is known from WO03 / 094888 that describes a drug delivery device that aims at providing a high initial drug release, i. e. said application relates to a different purpose than the present invention. The device comprises a drug core and an outer layer, that preferably both are biodegradable.

[0016] The applicant' s patent applications WO2023 / 139220 and WO2023 / 139221 disclose drug delivery systems (e. g. an intravaginal ring that can release more than one active ingredient). Said system comprises a core comprising a first active ingredient (e. g. an estrogenic steroid) and a sheath comprising a second active ingredient ( e. g. a progestational steroid) in a concentration of at least 10 wt% based on the weight of the sheath.

[0017] The applicant' s application no. EP23184215.4 relates to a corresponding system, but with three layers, wherein the core or intermediate layer comprises a first active ingredient. These drug delivery systems provide an independent and optimal release of the two active ingredients. In fact, the use of a sheath comprising at least 10wt% of an active ingredient in the sheath not only ensure physical stability of said active ingredient, but also that a desired near zero-order release behavior of the active ingredient in the core can be observed for a longer period of time, since the second active ingredient in the sheath will function as a filler and control the release rate of the first active ingredient from the core.

[0018] In the applicant' s known drug delivery systems the active ingredient ( s ) may be present in a solid state (crystals ) and / or in a molecular dissolved state. A solid state fraction will be stationary and will not redistribute during storage, whereas a dissolved fraction is subj ect to internal diffusion and will re-distribute until thermodynamic equilibrium is reached. Such an "equilibration period" also called a maturing period allows the dissolved fraction of the active ingredient in the core to diffuse into the sheath in order to reach equilibrium. Before equilibrium is reached, insufficient active ingredient has diffused from the core to the sheath, resulting in an unfavorable administration profile, which in some situations can have severe consequences for the patient. Thus, even though the drug delivery systems can be used before said equilibrium is reached, it is only after equilibration that stable release profiles are obtained.

[0019] Accordingly it is preferred that equilibrium in the drug delivery system must be reached before the drug delivery system is placed on the market. However, the equilibration period depend on a number of factors, e. g. the storage conditions, such as temperature and humidity; the characteristics of the sheath, such as the polymer ( s ) the sheath is made of; the thickness of the sheath ( since thicker sheaths require longer equilibration periods ), etc.

[0020] Using a higher storage temperature would lead to a faster thermal equilibration of the drug delivery system, however higher temperatures will result in dissolution of more active ingredient ( s ) in the polymer ( s ) as the saturation level is a strong function of temperature. This is undesirable as it may lead to physical stability issues of the active ingredients, and result in undesirable levels of chemical degradation. Finally, equilibration periods of more than several weeks result in long lead times between manufacturing and testing for batch release which is economically and logistically very unfavorable.

[0021] Accordingly, the equilibration period is very difficult to predict and accordingly implement from a practical point of view. Thus, equilibration periods longer than the normal lead time for the respective drug delivery system, i. e. the time between the initiation and completion of a production process are impractical and expensive. For an intravaginal ring the lead time is normally less than about one to two weeks, however equilibration has often not been reached in said period.

[0022] Thus, there is a demand for a novel drug delivery system arranged for releasing active ingredient ( s ) / drug ( s ) in a controlled manner and in the correct ratio that can be used immediately after production, i. e. without a need for a separate equilibration period.

[0023] It is a first aspect of the present invention to provide a ready-to-use drug delivery system wherein the need for an equilibration period is eliminated.

[0024] In a second aspect according to the present invention is provided a drug delivery system loaded with a first active ingredient and a second active ingredient and wherein each active ingredient is released at a controlled rate independently of the other active ingredient.

[0025] In a third aspect according to the present invention a provided a delivery system in which the known problems relating to complicated and expensive manufacturing processes, and which at the same time can provide a substantially zero-order release rate of the first active ingredient. In a fourth aspect according to the present invention a provided a delivery system arranged for implantation e. g. subcutaneous, or for vaginal or uterine placement in an animal or human.

[0026] The novel and unique features whereby these and further aspects are achieved according to the present invention is by providing a ready-to-use drug delivery system which at the time of manufacturing comprises

[0027] - a first layer comprising a first polymeric material and a first active ingredient, and

[0028] - a sheath comprising a second polymeric material and a second active ingredient, and

[0029] - wherein the sheath further comprises the same first active ingredient that is loaded in ( i. e. comprised in or placed in) the first layer.

[0030] The ready-to-use drug delivery system according to the invention relates to a system that comprises a first layer surrounded, at least partly and preferably completely, by a sheath, which is the outer layer of the drug delivery system. The first layer and the sheath are preferably co-axially / concentric arranged, i. e. they share a common axis.

[0031] In a conventional drug delivery system, i. e. a system with one active ingredient in the first layer and one active ingredient in the sheath, the active ingredient in the first layer will diffuse from high concentration to low concentration regions until uniformity (equilibrium) in composition is attained after several weeks; thus, the concentration gradient is the driving force for the diffusion process.

[0032] Since the first active ingredient in the present invention is loaded in the sheath ( i. e. added to the polymeric material of the sheath) during the manufacturing process, the sheath already comprises the same first active ingredient as the first layer during the manufacturing process, i. e. the sheath is loaded with both the first and second active ingredient during the manufacturing process. By preloading the sheath i. e. loading the sheath with same first active ingredient as present in the first layer already during manufacturing of the drug delivery system, it is ensured that said drug delivery system is inherently ready-to-use, i. e. the need for a time-consuming equilibration period is eliminated. Thus, the equilibration period commonly used to ensure that the first active ingredient (that conventionally only is present in the first layer during manufacturing) slowly diffuses (redistribute ) into the sheath before the drug delivery system can be used, is no longer required.

[0033] Within the context of the present invention the term "preloading" and "loading" is used for active ingredients added to the polymeric material of the respective layer e. g. sheath or first layer during manufacturing of the drug delivery system, i. e. the load of active ingredient in e. g. the sheath and / or first layer it is not a result of later diffusion of active ingredient during a storage period or a treatment period.

[0034] In one embodiment the ready-to-use drug delivery system only comprises the first layer and the sheath, i. e. the drug delivery system is a two layered drug delivery system wherein the first layer constitutes the core, and the sheath surrounds said core, partly or completely.

[0035] In another embodiment the ready-to-use drug delivery system further comprises a second layer comprising a third polymeric material, thereby providing a three-layered drug delivery system, comprising a core, a sheath, and an intermediate layer, placed between the core and the sheath. In a preferred embodiment, the intermediate layer completely surrounds the core, and sheath completely surrounds the intermediate layer. The first layer may be either the core or the intermediate layer, the other being the second layer. Accordingly, when the first layer is the core, the second layer is the intermediate layer, and when first layer is the intermediate layer, the second layer is the core. The three-layers of the drug delivery system are preferably co-axially arranged, i. e. the core, intermediate layer and sheath share a common axis.

[0036] The ready- to-use drug delivery system may also comprise more than one second layer, e. g. two or three intermediate layers, however all embodiments comprises a sheath comprising a second polymeric material and a second active ingredient and wherein said sheath is preloaded with the first active ingredient, i. e. both the first and second active ingredients are added to the sheath during the manufacturing process. When the ready-to-use drug delivery system comprises a second layer ( intermediate layer), and the first layer is the core, it is preferred that the first active ingredient in addition to being preloaded in the sheath also is preloaded in the second layer ( intermediate layer) during the manufacturing process. Such a system would in a similar way as the two layered system be inherently ready-to-use system since the first active ingredient present in the core does not have to diffuses (redistribute) into the intermediate layer and sheath before the drug delivery system can be used.

[0037] When the second layer is the core, i. e. the first layer is the intermediate layer; the inventors have found that the requirement to load the second layer (core) with the first active ingredient during the manufacturing process to obtain a ready-to-use drug delivery system is not necessarily required. In fact the inventors of the present invention have found that the use of a core that only consists of a polymeric material (during manufacturing), ensures that a small fraction of the first active ingredient loaded in the intermediate layer ( first layer) and a small fraction of the second active ingredient loaded in the sheath can diffuse back into the "empty" core. This mechanism can / will eliminate any persisting supersaturation and provide a more reliable and constant release rate, and a lower initial burst, of said active ingredients. Thus, said embodiment provides a ready-to-use drug delivery system with an even better release profile than hitherto known. It is accordingly preferred that the drug delivery system according to the invention provides a constant release rate of one and / or both active ingredients during the treatment period.

[0038] However, in some embodiments it may be desirable to avoid such back-diffusion into the second layer (core), and accordingly said second layer may also be preloaded with the first active ingredient during manufacturing.

[0039] The inventors of the present invention have found that by having a second layer not preloaded with an active ingredient (when the second layer is the core) or only loaded with the first active ingredient (when the second layer is the intermediate layer) the release rate of the first active ingredient from the first layer (the intermediate layer or core, respectively), is substantially constant over time, thereby providing a substantially zero-order release rate of the first active ingredient during the desired treatment period.

[0040] For the embodiment where the second layer is the core, and the first layer is the intermediate layer, the substantially zero order release rate can be attributed to the barrier properties of the sheath, where the particles of the second active ingredient will act as ' filler ' and likely contribute to the barrier properties of said sheath. For the embodiment with the second layer is the intermediate layer, and the first layer is the core, zero order release is likely attributed to the combined barrier properties of the intermediate layer and the sheath with particles of the second active ingredient.

[0041] In a modified embodiment according to the present invention the sheath does not comprise the second active ingredient, i. e. said sheath is only loaded with the first active ingredient during manufacturing. This is relevant when the first and the second polymeric materials are different materials, i. e. the first layer is made of the first polymeric material and will function as a reservoir and the sheath is made of a second polymeric material and will act as a controlling membrane i. e. the drug delivery system will provide a controlled release of the first active ingredient. Such an embodiment will only comprise a single active ingredient, e. g. estradiol, but since the polymeric materials of the respective layers are different, e. g. two different ethylene-vinyl acetate (EVA) copolymers, the equilibrating period can also be eliminated for such a drug delivery system by loading the same active first ingredient in the sheath and first layer in a similar manner as described when the first and second active ingredient are different.

