Drug Delivery Systems

Abstract

The present invention relates to a drug delivery system (1) comprising a core (2) and a sheath (5), the core (2) being made of a polymeric material (3) and containing a first active ingredient (4), the sheath (5) being made of a second polymeric material (6) and containing a second active ingredient (7) dispersed and / or incorporated in the second polymeric material at a concentration of more than 10% by weight based on the weight of the sheath (5) and below the permeation threshold of the second active ingredient in the sheath (5). The inventors have found that by using the drug delivery system according to the invention, it is possible to achieve an optimal independent release of the two active ingredients without complex assembly of components and without sophisticated multi-layer extrusion techniques.

Description

[Technical field]

[0001] The present invention relates to a drug delivery system, a method for making the system, and uses of the system.

[0002] Various types of delivery systems have been developed to provide a controlled, sustained release of active ingredients, preferably by diffusion through the surface of the device.

[0003] One such device is the intrauterine device (IUD). Mirena® is considered one of the safest and most efficient contraceptive methods used worldwide. In addition to preventing unwanted pregnancy, this device has several advantages: its use is controlled by the woman; the drug dose can be better regulated without the user's attention; compared to its orally administered counterpart, the destruction of a significant part of the daily dose of the drug (by the intestine and by passing through the liver first) can be avoided.

[0004] Other devices on the market today are intravaginal rings (IVRs) (e.g., Estring®, Femring®, and Nuvaring®), or subdermal contraceptive implants (e.g., Implanon®), all of which provide a controlled, continuous release of steroid molecules over an extended period of time (e.g., weeks / months).

[0005] These known vaginal rings have proven particularly useful for the delivery of steroids, whose relatively small molecular size and substantially water-insoluble nature allows for effective penetration through hydrophobic polymers such that therapeutic concentrations can be rapidly achieved in the body.

[0006] However, it is known that diffusion in polymers is complex and depends on several different factors, such as temperature, manufacturing process, solubility and diffusibility of the drug in the polymer, surface area of ​​the drug reservoir, the distance the drug diffuses through the device to reach the device surface, and molecular weight of the drug.Therefore, it is still difficult to understand, predict, and control the diffusion of small and large molecules into polymer systems.In this regard, the use of drug delivery devices to deliver drugs requires a design that controls the release rate so that the appropriate daily dose can be reliably provided to the user throughout the life of the device.

[0007] In a reservoir system, i.e., a drug-loaded core surrounded by a non-medicated membrane / sheath, the drug first distributes from the reservoir into the sheath and then diffuses to the other side of the sheath where it is taken up by the receiving medium. While the reservoir is saturated, a constant concentration gradient of drug is maintained within the membrane, the rate of drug flux is constant, and zero-order release is achieved. However, as the drug concentration in the reservoir decreases, so does the gradient across the membrane and the rate of drug release.

[0008] 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.

[0009] These problems are avoided in monolithic systems where the drug is loaded directly into the polymer, which acts as both the reservoir and the diffusion mediator. The drug is usually loaded uniformly into the monolithic device, and its release is controlled by diffusion through the monolithic matrix material or through the aqueous pores. Over time, however, the release rate slows as the drug deeper inside the monolithic device must diffuse to the surface, as the distance traveled increases and a quadratic relationship between distance and time becomes important. Geometric factors become important at this point, and the effect can be minimized by using other geometric shapes or hemispherical monoliths to provide a near zero order release, but such devices are neither easy nor inexpensive to fabricate.

[0010] Simultaneous delivery / release of drugs has found applications in a variety of different areas. However, placing a blend of drugs in one delivery device in a ratio equal to the desired delivery rate ratio rarely produces the desired results. In many cases, drugs are present in a blend, so they do not diffuse together at the same rate through a surface or membrane. Instead, this rate will depend on the intrinsic rate of the normalized permeation rate of the drug through, for example, a rate-controlling membrane. Thus, flexibility is limited to the selection of suitable polymer candidates for the sheath. Thus, the range of delivery rate ratios and the degree of control over the delivery rate ratios are very limited.