[0042] The modified embodiment ( s ) may also comprise a second layer comprising a third polymeric material wherein the third polymeric material is the same or different from the first and / or second polymeric material. The second layer may or may not comprise the first active ingredient. The advantages of this modified embodiment are similar to the advantages for the other embodiments in this application.

[0043] In a preferred embodiment according to the present invention the first active ingredient is an estrogenic steroid and the second active ingredient is a progestational steroid. Dual administration of both a progestational steroid and an estrogenic steroid finds application in a number of different areas, e. g. in contraceptive vaginal rings and in vaginal rings providing hormone replacement. For such drug delivery systems it is required to release the two steroids simultaneously and at the same time. It is therefore necessary to adj ust the release rate of these steroids independently to the physiological optimal rate (mg / day). Using the drug delivery system according to the present invention the inventors have found that it is possible to attain independent and optimal release of the two active ingredients; an estrogenic steroid and a progestational steroid.

[0044] It should be noted that placement of more than one active ingredient ( steroid) in a single polymer (matrix) normally provides a number of problems. Not only has it been very difficult to obtain the desired delivery rate and / or delivery ratio, since the active ingredients will not diffuse together through the surface or membrane at the same ratio as they exist in the polymer, but undesirable mechanical properties (especially for high concentrations of steroids ) may also be observed.

[0045] The inventors of the present invention have surprisingly found that when the sheath is loaded with the same first active ingredient (e. g. an estrogenic steroid) as loaded in the first layer, a highly favorable delivery system, with the desired release profile and release ratio of the active ingredients, are obtained.

[0046] A further advantage is that an overall lower concentration of the first active ingredient needs to be loaded into the drug delivery system in order to obtain the desired release rate and / or ratio. Conventionally the amount of an active ingredient loaded only in the first layer will decrease over time and with distance from the surface, and the active ingredient is therefore often added in larger concentrations than actually required from a therapeutically point of view. The effect being that larger dosages of the active ingredient are released from the device during the treatment period. This will not only result in a higher production costs, but the user will also be subj ected to higher dosages of the active ingredient than is needed or desired.

[0047] By preloading the first active ingredient in both the first layer and the sheath and optionally the second layer, a lower concentration of the first active ingredient ( e. g. an estrogenic steroid) has proven able to obtain and maintain the desired (e. g. constant ) release rate during the desired treatment period. Accordingly, a higher percentage of the first active ingredient loaded in the drug delivery system can be delivered to the surrounding environment, leaving a reduced remnant content of the first active ingredient in the system after use, thereby both reducing manufacturing cost and the impact on the environment.

[0048] In order to ensure that thermodynamic equilibrium has been reached in the drug delivery system according to the invention already during the manufacturing process, it is preferred that the chemical potential of the first active ingredient in the first layer and sheath is substantially the same, i. e. that thermodynamic equilibrium has been reached.

[0049] Within the context of the present invention the term "chemical potential" refers to the concentration of the active ingredient in a mixture (polymeric material and the active ingredient ( s ) in said material ) that is necessary to level off the diffusion gradient which drives the net movement of molecules of the first active ingredient between layers. When the same polymer is used in both layers, the concentration of the active ingredient in the polymer should be nearly identical in each layer. However, if different polymers are used, even at equilibrium, the partitioning of the active ingredient between the layers will still be observed, as will be explained in more details in the following.

[0050] A person skilled in the art will based on the present disclosure understand that thermodynamic equilibrium of the first active ingredient in the drug delivery system according to the invention depends on both the concentration, state of the active ingredient (e. g. dissolved and / or crystal form), and solubility of the first active ingredient in the respective layer, i. e. in the first layer and the sheath, and optionally the second layer.

[0051] It is accordingly relevant to calculate which weight percentage (wt% ) are required of the first active ingredient, based on the weight of the respective layer ( first layer, sheath and / or optionally the second layer), in order to obtain the same chemical potential of the first active ingredient in the relevant layers.

[0052] In one preferred embodiment the first layer and sheath, and optionally the intermediate layer, are made of the same polymeric material. Thus, in order to obtain thermodynamic equilibrium the concentration in wt% of the first active ingredient in the first layer and sheath are substantially the same, i. e. if the first layer, e. g. the core comprises 0. 3 wt% of the first active ingredient (dissolved concentration), the sheath and optionally the second layer, also comprises 0.3wt% of the same first active ingredient. All weight percentages are based on the weight of the respective layer.

[0053] It should in this respect be taken into account that the sheath in addition to the second polymeric material also comprise the second active ingredient, and accordingly the weight of said active ingredient should be taken into account when calculating the amount of the first active ingredient required in the sheath to obtain the same chemical potential as in the first layer.

[0054] The concentration of the first active ingredient in the first layer can be calculated as follows:

[0055]

[0056] In order to calculate the amount (weight) of first active ingredient required to reach the same chemical potential in the sheath, the wt% of the second polymeric material in the sheath (wpolymer-2) is first calculated as follows;

[0057]

[0058] The concentration of the first active ingredient in the sheath can then be calculated as follows:

[0059]

[0060] As initially stated the state of the first active ingredient, e. g. if it is in a dissolved and / or crystal form is also relevant when determining the amount of first active ingredient needed in order to reach the same chemical potential in the sheath and the first layer. When the first active ingredient is present only in dissolved form in the first layer, then cAP,, = c'AP,, and the weight (amount ) of the first active ingredient (m' ^-!) needed to reach the same chemical potential in the sheath as in the core, can be calculated as follows:

[0061]

[0062] When the first active ingredient is present in both a dissolved form and in a crystal form in the first layer, the concentration of the first active ingredient in the sheath in order to obtain the same chemical potential as in the first layer corresponds to the saturation concentration of the first active ingredient in the second polymer of the sheath.

[0063] The amount of the first active ingredient in the sheath to saturate the sheath can be calculated as follows:

[0064]

[0065] wherein

[0066] C'Api-is is the solubility concentration of the first active ingredient in the second polymeric material ( sheath).

[0067] In an alternative embodiment the first layer and sheath are made of different polymeric materials. If a second layer is included in the drug delivery system said second layer may be made of the same polymeric material as either the first layer or the sheath, or the second layer may be made of a third polymeric material.

[0068] As mentioned earlier the chemical potential of the first active ingredient depends on the solubility of the first active ingredient in the polymeric material used, and the concentration of the first active ingredient. However, when the polymeric materials used for the respective layers, the equilibrium concentration also depends on the interface between the respective layers. An interfacial partitioning of the first active ingredient between the first layer and / or the sheath and / or the optional second layer, that is related to the solubility in the first layer (Clayer_i), the solubility in the sheath (C3heath), and optionally the solubility in the second layer (Clayer-2) can be expected due to the affinity of the active ingredient to the polymers (Hans Van Laarhoven, Thesis ''Physico-chemical aspects of a coaxial sustained release device based on poly-EVA" 2005 ).

[0069] In a two layered drug delivery system comprising a core ( first layer) and a sheath a partitioning coefficient (K) between the first layer and sheath be defined as:

[0070]

[0071] Thus, the weight of the first active ingredient in the sheath in thermodynamic equilibrium with the first layer can be calculated as follows:

[0072]

[0073] Similar partitioning coefficients can be provided between the first and second layer, and / or the second layer and the sheath.

[0074] As an example can be mentioned that for a two-layered drug delivery system comprising a core ( first layer) made of a first polymeric material e. g. an EVA28, enclosed by a sheath made of a second polymeric material e. g. an EVA9, a thermodynamic equilibrium is obtained when the core is loaded with 0.35wt% etonogestrel and the sheath is loaded with 0. 046 wt% etonogestrel. The weight percentages (wt% ) are calculated based on the weight of the layer, e. g. core or sheath.

[0075] By ensuring that the concentrations of the first active ingredient loaded into the first layer, and sheath (and the optional second layer) are in thermodynamic equilibrium, (the same chemical potential ), an inherent ready-to-use drug delivery system is provided without an equilibrium period and with the desired release profiles of both the first and second active ingredient.

[0076] In an alternative embodiment, the concentration or chemical potential of the first active ingredient in the sheath is lower than the concentration (or chemical potential ) of the first active ingredient in the first layer and the optional second layer, whereby the equilibrium period is reduced, but not completely eliminated. In the above calculations c' ^-j or c'API_ismay then be selected to any desired concentration of the first active ingredient in the sheath, but said concentration would be lower than cAPI_i. Providing a concentration of the first active ingredient in the sheath which does not correspond to equilibrium may be advantageously in some situations, if it e. g. turns out that providing an equilibrium value from the beginning would lead to instabilities, e. g. a higher burst or negative interactions between the first and second active ingredients.

[0077] The polymeric materials used in the drug delivery system of the present invention are preferably suitable for placement in the uterus or vaginal tract, or for subcutaneous insertion / implantation, i. e. the materials are e. g. one or more of non-toxic, not biodegradable, non-absorbable, non-degradable and / or non-dissolvable in a patient or animal. In this respect a variety of inert thermoset or thermoplastic elastomer, as well as combinations of polymeric materials are contemplated within the scope of the present invention. In one embodiment the first and / or second and / or third polymeric material is a silicone polymer (thermosetting type ). Silicone elastomers, such as poly (dimethylsiloxane) are already used conventionally for IVRs and similar silicones are also contemplated within the scope of the present invention.

[0078] It is however preferred that the first and second polymeric material, and the optional third polymeric material is a thermoplastic polymer, which in principle can be any extrudable thermoplastic polymer material suitable for pharmaceutical use, such as ethylene-vinyl acetate (EVA) copolymers, low-density polyethylene, polyurethanes, and styrene-butadiene copolymers.

[0079] In one embodiment, ethylene-vinyl acetate (EVA) copolymers are used as both the first and second polymeric material, as well as the optional third polymeric material due to their excellent mechanical and physical properties.

[0080] In one embodiment the first active ingredient is dissolved in both the first polymeric material of the first layer and the second polymeric material of the sheath. In these embodiments the first active ingredient is preferably present in the first and second polymeric material at concentration at or below the saturation concentration of said first active ingredient at 25°C.