[0011] Of course, the need to maintain a specific delivery rate ratio can be met by using a separate delivery device for each drug. However, this is clearly undesirable, since even one delivery device can cause disruption to the normal physiological activity of animals or humans, and the presence of two or more delivery devices compounds this disruption. In addition, the failure of one delivery device will result in the loss of the desired delivery ratio. Furthermore, a complete treatment with one implantable or insertable delivery device is more acceptable to patients and more efficient to insert and remove. The adjustment of a specific delivery rate can also be met by a delivery system composed of several elements, each of which releases a drug at a specific rate. Examples are two or multiple compartment intravaginal rings and ring bodies containing drug-releasing capsules. However, it is complicated and expensive to manufacture such rings on an industrial scale.

[0012] A further problem with known devices configured to release multiple drugs is that such devices typically exhibit suboptimal release patterns for different drugs, while it is generally preferred that all drugs are released at a controlled rate over a particular duration. Furthermore, each drug / delivery device combination behaves uniquely, and therefore drug combinations can significantly affect the release profile of one or more drugs.

[0013] Thus, there is a need for a novel drug delivery system configured for controlled release of two active ingredients / drugs at precise rates, and a simple, inexpensive method for manufacturing the system.

[0014] Thus, a first aspect of the present invention is to provide a drug delivery system which can be loaded with two active ingredients, each of which is released at a controlled rate independent of the other active ingredient.

[0015] According to a second aspect of the present invention, a delivery system is provided which reduces variability in the release rate of an active ingredient over time.

[0016] According to a third aspect of the present invention, a delivery system is provided which overcomes known problems associated with complex and expensive manufacturing processes, dose dumping and initial burst of drug, while at the same time providing a substantially zero order release rate for the active ingredient in the core.

[0017] According to a fourth aspect of the present invention, there is provided a delivery system which is stable at room temperature.

[0018] According to a fifth aspect of the invention, there is provided a delivery system configured for implantation (eg for placement subcutaneously, or in the vagina or uterus of an animal or human).

[0019] The novel and unique features which achieve these and further aspects of the present invention include: a core comprising a first polymeric material and a first active ingredient, a sheath comprising a second polymeric material and a second active ingredient, the second active ingredient being dispersed and / or incorporated in the second polymeric material at a concentration of at least 10% by weight based on the weight of the sheath; The drug delivery system includes:

[0020] The drug delivery system according to the present invention relates to a system comprising a core at least partially, but preferably completely, surrounded by a sheath / membrane. However, in contrast to conventional systems of this kind, the sheath according to the present invention also contains a high concentration of the active ingredient, which allows the simultaneous release of the two active ingredients.

[0021] In the context of the present invention, the term "active ingredient" means a substance intended to be released into the surrounding medium, which has an effect of diagnosing, curing, mitigating, treating or preventing a disease, or which has an effect of restoring, correcting or altering a physiological function in a subject (e.g., an animal or a human).

[0022] Dual administration has application in a variety of different areas, such as contraceptive rings and dual delivery systems, such as implants and rings, providing, for example, hormone replacement therapy or contraception and protection against infectious diseases, such as HIV infection.

[0023] In such a dual administration system, the two active ingredients must be released simultaneously and at the same time. Therefore, the release rates of these drugs must be independently adjusted to the physiological optimum rate (mg / day). The inventors have found that by using the drug delivery system according to the present invention, the two active ingredients can be independently and optimally released without the need for complex assembly of components or the need for sophisticated multi-layer extrusion technology.

[0024] By using a drug delivery system with a concentration of active ingredient in the sheath of at least 10% by weight, it is ensured that the desired near zero-order release behavior of the active ingredient in the core is observed over a longer period of time. In addition, such a high concentration of active ingredient is associated with good physical stability of the associated active ingredient.