[0081] Within the context of the present invention, the term "the saturation concentration" refers to the maximum possible quantity of the first active ingredient that can dissolve in the polymeric material of the respective layer, at 25°C and normal atmospheric pressure.

[0082] Thus, the inventors of the present invention have found that if the concentration of the first active ingredient in the first layer (core or intermediate layer) is enough to sustain the release (e. g. in crystal form) the desirable and preferably zero order release rate of the first active ingredient can be obtained with lower concentrations of the first active ingredient when said active ingredient is loaded into both the first layer and the sheath (and optionally the second layer e. g. intermediate layer) during manufacturing, compared to a drug delivery system ( e. g. core / sheath) in which the first active ingredient initially is present only in a single layer, e. g. the core.

[0083] In a preferred embodiment according to the invention, the sheath comprises a concentration of at least 10 wt% of the second active ingredient based on the weight of the sheath. Using a drug delivery system in which the concentration of the second active ingredient (e. g. a progestational steroid) in the sheath is at least 10wt%, it is ensured that the desired near zero-order release behavior of the first active ingredient are observed for a longer period of time. In addition such high concentrations of the active ingredient are associated with good physical stability of the second active ingredient.

[0084] By substantially zero order is meant that a substantially constant amount of the first active ingredient is released over a given period of time. In some embodiments, the system exhibit a substantially zero order release profile of the first active ingredient (e. g. an estrogenic steroid) over a treatment period of at least 28 days, preferably around two to three months.

[0085] It is a well known problem that the release rate of the active ingredient in the first layer (core or intermediate layer) decreases as active ingredient ( s ) that is deeper inside the system must diffuse to the surface. However loading the sheath with both the second active ingredient and the first active ingredient also present in the first layer, the inventors of the present invention has found that the release rate of the first active ingredient is constant for a longer period of time and with a substantially zero-order release rate of the first active ingredient during the desired treatment period.

[0086] The presence of the second active ingredient in the relatively high concentrations in the sheath will not only lead to an increase in the mean path length the molecules of the first active ingredient in the core have to travel between two points in the sheath, but will also reduce the amount of the first active ingredient which can be dissolved in the second ethylene-vinyl acetate copolymer of the sheath, accordingly decreasing the release rate of the first active ingredient though said sheath and providing a lower burst. This will provide a reliable and constant release rate of the first active ingredient. Accordingly, the sheath can be made smaller, providing a smaller product.

[0087] Furthermore, the release rate of the first active ingredient in the drug delivery system can be specifically tailored to meet specific requirements by modifying the sheath thickness. For instance a thicker sheath increases the diffusion path for the first active ingredient in the core, and accordingly decreases the release rate.

[0088] It is in this respect preferred that the second active ingredient (e. g. a progestational steroid) is incorporated and / or dispersed in the second polymeric material in the form of particles, preferably crystals. Such particles / crystals will form a repository of solid, undissolved crystals which will act as a slow release depot. Over time, when the second active ingredient is delivered to the surroundings, some of the crystals will be dissolved in the second polymeric material, thereby providing a prolonged release of the second active ingredient. Furthermore, the stability of the second active ingredient in the drug delivery system is improved when the second active ingredient is incorporated into the sheath as undissolved particles / crystals. Without being bound by theory it is believed that maintaining a concentration of the second active ingredient at high concentrations in the sheath it is assumed that a porous network path is created by crystals and wherein a number of sites / openings / pores in the matrix of the second polymeric material remains empty, ensuring that the first active ingredient only can be released through a tortuous path in the sheath, thereby the diffusion length increases and the release rate is controlled.

[0089] It is preferred that the first active ingredient is incorporated in the first polymeric material in a dissolved form and / or dispersed in said material in the form of particles, preferably crystals. As already discussed for the second active ingredient, having an active ingredient in crystal form increases that the stability of said active ingredient in the drug delivery system. The same is the situation for the incorporation of the first active ingredient in the polymeric material of the respective layers.

[0090] It is important that the second active ingredient is dispersed and / or incorporated in the second polymeric material to an extent sufficient to control the diffusion rate of the first active ingredient through the sheath.

[0091] Without being bound by theory, it is believed that the second active ingredient in the sheath will function as a filler and control the release rate of the first active ingredient. When the second active ingredient present in the sheath is released to the surroundings, the concentration of said second active ingredient is reduced and it is believed that diffusion of water into the sheath may be facilitated leaving behind an empty porous matrix and / or empty pockets / holes and / or the sheath may collapse thereby ensuring the desired zero-order release profile of the first active ingredient. Thus, it is believed that the space initially occupied by the second active ingredient leaves behind an empty porous matrix which may become water filled due to ingress of water and / or may leave behind empty pockets / holes. This is contrary to the conventional findings in which the release rate of an active ingredient ( in crystalline form) in a core surrounded by a nonmedicated sheath slightly decreases over time, i. e. the desired zero order release rate cannot be maintained over a desired treatment period for such conventional vaginal rings.

[0092] In some embodiments it is preferred that at least 14 wt% of the second active ingredient is dispersed and / or incorporated in the second polymeric material, even more preferred at least 20 wt%, and even more preferred at least 25 wt%.

[0093] In a preferred embodiment the first polymeric material is a first ethylene-vinyl acetate (EVA) copolymer, the second polymeric material is a second ethylene-vinyl acetate copolymer, and the optional third polymeric material is a third ethylene-vinyl acetate copolymer. The first, second and third EVA-copolymer may be the same or different. For example, the first and optional second layer may be made of the same EVA-copolymer, and the sheath of a different EVA-copolymer, or alternatively the first layer is made of one EVA-copolymer and the sheath and second layer of the same or different EVA-copolymers. The EVA- copolymers for the first, second and / or third layer may be any EVA-copolymer but it is preferred that the first, second and / or third ethylene-vinyl acetate copolymer has a vinyl acetate content from 9 to 40 wt%.

[0094] The vinyl acetate concentration of the EVA-copolymer determines the rate of diffusion and solubility of the active ingredients through the system and generally, the lower the vinyl acetate concentration, the slower the active ingredient will be released from the copolymer or migrate through it. In order to provide the desired release profile of the first active ingredient it is preferred that the first layer comprises an ethylene-vinyl acetate copolymer with a vinyl acetate content from 26 to 40 wt%, preferably 26 wt%, 33 wt% or 40 wt%.

[0095] The second ethylene-vinyl acetate copolymer of the sheath may have a vinyl acetate content from 12 to 28 wt%, preferably between 14 and 24 wt%, such as around 20 wt%, as these materials will provide the desired release profile through the sheath, e. g. by ensuring that the second active ingredient release rate is at the optimal level, however a higher vinyl acetate content such as e. g. 33 wt% or 40 wt% can also be used in the present invention.

[0096] In one embodiment of the present invention the first and second ethylene-vinyl acetate copolymer have the same vinyl acetate content, i. e. the first and second ethylene-vinyl acetate copolymer are the same.

[0097] The third ethylene-vinyl acetate copolymer of the optional second layer may be the same as the first and / or second ethylene-vinyl acetate copolymer, or a different ethylene-vinyl acetate copolymer, e. g. an ethylene-vinyl acetate copolymer with a vinyl acetate content from 9 to 40 wt%.

[0098] When a specific vinyl acetate content e. g. 20 wt% is mentioned it refers to the weight% content provided by the manufacture. However, manufactures may use different internal analytical methods for determining vinyl acetate content, and there may therefore be variations in the range of 1 - 2 % in the actual vinyl acetate content depending on the manufacture. Thus, in the present invention the vinyl acetate content refers of the vinyl acetate content in the ethylene-vinyl acetate copolymer determined by high resolution NMR according to standard methods. The wt% of the vinyl acetate content in the ethylene- vinyl acetate copolymer is the wt% content based on the weight of the ethylene-vinyl acetate copolymer.

[0099] The drug delivery system according to the invention is preferably a dual-drug delivery system, i. e. it releases two active ingredients the first and the second active ingredient. However, the drug delivery system according to the invention may also comprise only a single active ingredient, as in the modified embodiment, or more than two active ingredients, e. g. a further third active ingredient etc. It is in this respect preferred that the active ingredients used in the drug delivery system are locally or systematically active medicaments, which can be administrated subcutaneously, subdermally, vaginally or to the uterus.

[0100] It is however preferred that the first active ingredient and / or second active ingredient and / or further active ingredients is / are selected from a hormone, e. g. steroids ( such as an estrogenic steroid, a progestational steroid and / or danazol ), a spermicide, an antimicrobial agent, an anti-viral agent, an aromatase inhibitor ( such as anastrozole, letrozole and exemestane), and combinations of said ingredients.

[0101] In one preferred embodiment the first active ingredient is an estrogenic steroid and the second active ingredient is a progestational steroid.

[0102] The estrogenic steroid is preferably estradiol and the progestational steroid is selected from the group consisting of a progestogen, progesterone, etonogestrel, levonorgestrel, d-1-norestrel, segesterone and norethindrone, preferably levonorgestrel.

[0103] The steroids can be selected for preventing contraception, for treating a condition such as vaginal atrophy and endometriosis; and / or for hormone replacement therapy e. g. relating to symptoms associated with menopause, such as hot flashes.

[0104] The drug delivery system according to the invention is adapted to deliver pharmaceutically effective amounts of the active ingredients. By "pharmaceutically effective, " it is meant an amount, which is sufficient to affect the desired physiological or pharmacological change in the subj ect. This amount will vary depending upon such factors as the potency of the active ingredient, the desired physiological or pharmacological effect, and the time span of the intended treatment. Those skilled in the arts will be able to determine the pharmaceutically effective amount for any given active ingredient in accordance with standard procedures.

[0105] It is however preferred that at the time of manufacturing the first layer and / or second layer does not comprise further active ingredients besides the first active ingredient, and / or that the sheath does not comprise further active ingredients besides the first active ingredient and the second active ingredient. In this way an optimal release profile is provided for the ready-to-use delivery system.