[0025] Substantially zero order release means that the associated active ingredient is released in a substantially constant amount over a given period of time. In some embodiments, the system exhibits a substantially zero order release profile for one or more first active ingredients over a treatment period of at least one month, preferably at least two months, and even more preferably more than three months or longer, such as one year.

[0026] As mentioned above, the problem of the release rate of the active ingredient in the core is well known, because one or more active ingredients deeper in the core / reservoir must diffuse to the surface.However, the inventors have found that by loading the active ingredient in the sheath at a high concentration, the release rate of the first active ingredient in the core increases slightly over time, thereby compensating for the additional distance that the active ingredient must travel to the surface of the delivery system for release to the environment, thereby providing a substantially zero-order release rate for the first active ingredient over the desired treatment period.

[0027] It is important that the second active ingredient is dispersed and / or incorporated into the second polymeric material sufficiently to control the diffusion rate of the first active ingredient through the sheath, while the reduced diffusion rate is still sufficient to maintain an effective level of the active ingredient at the surface of the drug delivery system according to the present invention.

[0028] Without being bound by theory, it is believed that the second active ingredient in the sheath acts as a filler and controls 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 the second active ingredient decreases, facilitating the diffusion of water into the sheath, leaving an empty porous matrix and / or empty pockets / holes, and / or the sheath collapses, ensuring the desired zero-order release characteristics for the first active ingredient. Thus, it is believed that the space initially occupied by the second active ingredient may leave an empty porous matrix (which may be filled with water due to water intrusion) and / or leave an empty pocket / hole. This contradicts the conventional knowledge that the release rate of the active ingredient in the core surrounded by a non-medicated sheath decreases slightly over time (i.e., the desired zero-order release rate cannot be maintained for the desired treatment period for such conventional systems).

[0029] In some embodiments, the second active ingredient is dispersed in the second polymeric material, preferably at least 15% by weight, even more preferably at least 20% by weight, even more preferably at least 25% by weight, or more. The exact amount of the second active ingredient depends on the polymer(s) and active ingredient(s) used.

[0030] The presence of a relatively high concentration of the second active ingredient not only leads to an increase in the average path length that the molecules of the first active ingredient must travel between two points in the sheath, but also reduces the amount of the first active ingredient that can be dissolved in the polymeric material of the sheath, thus reducing the release rate of the first active ingredient through the sheath. This results in a more reliable release rate and a lower initial burst of the first active ingredient. Thus, the sheath can be made smaller, providing a smaller product with a significantly lower burst of the first active ingredient.

[0031] In this respect, the second active ingredient is preferably incorporated and / or dispersed in the second polymeric material in the form of particles, preferably in the form of crystals. Such particles / crystals will form a reservoir of undissolved solid crystals, which act as seed crystals, i.e., as a sustained release reservoir. Over time, when the second active ingredient is delivered to the surroundings, some of the crystals will be released into the second polymeric material, which allows the second active ingredient to be released for a long period of time. Furthermore, the stability of the second active ingredient in the drug delivery system is improved when the active ingredient is incorporated into the sheath as undissolved particles / crystals.

[0032] In order to obtain the desired zero-order release characteristics for the first active ingredient during the treatment period, the first active ingredient is preferably dispersed and / or incorporated in the first polymeric material of the core at a concentration of at least 5% by weight of the total weight of the core, preferably at least 10% by weight, preferably at least 15% by weight, even more preferably at least 20% by weight. However, the concentration of the first active ingredient can be higher, for example at least 30% by weight of the total weight of the core.

[0033] The first active ingredient is also preferably present in the core in the form of particles, preferably in the form of crystals, for the same reasons as disclosed for the second active ingredient, thus improving the stability of both the first and second active ingredients, and thus the stability of the drug delivery system according to the invention.

[0034] Alternatively, the first active ingredient may be dissolved in the first polymeric material, and in these embodiments, the first active ingredient is preferably present in the first polymeric material at a concentration that is below the saturation concentration of the first active ingredient at a temperature of 25° C.

[0035] Because it is expected that some of the first active ingredient may redistribute throughout the intravaginal ring upon storage (i.e., the concentration of the first active ingredient in the core decreases as some of the first active ingredient diffuses into the sheath), the term "below saturation concentration" refers to the concentration of the first active ingredient in the core as measured in an equilibrated drug delivery system (i.e., when equilibration of the first active ingredient has been achieved in the system).

[0036] Without being bound by theory, it is believed that by maintaining a high concentration of the second active ingredient, the crystals create a porous network pathway, leaving many sites / openings / pores open within the matrix of the polymeric material, ensuring that the active ingredient can only be released through a tortuous pathway within the sheath, thereby increasing the diffusion length and controlling the release rate.

[0037] However, to obtain a desired release rate for the first active ingredient, it is preferred that the concentration of the second active ingredient in the second polymeric material does not exceed the permeation threshold of the second active ingredient within the sheath.

[0038] The permeation theory can be applied to inert matrix systems (where the sites / openings / pores of the matrix material are randomly occupied by particles of a particular component). When particles occupy adjacent sites in the matrix, a cluster is formed, and when this cluster permeates the entire matrix, it is considered a cluster across the sample, i.e., an infinite cluster or a permeating cluster. The concentration of a component at which the probability of clusters of that component appearing across the sample is maximized is called the permeation threshold (see Millan M, Caraballo I, Rabasco A.: The role of the drug / excipient particle size ratio in the percolation model for tablets. Pharm Res. 1998;15(2):220-224). Thus, in simple terms, the permeation threshold corresponds to the minimum concentration of each active component at which infinite clusters are across the matrix.

[0039] As applied to the present invention, the matrix is ​​formed by a second polymeric material, and the clusters formed by the particles of the second active ingredient provide a continuous phase throughout the matrix of the sheath until a permeation threshold is reached. Without being bound by theory, it is believed that above the permeation threshold, the effective length decreases because the clusters of the active ingredient connect with the surface, resulting in an increased release rate of the active ingredient.

[0040] The permeation threshold depends, inter alia, on the particular active ingredient, the polymeric material used, and the size of the core and / or sheath of the drug delivery system according to the invention. However, the skilled person can determine the permeation threshold for a given active ingredient or ingredients in the drug delivery system according to the invention by standard procedures, for example by the procedures disclosed in Pharmaceutical Research, Vol. 23, No. 10, October 2006; AAPS PharmSciTech, Vol. II, No.2, June 2010; and / or Pharmaceutica Acta Helvetiae, Vol. 68, issue 1, July 1993, pages 25-33.

[0041] In an alternative embodiment, the concentration of the second active ingredient in the second polymeric material is 40% or less by weight, preferably 35% or less by weight, based on the weight of the sheath.

[0042] Similarly, the concentration of the first active ingredient in the first polymeric material should be below the permeation threshold of the first active ingredient in the core, or the concentration of the first active ingredient in the first polymeric material should be 40% by weight or less, for example 30% by weight or less, based on the weight of the core.

[0043] It should be noted that although the sheath surrounding the drug-loaded core is known to contain low concentrations of active ingredient (see, for example, WO2013 / 120888), it is not known to have the sheath contain high concentrations of active ingredient as claimed in the present invention. Low concentrations of active ingredient, i.e., well below 10% by weight, have no or only a very limited effect on the release rate of the active ingredient in the core and are therefore not critical to the present invention.

[0044] Based on the context of the present invention, one skilled in the art will understand that the diffusion rate through the sheath can be controlled and / or tailored by varying the amount / concentration of the second active ingredient in the sheath, by using different polymeric materials, and / or by using different particle sizes or blends of different particle sizes for the second active ingredient.