[0106] The thickness of the sheath, which preferably is the outer layer of the drug delivery system according to the present invention, can be varied to further control the release rate of the first active ingredient. Thus, the drug delivery system according to the invention does preferably not contain / comprise any sheath / membrane (e. g. a rate-controlling sheath) without the first active ingredient.

[0107] In one embodiment the thickness of the sheath is between 0. 05 mm and 3 mm. Said thickness can preferably be from 50 μm to 1 mm, more preferred from 300 μm to 900 μm, and even more preferred from 400 to 800 μm. In certain embodiments the thickness of the sheath is 50 μm, 100 μm, 200 μm, 300 μm, 400 μm, 500 μm, 600 μm, 700 μm, 800 μm, 900 μm, and 1000 μm.

[0108] A person skilled in the art will in view of the present invention understand that a thin sheath can contain less active ingredient than a thicker sheath; and that the concentration of the second active ingredient in the sheath should be enough to sustain release over the desired treatment period. By using an ethylene-vinyl acetate copolymer grade with higher or lower vinyl acetate-content the sheath' s thickness can be altered while maintaining essentially the same average release rate of the first active ingredient. For instance, if a thicker sheath is desired because more of the second active ingredient has to be accommodated in the sheath, an ethylene-vinyl acetate copolymer grade with higher vinyl acetate content can be chosen.

[0109] For human use, the core preferably has a round cross-section with a cross-sectional diameter of between 2 and 8 mm, more preferably between 3 mm and 6 mm and even more preferably around 5 mm. Other dimensions are contemplated within the scope of the present invention for use in animals.

[0110] In a preferred embodiment the drug delivery system according to the present invention is an intravaginal ring, an implant or an intrauterine device.

[0111] The dimensions of the drug delivery system may vary depending upon the administration site of the system, the anatomy of the subj ect, the amount of active ingredient to be delivered to the patient, the time over which the active ingredient is to be delivered, the diffusion characteristics of the active ingredient and other manufacturing considerations.

[0112] I f the drug delivery system is an intravaginal ring, the main requirement being that the drug delivery system should be flexible enough to enable bending and insertion inside the vaginal cavity and rigid enough to withstand the expulsive forces of the vaginal musculature without causing abrasion to the vaginal epithelium. The outer diameter of such an intravaginal ring may range, e. g. from about 45 mm to about 65 mm, and / or the length of the fiber elements forming the intravaginal ring may have a length from 150 to 170 mm, preferably from 154 to 165 mm, such as about 163.5 mm.

[0113] In the context of the present invention the term intravaginal ring, also contemplates ring designs or structures, which have other shapes, e. g. polygonal shapes and / or wavy shapes, or where the structure is not a complete and / or closed circle / shape.

[0114] In a preferred embodiment the intravaginal ring at the time of manufacturing comprises:

[0115] - a first layer comprising a first ethylene-vinyl acetate copolymer having a vinyl acetate content of 28 wt% or 33 wt%, and an estrogenic steroid in dissolved form e. g.

[0116] 0.277 wt% in EVA28 ( saturation concentration) and

[0117] - a sheath comprising a second ethylene-vinyl acetate copolymer having a vinyl acetate content of 15 wt%, 20wt%, 24 wt%, 28 wt%, 33 wt% or 40 wt%, and

[0118] ■ 27 wt% of an progestational steroid based on the weight of the sheath, and

[0119] ■ the same estrogenic steroid as loaded in the core in a concentration that will provide the same chemical potential as in the core, or alternatively in a lower concentration.

[0120] The core of said preferred embodiment has a cross-sectional diameter of 5 mm and the sheath a thickness of 850 or 900 μm. The outer diameter of the ring is 57 mm.

[0121] In a first preferred embodiment according to the present invention the intravaginal ring does not comprise more than the two active ingredients, e. g. an estrogenic steroid and a progestational steroid, and / or does not comprise further cores and / or layers such as sheaths and membranes, i. e. the intravaginal ring according to the invention consists of a single core and a single sheath completely surrounding said core, and wherein, at the time of manufacturing said intravaginal ring, an estrogenic steroid is loaded in the core and the sheath, and an progestational steroid is loaded in the sheath.

[0122] In a second preferred embodiment according to the present invention the intravaginal ring comprises three layers, a core completely surrounded by an intermediate layer, which is further completely surrounded by a sheath. A progestational steroid is loaded in the sheath and in a first alternative embodiment the estrogenic steroid is preloaded in the core, the intermediate layer and the sheath, and in a second alternative embodiment the estrogenic steroid is preloaded in the intermediate layer and the sheath, i. e. the core is not pre-loaded with the estrogenic steroid.

[0123] The present invention also relates to a method of manufacturing the drug delivery system according to the present invention.

[0124] Said method comprises

[0125] a. providing a first layer comprising a first polymeric material and a first active ingredient,

[0126] b. providing a sheath comprising,

[0127] - a second polymeric material and a second active ingredient, and

[0128] - the same first active ingredient as in the first layer, and

[0129] c. forming said ready-to-use drug delivery system.

[0130] In order to provide a homogeneous composition of the sheath it is preferred that the first and second active ingredient individually are mixed with the second polymeric material, e. g. gently mixing the respective active ingredient and the second polymeric material with a spoon, thereby providing a first and second sheath mixture that each comprise an active ingredient. Thereafter the first and second sheath mixtures are combined and mixed in order to provide the composition of the sheath.

[0131] The method according to the invention may further comprise step b' which is providing a second layer comprising a third polymeric material. Step b' is provided before step c.

[0132] When the first layer is the core, the second layer is an intermediate layer, and said intermediate layer comprises the same first active ingredient as in the first layer.

[0133] When the first layer is the intermediate layer, the second layer is the core, and said core does not comprise the first active ingredient at the time of manufacturing. However, in an alternative embodiment when the first layer is the intermediate layer, the core may also be loaded with the first active ingredient. This is especially relevant when the first active ingredient is loaded in the intermediate layer in dissolved form, as the presence of the first active ingredient in the core ( second layer) will prevent back-diffusion into said core.

[0134] Preferably, both the two-layered and three-layer ready-to-use drug delivery systems are co-axially arranged, i. e. the core, intermediate layer and sheath share a common axis.

[0135] In order to provide the drug delivery system according to the invention it is preferred that step c. i. e. the forming step comprises

[0136] i. co-extruding the first layer and sheath, and optionally the second layer, into a fiber, ii. cutting the fiber into an appropriate length thereby providing a fiber element, iii. using said fiber element to form the ready-to-use drug delivery system.

[0137] As the first layer and sheath, and the optional second layer are co-extruded in step i., a very simple and inexpensive embodiment according to the invention is provided. However the first layer and sheath, and the optional second layer can be formed in separate inj ection molding or extrusion steps if preferred. Inj ection molding and extrusion are well known in the art and will not be discussed further in this application.

[0138] It is preferred that forming the ready-to-use drug delivery system in step iii. is obtained by combining the ends of the fiber element to form an intravaginal ring; or forming an implant out of the fiber element; or using the fiber element to form an implant or an intrauterine device.

[0139] During extrusion the active ingredients (e. g. steroids ) will to some degree dissolve in the polymer melt as result of higher solubility at higher temperatures. Upon cooling the amount dissolved in excess relative to the amount that can dissolve at room temperature should re-crystallize. I f this process is delayed the result is a physically instable product. It is accordingly preferred that the method further comprises a cooling step in which the provided fiber or fiber element is cooled to a temperature of 20°C or below for providing the crystals of the active ingredient ( s ) in the sheath and / or the first layer and / or the optional second layer. This may be obtained e. g. by placing the fiber into a cooling water bath.

[0140] Without being bound by theory, the inventors believe that active substances dissolved at elevated extrusion temperatures in the polymer melts will re-crystallize in the sheath and the first layer (and in the optional second layer, if said layer also contains the first active ingredient) upon cooling as a result of a sharp drop of the saturation solubility of the active ingredients in the polymers. This process should preferably take place promptly to avoid severe supersaturation which is undesirable. The re-crystallization process is believed to be facilitated by "seed" crystals. For instance, a relatively high concentration of progestational steroid in the sheath of at least 10 wt% based on the weight of the sheath, will result in a higher concentration of "seed" crystals, upon which recrystallization can occur when the fiber is cooled after co-extrusion. Thus, in the cooling step prompt recrystallization is facilitated by crystals surviving the extrusion process and for this reason a high drug load of at least the second active ingredient is desired in order to avoid that most or all crystals disappear during extrusion and no seeds are left to prompt re-crystallization. It should furthermore be noted, that in the present invention the sheath comprises both the first and second active ingredient, e. g. estradiol and progestogen respectively, during extrusion, and accordingly the recrystallisation of the progestogen will take place in the presence of estradiol. Surprisingly the inventors of the present invention have shown that this, contrary to the expectations, has no effect on the release of the progestogen from the drug delivery system, thereby providing a system with a reliable and desired release rate.

[0141] It is preferred that said cooling step is performed immediately after step i., i. e. as fast as is practically possible from a production point of view, i. e. preferably within less than 30 minutes from completion of the fiber in step i., and even more preferred within a period of a few ( 1 - 5) seconds to 10 minutes from completion of the fiber in step i., and even more preferred not more than about 2 minutes from completion of said fiber.

[0142] It is preferred that the vaginal rings are produced by heat welding the fiber ends together without the addition of further EVA material or adhesive. The method according to the invention may be modified in that the sheath does not comprise the second active ingredient, as discussed earlier for the modified embodiment.