[0045] However, the particles / crystals of the second active ingredient, and optionally the first active ingredient, preferably have an average particle size of 3 μm to 40 μm, preferably 8 μm to 24 μm, even more preferably 10 μm to 24 μm, as such particle sizes have been found to provide the desired near zero order release rate over an extended period of time, i.e. over the desired treatment period of at least one month.

[0046] As used herein, the term "crystal" refers to particles of active ingredient arranged in an ordered microscopic structure to form a crystal lattice. The term "crystal size" or "particle size" refers to the average particle diameter of the crystal or particle. Particle size, crystal size and / or particle size distribution are preferably measured using laser diffraction, for example, using a Malvern laser scattering particle size analyzer. However, other particle measurement devices or techniques known to those skilled in the art can also be used, such as dynamic light scattering or sieve analysis. As used herein, the term "crystal size" or "particle size" refers to the particle distribution diameter of the particle / crystal. In one example, D90 means that 90% of the particles have a diameter below a given value, for example, as measured by laser diffraction, dynamic light scattering, or sieve analysis.

[0047] The polymeric materials used in the drug delivery system of the present invention are preferably suitable for subcutaneous insertion / implantation or for placement in the uterine or vaginal canal, that is, the materials are non-toxic and non-absorbable to the patient or animal. In this regard, various inert thermoset or thermoplastic elastomers, as well as combinations of polymeric materials, are contemplated within the scope of the present invention.

[0048] In one embodiment, the first and / or second polymeric material is a silicone polymer (thermosetting type). Silicone elastomers, such as poly(dimethylsiloxane), are already routinely used for IVR, and similar silicones are also considered within the scope of the present invention.

[0049] However, the first and second polymeric materials are preferably thermoplastic polymers, which may essentially be any extrudable thermoplastic polymer material suitable for medical applications, such as ethylene-vinyl acetate (EVA) copolymers, low density polyethylene, polyurethanes, and styrene-butadiene copolymers.

[0050] In one embodiment, ethylene-vinyl acetate (EVA) copolymer is used as both the first and second polymers because of its excellent mechanical and physical properties.

[0051] The vinyl acetate concentration of the EVA polymer determines the rate at which the active ingredient diffuses generally through the system; the lower the vinyl acetate concentration, the slower the rate at which the active ingredient is released from or migrates through the polymer.

[0052] In this respect, it is preferred that the second polymeric material of the sheath is an ethylene-vinyl acetate copolymer having a vinyl acetate content of 12-28% by weight, preferably a vinyl acetate content of 14-24% by weight (e.g. approximately 20%), as this material provides the desired release characteristics through the second polymeric material, i.e. through the sheath.

[0053] To provide the desired zero order release profile for the first active ingredient, it is preferred that the release rate through the core is relatively high so that the sheath is the rate limiting factor.Thus, it is preferred that the first polymeric material of the core is an ethylene-vinyl acetate copolymer having a vinyl acetate content of 26-40% by weight, preferably 28%, 33% or 40% by weight.

[0054] When a specific vinyl acetate content, e.g. 20 wt%, is mentioned, this refers to the wt% content provided by the manufacturer. However, because manufacturers may use different internal analytical methods to determine the vinyl acetate content, the actual vinyl acetate content may vary from 1-2% depending on the manufacturer. Thus, in the present invention, vinyl acetate content refers to the vinyl acetate content in an ethylene-vinyl acetate copolymer, as determined by high-resolution NMR according to standard procedures. The wt% of vinyl acetate content in an ethylene-vinyl acetate copolymer is based on the weight of the ethylene-vinyl acetate copolymer.

[0055] The drug delivery system according to the present invention is a dual drug delivery system, i.e. it contains two active ingredients. The active ingredients may in principle be any type of locally or systemically active medicine, which may be administered subcutaneously, subdermal, vaginally or uteri. However, the first and / or second active ingredient are preferably selected from hormones, steroids, spermicides, antibacterial agents, antiviral agents and combinations of said active ingredients.