[0143] The invention will be explained in greater detail below, describing exemplary embodiments of intravaginal rings ( IVRs ) according to the invention, wherein

[0144] Figure la shows a perspective view of a first preferred embodiment of an intravaginal ring according to the invention,

[0145] Figure lb shows a perspective view of a first alternative of a second preferred embodiment of an intravaginal ring according to the invention,

[0146] Figure 1c shows a perspective view of a second alternative of a second preferred embodiment of an intravaginal ring according to the invention,

[0147] Figure 2 are microscopy pictures showing layer thicknesses of sheath, intermediate layer and core for IVRs KI - K6,

[0148] Figure 3a shows the average daily release of progesterone for 28 days for IVRs: KI, K2, and K3,

[0149] Figure 3b shows the average daily release of progesterone for 28 days for IVRs: K4, K5 and K6,

[0150] Figure 4a shows the release of progesterone for IVRs: KI and K4,

[0151] Figure 4b shows the release of progesterone for IVRs: K3 and K6, Figure 5 shows the simulated average daily release of estradiol from IVR with a sheath thickness of 50 pm 100 pm, 300 pm, and 650pm,

[0152] Figure 6 shows the average daily release of estradiol from KI and K4 at two time points TO and after 23 days,

[0153] Figure 7a shows simulated equilibration time of IVRs with 650 pm sheath thickness at 25°C. Time point: 1, 10, 30, 50 and 100 days,

[0154] Figure 7b shows simulated equilibration time of IVRs with 300 pm sheath thickness at 25°C. Time point: 1, 10, 30, 50 and 100 days,

[0155] Figure 7c shows simulated equilibration time of IVRs with 100 pm sheath thickness at 25°C. Time point: 1, 10, 30, 50 and 100 days,

[0156] Figure 8 shows simulated release rate for a different preloading amount in the sheath of a two-layered IVR ( 5 mm diameter, 163.5 mm fiber length, 550 μm sheath thickness ),

[0157] Figure 9 shows simulated release rate for a different preloading amount in the sheath of a three-layered IVR ( 5 mm diameter, 163.5 mm fiber length, 650 pm sheath thickness ),

[0158] Figure 10 shows release rates for a different preloading amount in the sheath of KI ( 0 % equilibration concentration), K2 ( 50 % equilibrium concentration), and K3 ( 100 % equilibrium concentration), in addition to KI after a period of 23 days (equilibration),

[0159] Figure 11 shows the release rate of estradiol after a four-month equilibration period for IVRs KI and K3, Figure 12 shows the release rate of estradiol for different estradiol preloading amounts in the sheath of K4, K5, and K6, in addition to the release rate of estradiol for K4 after 23 days of equilibration,

[0160] Figure 13 shows the release rate of estradiol for IVRs K4 (before and after a four-month equilibration period) and K6 (after manufacturing), and

[0161] Figure 14 shows the release rate of progesterone for IVRs KI, K3 and K4 (before and after a four-month equilibration period) and K6 (after manufacturing).

[0162] The invention is described with the assumption that the drug delivery system is an intravaginal ring and the first active ingredient is an estrogenic steroid and the second active ingredient is an progestational steroid. However, these assumptions are not to be construed as limiting, and the system could just as easily be an IUD, such as a hormone spiral, or an implant and one or both of the active ingredients could be different steroids, hormones, spermicides, antimicrobial agents, anti-viral agents, aromatase inhibitors, or combinations of said agents.

[0163] Fig. la shows a first embodiment of an intravaginal ring ( IVR) la according to the invention. In said embodiment the IVR is a two layered system comprises a first layer 2a defining a core 3a, and a sheath 4 surrounding said core. Said first layer 2a is made of a first ethylene-vinyl acetate copolymer 5 and comprises an estrogenic steroid 6, and the sheath is made of a second ethylene-vinyl acetate copolymer 7 and comprising a progestational steroid 8 and an estrogenic steroid 6 at the time of manufacturing, i. e. the sheath is preloaded with both the progestational steroid 8 and the estrogenic steroid 6. Fig. lb shows a first alternative of a second embodiment lb of a three-layered intravaginal ring ( IVR) according to the invention. In said embodiment the IVR comprises a second layer 9 defining a core 3b, a first layer 2b defining an intermediate layer 10, and a sheath 4 surrounding said intermediate layer. The first layer 2b ( intermediate layer 10 ) is made of a first ethylene-vinyl acetate copolymer 5 and an estrogenic steroid 6. The sheath 4 is made of a second ethylene-vinyl acetate copolymer 7 and is preloaded with a progestational steroid 8 and the estrogenic steroid 6. The second layer 9 (core 3b) is made of a third ethylene-vinyl acetate copolymer 11, and does not comprise any active ingredients at the time of manufacturing the IVR, i. e. the core is not preloaded with the estrogenic steroid. As is evident from the drawings, the three-layers of the intravaginal ring are co-axially arranged, i. e. the core, intermediate layer and sheath share a common axis.

[0164] Fig. 1c shows a second alternative of the second embodiment of the three-layered intravaginal ring ( IVR) 1c according to the invention. Said IVR corresponds to the first alternative in fig. lb, with the modification that the first layer 2c defines the core 3c and the second layer 9' defines the intermediate layer 10 '. In the second alternative the first layer 2c ( the core 3c) is made of the first ethylene-vinyl acetate copolymer 5 and comprises the estrogenic steroid 6, the second layer 9' (the intermediate layer 10' ) is made of the third ethylenevinyl acetate copolymer 11 and is preloaded with the estrogenic steroid 6. The sheath 4 is the same as for the first alternative, i. e. sheath 4 is made of a second ethylene-vinyl acetate copolymer 7 and is preloaded with a progestational steroid 8 and the estrogenic steroid 6.

[0165] Figs. 2 - 14 are discussed in further details below with reference to the following examples. EXAMPLES

[0166] A number of experiments and stimulations were performed in order to investigate if preloading of the sheath (and / or the optional second layer) can provide an inherently ready-to-use drug delivery system, i. e. if the need for a time-consuming equilibration period can be eliminated, and if such a ready-to-use preloaded drug delivery system had any effect on the release rate of the first and second steroids.

[0167] Example 1: Manufacturing of intravaginal rings.

[0168] A number of drug delivery system in the form of intravaginal rings ( IVRs ) was produced. The first steroid is estradiol (E2 ) and the second steroid is progesterone ( PGN). The targeted length of the fiber ( fibers that form the IVRs ) is 163.5 mm, and the fiber diameter is 5 mm for all the IVRs. The first, second and third polymeric material are ethylene-vinyl acetate copolymer with a vinyl acetate of 28 wt%, EVA28.

[0169] The following six batches of three-layered intravaginal rings were produced.

[0170]

[0171] Table 1: Produced batches of three-layered IVRs. All layers, i.e. first layer, second layer and sheath are made of EVA28. The wt% of estradiol in the sheath is calculated using the formulas discussed earlier in the present application. Solubility of estradiol in EVA28 at 37 °C is 2.77 mg / g.

[0172] In each of the batches KI - K3 the first layer (core ) and the second layer (intermediate layer) are made of the same ethylene-vinyl acetate copolymer, EVA28 and contains the same amount of estradiol (KI: 0.30 wt%, K2: 0.24 wt%, and K3: 0.20 wt% ). Accordingly there will be no interfacial partitioning of estradiol between the core and intermediate layer, and said two layers will therefore function as a single layer ( core ) in relation to among others the release profile of estradiol. The three-layered batches KI, K2 and K3 will therefore correspond to a two-layered intravaginal ring having a first layer with the respective amount of estradiol and a sheath comprising progesterone. For batches K2 and K3 the sheath also comprises estradiol.

[0173] Since the initial concentration of estradiol in the IVRs have an effect of the release of estradiol, each of the batches KI -K3 have the same theoretical target content of estradiol ( 5.55 mg) in order to eliminate said concentration effect.

[0174] In relation to the "two-layered" batches KI - K3 the sheath of batch KI is not preloaded with estradiol, the sheath of K2 is partly preloaded with estradiol ( 50% equilibrium concentration reached) and the sheath of K3 is completely preloaded with estradiol ( 100% equilibrium concentration reached), i. e. the sheath of K3 is in thermodynamic equilibrium with the first layer ( core or intermediate layer respectively) at 25°C at the time of manufacturing.

[0175] In relation to the three-layered batches K4 - K6, the sheath of batch K4 is not preloaded with estradiol, the sheath of K5 and K6 are each partly preloaded with estradiol, i. e. the concentration o f estradiol in the sheath is below saturation. The sheath of K5 i s (pre- loaded with 0. 088 % wt% estradiol in the sheath ( about 43% eguil ibrium concentration reached) and K6 i s preloaded with 0. 146 wt% estradiol in the sheath ( about 72 % equil ibrium concentration reached).

[0176] In KI, K2 and K3 the estradiol concentration is relatively low i. e. the estradiol i s loaded in the batches in dis solved form in both the f irst layer ( core ) and second layer ( intermediate layer. As already stated, s ince said two layers o f each batch are made of the same EVA and have the same estradiol concentration, said two layers are in e f fect a single layer, i. e. KI - K3 are as such two- layered IVRs.

[0177] In K4, K5 and K6 estradiol i s loaded in the intermediate layer ( first layer ) in a higher concentration ( 10 wt% ) i. e. estradiol wil l be present in both di ssolved and crystal form in said layer. The core ( second layer ) i s inactive, i. e. it cons ists only of EVA 28 at the time of manufacturing the IVRs.

[0178] For batches having a low estradiol content ( KI - K3 ) it is relevant to ensure that the preloaded and not preloaded rings have the same estradiol content, since the estradiol release is dependent on the initial concentration o f estradiol in the batch. The chosen estradiol concentration in the core i s 0. 3 wt% which leads to an estradiol content of about 5. 55 mg in the rings. For the preloaded rings, K2 and K3, thi s amount should be di stributed in both the core and sheath, thus increas ing the preloading in the sheath wi ll decrease the amount of estradiol in the core and vice-versa.

[0179] In the current examples, two levels o f preloading are considered. First, the estradiol equil ibrium concentration in the K3 batch i s calculated as 0. 2 wt%, (per weight o f the core ). The concentration o f progesterone in the sheath i s 27wt%, i. e. the concentration o f estradiol in the sheath can be calculated as ( 1- 0. 27 ) * 0. 2, i. e. the estradiol concentration in the sheath of the K3 batch is 0. 146 wt% (by weight of the sheath).

[0180] For a preloading lower than the equi librium value, as in batch K2, the concentration in the core was chosen to be 0. 24 wt% ( any other value can be chosen but should be lower than 0. 3 wt% ), and the remaining amount o f estradiol ( from 5. 55 mg) in the sheath leads to a concentration in EVA 28 o f 0. 12 wt% (weight o f EVA28 in the sheath), then accounting for the presence o f progesterone, the concentration of estradiol becomes 0. 087 6 wt% ( 0. 12 * ( 1 - 0. 27 ) ). For the subsequent examples, thi s concentration is referred to as 50 % equi librated as the preloading level i s close to the hal f of the equil ibration concentration in the sheath ( 0. 14 6 wt% ).

[0181] The IVR batches were manufactured using the method according to the invention, with the fol lows consecutive steps:

[0182] 1. Weighing of mi lled EVA and relevant steroid ( estradiol and / or progesterone ) according to the detail s in table 1 and table 3:

[0183] a ) weighing of mil led EVA and estradiol, wherein i. when the first l ayer i s the core ( KI, K2, K3 ):

[0184] weighing of mil led EVA and estradiol for the first layer and / or the second layer,

[0185] i i. when the f irst l ayer is the intermediate layer ( K4, K5, K6 ): weighing o f mi lled EVA and estradiol for the f irst layer, and weighing of mi lled or pelleted EVA for the second layer ( core ), and b ) weighing of mi lled EVA and progesterone (K1, K4 ), or weighing o f mil led EVA, progesterone and estradiol (K2, K3, K5, K6 ) for the sheath. 2. Mixing the respective EVAs and relevant steroid ( s ) for each layer, i. e. core, intermediate layer and sheath, 3. Compounding and pelletizing said mix for each layer, 4. Mixing the provided pelletized mix with magnesium stearate (mgst),

[0186] 5. Trico-extruding the core, intermediate layer and sheath into a fiber,

[0187] 6. Cutting the fiber into an appropriate length thereby providing a fiber element, and

[0188] 7. Combining the ends of fiber element to form IVRs of the batches KI - K6.

[0189] A two-layered intravaginal ring is manufactured in a similar manner, but the steps relating to the intermediate layer is omitted.

[0190] Table two shows the raw materials were used for the manufacture of the IVRs KI - K6.

[0191]

[0192] Table 2: Raw materials

[0193] Step 2 was obtained by transferring the milled EVA and steroids to a mixing bag in the proportions specified in table 3.

[0194]

[0195] Table 3: Formulations for preparing the layers of the IVR batches KI -K6 (after compounding and addition of Mgst).

[0196] * theoretical values

[0197] The formulations containing only progesterone ( sheath of KI and K4 ) were mixed using a blender, formulations containing estradiol were mixed manually for 3 min.

[0198] The compounding in step 3 was conducted using an 11 mm closely intermeshing twin screw extruder (Pharma 11 twin screw extruder from Thermo Scientific). The compounding set temperature of all batches is 90 °C in order to produce the relevant pellets with the respective steroids.

[0199] To enhance the processing properties of the pellets in the triextrusion process, Magnesium stearate (Mgst) was added to all batches in step 4. First, 0. 1 wt% of Mgst was added to the mixing bags with the relevant pellets and then manually mixed for around 3 minutes. Mgst is also added to the EVA pellet for the second layer (core) for bathes K4, K5 and K6 in the same portion. In said batches estradiol are not preloaded in the core. In step 5 a tri-extruder with a 6 mm die was used to produce the tri-layer fibers with a diameter of 5 mm. The tri-extruder line comprises a single screw extruder 16 / 25 (D / L) ( i. e. 16 is the diameter and 25 is the length) for the core, and a single screw extruder 12 / 33. 3 for the sheath and intermediate layers. The volume of the melt pumps is 0. 6 cm3for the core and 0. 3 cm3for the sheath and intermediate.

[0200] The production speed was set to around to 1 m / min, see also table 4. The fiber characteristics ( e. g., diameter and layer thicknesses ) were controlled by the melt pump speed for the three extruders to produce a fiber with a 5 mm diameter with the required layers thickness. All the fibers were extruded using extrusion temperature between 90 °C and 100 °C. The die temperature was set to 90 °C.

[0201]

[0202] Table 4: Melt pump speed of the three extruders

[0203] The melt pump speed was calculated based on the capacity of the pumps, with some adj ustments to reach the target. The melt pump values are shown in table 4.

[0204] After tri-extrusion, the fibers are cut into a length of 163.5 mm in step 6 and then welded together to form the intra-vaginal rings ( IVRs ) in step 7. For each batch 20 IVRs were produced.

[0205] In order to evaluate the thickness of the sheath and intermediate layer the respective IVRs were observed under a SMZ Microscope with zoom 2. 00x, exposure time 70 ms, using a camera DFK 33UX264. Two or three distinct layers were observed in the microscope, see fig. 2, and the sheath and intermediate thicknesses are measured for three samples from each batch.

[0206] The results are shown in fig. 2 and summarized in table 5.

[0207]

[0208] Table 5: Thickness of sheath and intermediate layer. Target dimension and measurement from microscopy pictures. Numbers in brackets are the measured standard deviation in pm.

[0209] * Since the core and the intermediate layer are made of the same material, there is no visual boundary between the core and intermediate later. Thus, the core and intermediate layer is considered to be a ] single layer, i.e. a core.

[0210] In order to investigate the release rate of estradiol and progesterone from the six batches KI - K6 the respective IVRs were tested in an in vi tro dissolution test comprising a shaking incubator apparatus and a simple aqueous dissolution media (Water with SDS surfactant ( 1 wt% ) ). The experiment was conducted at 37°C, and the medium is refreshed daily during the 28 days test period.

[0211] The following in-vi tro release analyses were made:

[0212] - Less than 5 days after the tri-extrusion a first in-vi tro release analysis started for all batches,

[0213] - For batches KI, and K4 a second in-vi tro release analysis were started at 23 days after tri-extrusion, and

[0214] - For batch KI, K3, and K4 a third in-vi tro release analysis were started after 4 months and 6 days after tri- extrusion.

[0215] The samples were analyzed by HPLC. The average daily release rates for the first in-vi tro release analysis for progesterone is shown in table 6, and will be discussed in further details in example 3.

[0216] The average daily release rates for the first in-vi tro release analysis for estradiol is shown in table 7 and will be discussed in further details in example 7.

[0217] Table 6: Average Daily release of progesterone (PGN) for 28 days in KI - K6

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224] Table 7: Average Daily release of estradiol (E2) for 28 days in KI - K6

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231] Example 3: Effect of preloaded estradiol in the sheath on the release rate of progesterone.

[0232] The release rate of progesterone was evaluated to investigate if said release rate depended on the preloading of estradiol in the sheath and / or the concentration of estradiol in the intravaginal ring (dissolved without estradiol crystals ).

[0233] The average daily release rates for the first in-vi tro release analysis for progesterone is shown in table 6, and in fig. 3a (KI - K3 ), and fig. 3b (K4 - K6 ). Fig. 3a shows the progesterone release of KI, K2 and K3 having a sheath thickness of 550 pm, and fig 3b, shows the progesterone release of K4, K5 and K6 having a sheath thickness of 650 pm.

[0234] The release characteristics of progesterone can be summarized as shown in Table 8.

[0235]

[0236] Table 8: Release characteristics of progesterone (PGN) of the IVRs KI - K6

[0237] As is evident from table 8 and figs. 3a and 3b, the average daily release of progesterone from the IVR-batches KI and K4 where the sheath is not preloaded with estradiol, corresponds to the progesterone release from the batches K2, K3 and K5, K6 that are preloaded with estradiol. Accordingly, it can be concluded that the progesterone release is not affected by the pre-loading of the sheath with estradiol.

[0238] Fig. 4a compares the progesterone release from the two IVR batches that was not preloaded with estradiol in the sheath, KI and K. From said figure it is evident that the progesterone release from the Kl-batch that contained dissolved estradiol in the core ( 0.3 wt% in the core and intermediate layer) showed a slightly lower release compared to the K4-batch that also contained estradiol crystals in the first layer ( 10 wt% estradiol in the intermediate layer). This effect might be attributed to more dissolved progesterone in the K4 batch, as said ring has a thicker sheath (K4: 650 μm vs. KI: 550 pm). In addition, a slight depletion of progesterone crystals is visible for the Kl-batch compared to the K4-batch after about day 20. This is likely due to the thinner sheath of KI, see table 5 and table 1.

[0239] However, as is evident from fig. 4b that compares the progesterone release of the preloaded IVR-batches K3 ( 550 pm) and K6 ( 650 pm), the difference in progesterone release relating to sheath thickness is reduced, as the progesterone release is substantial identical for said two batches during the 28 days testing period.

[0240] Example: Effect of sheath thickness on the release of estradiol from a two-layered intravaginal ring with estradiol only loaded in the core (first layer).

[0241] In order to investigate the effect of the sheath thickness on the release rate of estradiol, a series of two-layered intravaginal rings in which estradiol is only loaded in the core has been evaluated using computational modeling and simulation.

[0242] The simulated IVRs have the same dimensions as the produced KI - K6 batches, i. e. the fibers for forming the IVRs have a diameter of 5 mm and a length of 163.5 mm. The core and the sheath of the simulated IVRs are also made of EVA 28. The simulated IVRs have sheath thicknesses of 50 pm, 100 m, 300 pm, 650 pm. The core' s dimension decreases when the thickness of the sheath increases, i. e. the diameter of the IVR is the same for all examples.

[0243] The IVRs a loaded with 0.3 wt% of estradiol in the core ( first layer) and 27 wt% progesterone is loaded in the sheath, i. e. the simulated two layered IVRs correspond to the produced Kl-batch. It is assumed that no estradiol has diffused to the sheath at time 0 for the in-vi tro release simulations, i. e. no equilibrium period has taken place. The model considers the diffusion of the estradiol from the core to the sink, which is driven by the concentration gradient in the system, and it assumes the receiving medium to be a perfect sink. The release rate of estradiol is affected by the sheath thickness and the initial concentration of estradiol in the core. Initially, the estradiol is mainly located in the core ( 0.3 wt% ). During the equilibration period estradiol diffuses into the sheath.