[0056] In a preferred embodiment, the first and second active ingredients are different steroids, for example different contraceptives, such as estrogen steroids and / or progesterone steroids.In a preferred embodiment, the first active ingredient is estradiol, and the second active ingredient is a progestogen selected from the group consisting of levonorgestrel, etonogestrel, d-1-norestrel and norethindrone, preferably levonorgestrel.However, these steroids can also be selected to treat other conditions, such as vaginal atrophy, and symptoms associated with menopause, such as hot flashes.

[0057] In different embodiments, the first and second active ingredients may be spermicidal, antibacterial or antiviral agents. Such agents are well known to those skilled in the art and will not be discussed in further detail herein.

[0058] Regardless of the intended use of the first and second active ingredients or the device, the drug delivery system according to the present invention is adapted to deliver a pharmacologic effective amount of one or more active ingredients. "Pharmacologic effective" means an amount sufficient to affect a desired physiological or pharmacological change in a subject. This amount varies depending on the potency of the particular ingredient, the desired physiological or pharmacological effect, and the intended duration of treatment, etc. A person skilled in the art will be able to determine the pharmacologic effective amount of a given active ingredient or ingredients according to standard procedures.

[0059] The thickness of the sheath (the outer layer of the drug delivery system according to the invention) can be varied to further control the release rate of the active ingredient, and therefore the drug delivery system according to the invention preferably does not include / comprise a sheath / membrane that does not carry the active ingredient (e.g. a rate-controlling sheath).

[0060] In one embodiment, the sheath has a thickness between 0.05 mm and 3 mm. This thickness is preferably 0.05 to 2 mm, more preferably 0.1 mm to 2 mm, even more preferably 0.2 mm to 0.6 mm, depending on the active ingredient(s) and the polymeric material. In a particular embodiment, the sheath has a thickness of 120 μm, 240 μm, or 320 μm.

[0061] Those skilled in the art will understand that a thinner sheath may have less active ingredient than a thicker sheath, and that the concentration of the second active ingredient in the sheath should be sufficient to maintain the release of the associated active ingredient at the desired rate over the desired treatment period. By using a grade of ethylene-vinyl acetate copolymer with a higher or lower vinyl acetate content, the thickness of the sheath can be changed while maintaining substantially the same average release rate for the first active ingredient. For example, if a thicker shell is desired because more of the second active ingredient needs to be accommodated in the sheath, a grade of ethylene-vinyl acetate copolymer with a higher vinyl acetate content can be selected.

[0062] Similarly, the core preferably has a circular cross-section with a cross-sectional diameter of between 2 and 8 mm, more preferably between 3 and 6 mm, and even more preferably around 4 mm.

[0063] The drug delivery system according to the invention is preferably in the form of, formed into or part of an implant, intrauterine device or vaginal ring.

[0064] In a preferred embodiment, the system of the present technology is an intravaginal ring (IVR). The dimensions of the IVR may vary depending on the subject's anatomy, the amount of drug to be delivered to the patient, the period of time the drug is to be delivered, the diffusion characteristics of the drug, and other manufacturing considerations. The only requirement is that the IVR be flexible enough to be bent and inserted into the vaginal cavity, and rigid enough to withstand the expulsion force of the vaginal musculature without causing abrasion to the vaginal epithelium. The outer diameter of such an IVR may range, for example, from about 45 mm to about 65 mm, and / or the length of the fibers forming the IVR may be 150-170 mm, preferably 154-160 mm, for example about 157 mm.

[0065] In the context of the present invention, the term intravaginal ring also contemplates ring designs or configurations having other shapes, for example polygonal and / or wavy shapes, or where the configuration is not a complete and / or closed circle / shape.