[0244] Fig. 5 shows the simulated release rate of estradiol from each of the IVRs, and as is evident from said figure the release rate is initially (taken at time zero ) highest for the thinnest sheath of 50 pm, and lowest for the thickest sheath of 650 pm. Thus, since less estradiol has diffused into the thicker sheaths at said point in time, the release of estradiol decreases when the thickness of the sheath increases. In this transitory period a bell-shaped release profile is provided for the rings with a sheath thickness of 300 pm and 650 pm.

[0245] After several days, when estradiol has diffused into the sheath and equilibrium has been reached, the release profile converges to almost the same release rate depending on the sheath thickness.

[0246] Note that for the IVRs with a sheath of 650 jam, the estradiol molecules will be too diluted in the IVRs to provide the same estradiol release profiles as for the 50 m, 100 pm and 300 pm sheaths. Accordingly, for such low concentrations of estradiol ( 0.3 wt% ) the estradiol release rate will not be identical for a thick sheath ( 650 pm) compared to a thinner sheath ( 100 pm) after the burst period.

[0247] In order to compare the simulated data shown in fig. 5 with the produced IVR batches, fig. 6 shows the release profile of the IVRs KI ( 550 pm) and K4 ( 650 pm) i. e. the IVR batches having a sheath that is not preloaded with estradiol.

[0248] As is evident from fig. 6. the estradiol release analyzed after less than five days (not equilibrated) showed a bell-shaped estradiol release curve, whereas the analysis conducted after 23 days from the extrusion date (equilibrated 23 days ) showed the development of the burst release, i. e. estradiol had diffused into the sheath during said equilibration period. The burst is higher for the K4 batch since said batch comprises a higher concentration of estradiol ( 49. 19 mg) compared to the KI batch ( 5.55 mg).

[0249] Thus, the simulated data corresponds to the actual estradiol release for the produced batches.

[0250] Example 5: Equilibration period for different rings with estradiol only loaded in the core of a two-layered core / sheath intravaginal ring.

[0251] In order to investigate the effect of the sheath thickness on the equilibration period, the diffusion of estradiol in a number of further simulated two-layered IVRs with estradiol only loaded in the core was further investigated using computational modeling and simulation. To demonstrate only the effect of the sheath thickness and equilibration time in the present simulations, the sheath does not contain any steroid, e. g. progesterone.

[0252] The diffusion process of estradiol from the core to the sink through the sheath is dependent on the sheath properties such as solubility and diffusion of estradiol in the sheath.

[0253] Figs. 7a, 7b, and 7c show the concentration of estradiol in rings with different sheath thicknesses ( 650 pm, 300 pm, 100 pm) at different equilibration times ( 1, 10, 30, 50 and 100 days ), i. e. at different times after extrusion.

[0254] It is evident from said figures that the equilibration period depends on the sheath thickness. For instance, fig. 7a shows that for a sheath of 650 pm there is no (or almost no) estradiol in the sheath at day 1, that said amount is a bit higher at day 10, and even higher at day 100. However equilibrium (the concentration of estradiol is the same in core and sheath) is not reached even after a 100 days for said sheath thickness.

[0255] For the IVRs with a 300 pm sheath said equilibrium is reached around 100 days, see fig. 7b, and for the 100 ring the equilibrium is reached after 10 days, see fig. 3c.

[0256] Thus, as is evident from the figs. 7a - 7c, increased thickness of the sheath also increases the time needed to reach equilibrium at 25 °C. This is true for other equilibration temperatures as well.

[0257] It is further evident from said figures ( 7a - 7c), that a sheath thickness of 100 pm needs 1 day to reach about 76% of the equilibrium concentration. In contrast, a 300 pm sheath reaches about 30% of the equilibrium concentration in the same time, while a 650 pm thick sheath attains roughly 15% of the equilibrium concentration in 1 day.

[0258] Example 6: Simulated effect of preloading estradiol in the sheath on the release of estradiol in intravaginal rings.

[0259] To understand the impact of preloading the sheath with the same estrogenic steroid as also loaded in the core, the release rate of estradiol from a number of simulated two-layered and threelayered IVR-batches was evaluated. All simulated IVRs had a diameter of 5 mm, a 163.5 mm fiber length, and all layers were made of EVA28. The sheaths of all simulated IVRs were loaded with 27wt% progesterone, and various levels of initial concentration of estradiol. The two-layered rings had a sheath thickness of 550 pm, and the three-layered rings a sheath thickness of 650 μm.

[0260] The following estradiol loadings of the sheath were evaluated: 0% estradiol of equilibration concentration), 25% equilibration concentration, 50% equilibration concentration and 100% equilibration concentration (completely equilibrated sheaths ).

[0261] For the two-layered IVR-batches the total load of estradiol in the simulated core or core / intermediate layer is the same ( 0.3 wt% ) i. e. the load of estradiol conventionally placed in the core is redistributed throughout the sheath and core. For the unequilibrated IVR, the 0.3 wt% estradiol was only loaded in the core. The simulation further considers the reduced amount of EVA 28 in the sheath as progesterone weight represents 27 wt% of the sheath weight.

[0262] Fig. 8 displays the release profile of the simulated twolayered IVRs for unequilibrated, 25% equilibrated, 50% equilibrated and equilibrated sheaths with estradiol.

[0263] As is evident from said figure, when the estradiol load is the same for all IVRs, the level of preloading in the sheath has a significant impact on the release profile of estradiol. The unloaded IVR showed a similar pattern to the estradiol release profile seen in fig. 5 for sheath thicknesses of 300 pm and 650 pm.

[0264] It is further shown in fig. 8 that as the preload of estradiol in the sheath increases, the release rate of estradiol in the first few days also increase, however as estradiol diffuses into the sheath all simulated IVRs reaches the same estradiol release profile as the equilibrated sheath in a few days.

[0265] In a similar manner the estradiol release profile from a number of three-layered IVRs having estradiol in the intermediate layer in both dissolved and crystal forms (as K4 - K6). The core only consists of EVA28 ). The simulation uses the same estradiol concentrations as in the previous simulated twolayered IVRs, and also takes the progesterone concentration in the sheath into account.

[0266] The results for the three-layered IVRs are shown in fig. 9, and as is evident from said figure, the same trend as shown in fig.

[0267] 8 for the two-layered IVRs was observed for the tree-layered IVRs. Thus, the more estradiol the sheath contains the higher the initial release rate, however, for all IVRs a zero-order release is obtained after almost 8 days of estradiol burst. After this period, all the curves shows the same release rate, which is due to the availability of estradiol in the intermediate layer to sustain a high release rate, where the release rate is mainly limited with the sheath containing progesterone crystals (a high concentration of progesterone ).

[0268] Based on the simulated data it can be concluded that an IVR according to the invention comprising a sheath preloaded with estradiol can release estradiol already after the IVR has been manufactured.

[0269] Example 7: Effect of preloading estradiol in the sheath on the release of estradiol in intravaginal rings.

[0270] In order to evaluate if preloading of the sheath with estradiol can reduce the equilibration period needed, the estradiol release from the produced batches KI - K6 was evaluated. As is specified earlier the batches KI and K4 are 0% equilibrated with estradiol K2 is 50% equilibrated with estradiol, and K3 is 100% equilibrated with estradiol. K5 and K6 are partly equilibrated with estradiol (around 43% and 72% equilibrated).

[0271] The daily release rate of estradiol from these rings are shown in table 7, fig. 10 (KI - K3 ) and fig. 12 (K4 K6).

[0272] As is evident from said figures preloading the sheath with estradiol leads to a higher estradiol burst, and said burst increases when the preloading level of estradiol in the sheath increases. Thus, the estradiol burst is higher for 100% equilibration than for 50% equilibration. This corresponds to the simulated data, see fig. 8. The main difference between 100 % equilibrated (K3 ), and 50 % equilibrated (K2 ) was the release rate of estradiol in the first days. The difference in release profile between K2 and K3 decreased afterward where the release profile became almost coinciding.

[0273] The equilibration time also has an impact on the release of estradiol from IVRs that are not preloaded, see fig. 10 that initially shows a substantial difference in the release of estradiol between Kl-rings with a 0 days (no equilibration period) and 23 days equilibration period, where the not-preloaded batch had a very low estradiol release. However, after the not-preloaded batch (KI ) were stored for an equilibration period of 4 months at room temperature ( about 25°C) the release from the Kl-batch (not preloaded) showed the same release as the K3-batch (preloaded) at time 0, see fig.

[0274] 11. Thus, said data clearly shows that it is possible to eliminate the equilibration period, and providing a stable ready-to-use (preloaded) drug delivery system already at the time of manufacturing said system, i. e. at day 0. As is also evident from fig. 11 the further storage (equilibration) of the preloaded ring K3 ( stated with a 100% of equilibration value ) did not show any substantial change in the in-vi tro release, and even though any additional storage period is not required for the ready-to-use IVRs, a storage period will not negatively affect the release profile of the active ingredients and accordingly the user.

[0275] Fig. 12 shows the release of estradiol from the three-layered IVRs K, K5 and K6. As is evident from said figure, the preloading of estradiol leds to an increase in the burst of estradiol in the first days of the release (as in the simulations and the two-layered IVRs ), then all the rings showed the same release of estradiol after day 9 where a zeroorder release can be observed.

[0276] Compared with simulations for the three-layered IVRs in fig. 9, the release of estradiol from the preloaded IVRs (K5, K6 ) see fig. 12, is initially higher ( at day 0 ) and in the burst phase (2nd day to 7-10 days ) whereas the pseudo-steady state release (after day 10 ) for the K4 - K6 batches is substantially the same as predicted in the simulations, see fig. 9.

[0277] It is expected that the higher initial release is caused by some diffusion of estradiol to the sheath already during extrusion because of the high extrusion temperature and availability of estradiol crystals. This has not been taken into account in the simulations, leading to a higher estradiol release. Accordingly, the initial concentration of estradiol in the sheath, are not the same for the produced and the simulated IVR. Nonetheless, the burst phase may also involve transient mechanisms that are not captured by the simulations.

[0278] Rings from batch K4 (not preloaded) were stored for an equilibration period of 4 months at room temperature ( around 25°C). After said equilibration period the release from the K4- batch (not preloaded) lead to the same release of estradiol as the K6-batch (preloaded) at time 0. The results are shown in fig. 13, which also show the release of estradiol of K4-batch (not preloaded) before the equilibration period of 4 months. As can be seen in fig. 13, the pseudo-steady state release of estradiol is the same for the preloaded K6 batch and the equilibrated K4-batch (after 4 month) IVR batches. In addition, the first days of the estradiol release are comparable for batch K4 after an equilibration period of four month and K6 (ready-to-use after manufacturing).

[0279] Fig. 14 shows the release of progesterone from batch KI, K3 and K4 (before and after 4-months storage at temperature ( 25°C) and K6 ( ready-to-use after manufacturing). It can be concluded that release of progesterone for the shown batches exhibits substantially the same release of progesterone, indicating the stability of the progesterone release over time, and that said release is independent on the load of estradiol in the sheath.

[0280] Using the drug delivery system, e. g. an intravaginal ring, according to the present invention the inventors have found that it is possible to attain independent and optimal release of the two active ingredients; an estrogenic steroid and a progestational steroid.

[0281] The preloading concept according to the present invention can be applied to other drug delivery systems, e. g. implants, where an equilibration time is needed and / or for drug delivery systems comprising one or more other active pharmaceutical ingredients.

[0282] The drug delivery system according to the invention has a simple and inexpensive design, and can therefore be used equally well both privately and in medical or hospital facilities. Modifications and combinations of the above principles and designs are foreseen within the scope of the present invention.

Claims

Claims1. A ready-to-use drug delivery system ( 1 ) which at the time of manufacturing comprises,- a first layer ( 2 ) compris ing a first polymeric material ( 5 ) and a first active ingredient ( 6 ), - a sheath ( 4 ) compri sing a second polymeric material and ( 7 ) a second active ingredient ( 8 ), characterized in, that the sheath ( 4 ) further comprises the same first active ingredient ( 6 ) as loaded in the f irst layer ( 2 ).

2. A ready-to-use drug del ivery system ( la ) according to claim 1, wherein the drug delivery system ( 1 ) is a twolayered drug delivery system ( l a ) wherein the f irst layer ( 2 ) is a core ( 3a ) that i s at least partly, and preferably completely, surrounded by the sheath ( 4 ).

3. A ready-to-use drug del ivery system ( lb; l c ) according to claim 1, wherein said drug del ivery system ( 1 ) further compri ses a second layer ( 9 ) compri sing a third polymeric material ( 11 ), and wherein said second layer ( 9 ) either is loaded with the same first active ingredient ( 6 ) as loaded in the f irst layer ( 2 ) or is not loaded with said f irst active ingredient ( 6 ).

4. A ready-to-use drug del ivery system ( lb; l c ) according to claim 3, wherein the drug delivery system is a threelayered drug del ivery system ( lb; lc ), compris ing a core ( 3b; 3c ), a sheath ( 4 ), and an intermediate layer ( 10; 10 ' ), placed between the core ( 3b; 3c ) and the sheath ( 4 ), and wherein the f irst layer ( 2 ) is either the core ( 3b; 3c ) or the intermediate layer ( 10: 10 ' ), the other being the second layer ( 9; 9 ' ).

5. A ready-to-use drug delivery system ( 1 ) according to claim 4, wherein when the f irst layer ( 2b ) i s the intermediate layer ( 10 ) and the second layer ( 9 ) i s the core ( 3b ), the core ( 3b ) is not loaded with the f irst active ingredient during the manufacturing process.

6. A ready-to-use drug delivery system ( 1 ) according to claim 4, wherein the f irst layer ( 2 c ), the second layer ( 9' ) and the sheath ( 4 ) are al l loaded with the f irst active ingredient ( 6 ) during the manufacturing process.

7. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the chemical potential of the f irst active ingredient ( 6 ) in the first layer ( 2 ) and in the sheath ( 4 ) is substantial ly the same.

8. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the chemical potential of the first active ingredient ( 6 ) in the sheath ( 4 ) is lower than the chemical potential o f the f irst active ingredient ( 6 ) in the first layer ( 2 ).

9. A ready-to-use drug del ivery system ( 1 ) according to any of the claims 3 - 8, wherein the chemical potential of the f irst active ingredient in the second layer ( 9 ) is the same or lower than the chemical potential of the first active ingredient in the f irst layer.

10. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the f irst active ingredient ( 6 ) i s di ssolved in the first polymeric material ( 5 ) and / or dispersed and / or incorporated in the form o f particles in the f irst polymeric material ( 5 ).

11. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the second activeingredient ( 8 ) i s dispersed and / or incorporated in the second polymeric material ( 7 ) in the form of particles, such as crystals.

12. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the second active ingredient ( 8 ) i s dispersed and / or incorporated in the second polymeric material ( 7 ) in a concentration of at least 10 wt% based on the weight o f the sheath ( 4 ).

13. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the f irst polymeric material ( 5 ) and / or second polymeric material ( 7 ) and / or third polymeric material ( 11 ) is at least one inert thermoset or thermoplastic elastomer, such as ethylenevinyl acetate (EVA) copolymers, low-density polyethylene, polyurethanes, and styrene-butadiene copolymers.

14. A ready-to-use drug delivery system ( 1 ) according to claim 13, wherein- the first polymeric material ( 5 ) i s an ethylene-vinyl acetate copolymer with a vinyl acetate content from 26 to 40 wt%, preferably around 28 wt%, 33 wt% or 40 wt%, and / or- the second polymeric material ( 7 ) is an ethylene-vinyl acetate copolymer with a vinyl acetate content from 12 to 28 wt%, preferably a vinyl acetate content between 14 and 24 wt%, such as around 20 wt%, and / or- the third polymeric material ( 11 ) is an ethylene-vinyl acetate copolymer with a vinyl acetate content from 9 to 40 wt%.

15. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the f irst active ingredient ( 6 ) and / or second act ive ingredient ( 8 ) isselected from a hormone, e. g. steroids such as an estrogenic steroid, a progestational steroid and / or danazol; a spermicide; an antimicrobial agent; an antiviral agent; an aromatase inhibitor such as anastrozole, letrozole and exemestane; and combinations o f said active ingredients.

16. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the f irst active ingredient ( 6 ) is an estrogenic steroid ( 6 ), preferably estradiol, and / or wherein the second active ingredient ( 8 ) is a progestational steroid ( 8 ), pre ferably selected from group consi sting of progestogen, progesterone, etonogestrel, levonorgestrel, d- l -norestrel, segesterone and norethindrone.

17. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the thickness of the sheath ( 4 ) is from 0. 05 mm to 3 mm, preferably from 50 µm to 1 mm, more preferred from 300 pm to 900 pm, and even more preferred from 400 pm to 800 pm.

18. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, wherein the f irst layer ( 2 ) and / or the optional second layer ( 9 ) does not compri se further active ingredients bes ides the f irst active ingredient ( 6 ), and / or wherein the sheath ( 4 ) does not compri se further active ingredients bes ides the f irst active ingredient ( 6 ) and the second active ingredient ( 8 ).

19. A ready-to-use drug del ivery system ( 1 ) according to any of the preceding claims, modi fied in that the sheath ( 4 ) does not compri se the second active ingredient ( 8 ), and wherein the f irst polymeric material ( 5 ) and the second polymeric material ( 7 ) are di f ferent.

20. A method o f manufacturing a ready-to-use drug delivery system ( 1 ), said method compri sesa. providing a f irst layer ( 2 ) compri sing a f irst polymeric material ( 5 ) and a f irs t active ingredient ( 6 ),b. providing a sheath ( 4 ) compri sing- a second polymeric material ( 7 ), a second active ingredient ( 8 ), and the same f irst active ingredient ( 6 ) as in the core, andc. forming said ready-to-use drug delivery system.

21. A method according to claim 20, wherein said method further comprises step b' providing a second layer ( 9 ) compri sing a third polymeric material ( 11 ), thereby providing a three-layered ready-to-use drug delivery system ( lb; l c ) compris ing a core ( 3b; 3c ), an intermediate layer ( 10: 10 ' ) and a sheath ( 4 ), and wherein said second layer ( 9 ) either is loaded with the same first active ingredient ( 6 ) as loaded in the f irst layer ( 2 ) or i s not loaded with said f irst active ingredient ( 6 ).

22. A method according to claim 20 or 21, wherein the chemical potential of the f irst active ingredient ( 6 ) in the first layer ( 2 ) and in the sheath ( 4 ), and optional ly in the second layer ( 9 ), i s substantially the same or wherein the chemical potential of the f irst active ingredient ( 6 ) in the sheath ( 4 ) is lower than the chemical potential of the f irst active ingredient ( 6 ) in the f irst layer ( 2 ).

23. A method according to any o f the claims 21 - 22, wherein when f irst layer ( 2b ) i s the intermediate layer, only the intermediate layer ( 10 ) and the sheath ( 4 ) i s loaded with the f irst active ingredient ( 6 ) during themanufacturing proces s, i. e. the second layer ( 3b ) i s not loaded with the f irst active ingredient ( 6 ) during the manufacturing proces s.

24. A method according to any o f the claims 20 - 23, wherein the forming step comprisesi. co-extruding the core ( 2 ) and sheath ( 4 ) into a f iber,ii. cutting the f iber into an appropriate length thereby providing a f iber element, andi ii. us ing said f iber element to form the ready-to-use drug delivery system ( 1 ).

25. A method according to claim 24, wherein step i ii. is obtained by combining the ends of f iber element to form an intravaginal ring, or forming an implant out o f the fiber element, or us ing said f iber element to form an implant or an intrauterine device.

26. A method according to any of the preceding claims 20 - 25, modi f ied in that the sheath ( 4 ) does not compri se the second active ingredient ( 8 ), and wherein the f irst and the second polymeric materials are di f ferent.

27. An intravaginal ring, an implant or an intrauterine device compris ing or cons isting o f the ready-to-use drug delivery system def ined in any o f the claims 1 - 19 or obtained using the method according to any of the claims

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