[0066] In a preferred embodiment of the present invention, the drug delivery system does not comprise any other active ingredient than the two active ingredients (i.e. the first and second active ingredients) and / or does not comprise any further core and / or layers, such as sheaths and membranes. Thus, in a preferred embodiment, the drug delivery system according to the present invention consists of a core and a sheath completely surrounding the core, where the first active ingredient is part of the core and the second active ingredient is part of the sheath.

[0067] The present invention also relates to a method for producing the drug delivery system according to the present invention.

[0068] The method comprises: a. providing a core comprising a first polymeric material and a first active ingredient; b. providing a sheath comprising a second polymeric material and a second active ingredient, the second active ingredient being dispersed and / or incorporated in the second polymeric material at a concentration of greater than 10% by weight based on the weight of the sheath; and c. Co-extruding the core and sheath into a fiber It includes.

[0069] To form a drug delivery device, the fibers obtained in step c can be formed into an implant or IVR using conventional techniques, for example by cutting to an appropriate length, or can be formed into an IVR by combining with other elements to form an IUD.

[0070] Because the core and sheath are co-extruded, the present invention provides a very simple and inexpensive implementation, although if preferred, the core and sheath can be formed in separate injection molding or extrusion processes. Injection molding and extrusion are well known to those skilled in the art and will not be discussed further herein.

[0071] The method preferably further comprises a cooling step in which the prepared drug delivery system is cooled to a temperature below 20° C. to effect crystallization in the sheath and optionally the core. This can be accomplished, for example, by placing the fiber in a chilled water bath.

[0072] Without being bound by theory, the inventors believe that the crystals that form in the sheath and optionally the core are driven by recrystallization kinetics: the relatively high concentration of active ingredient in both the core and sheath loadings results in a relatively high concentration of "seed" crystals that can cause recrystallization when the fiber is cooled after co-extrusion.

[0073] Said cooling step is preferably carried out immediately after step c, ie as soon as practically possible from a manufacturing point of view, ie preferably within 30 minutes of completion of the fibre in step c.

[0074] The invention will now be explained in more detail by describing exemplary embodiments of the drug delivery system according to the invention. [Brief description of the drawings]

[0075] [Figure 1] FIG. 1 is a perspective view of a preferred embodiment of a vaginal ring according to the present invention. [Diagram 2] Photographs showing cross-sections of fibers having a core loaded with 0.39 wt% estradiol and a sheath loaded with 5 wt% progesterone, with sheath thicknesses of (a) 200 μm, (b) 300 μm, and (c) 400 μm. [Diagram 3] Photographs showing cross-sections of fibers having a core loaded with 0.39 wt% estradiol and a sheath loaded with 33.9 wt% progesterone, with sheath thicknesses of (a) 200 μm, (b) 300 μm, and (c) 400 μm. [Figure 4] Photographs showing cross-sections of fibers having a core loaded with 10 wt% estradiol and a sheath loaded with 33.9 wt% progesterone, with sheath thicknesses of (a) 200 μm, (b) 300 μm, and (c) 400 μm. [Figure 5A] 1 shows the release of progesterone and estradiol for an IVR with 0.39% w / w estradiol in the core and 5% w / w progesterone in the sheath. [Figure 5B] 1 shows the release of progesterone and estradiol for an IVR with 0.39% w / w estradiol in the core and 5% w / w progesterone in the sheath. [Figure 6A] 1 shows progesterone release from various IVRs. [Figure 6B] 1 shows progesterone release from various IVRs. [Figure 6C] 1 shows progesterone release from various IVRs. [Figure 7] Progesterone release is shown for various IVRs with 10% estradiol w / w in the core and 33.9% progesterone w / w in the sheath. [Figure 8A] Estradiol release is shown for different IVRs with different estradiol and progesterone concentrations in the core and sheath. [Figure 8B] Estradiol release is shown for different IVRs with different estradiol and progesterone concentrations in the core and sheath. [Figure 8C] Estradiol release is shown for different IVRs with different estradiol and progesterone concentrations in the core and sheath. [Figure 9A] Figure 2 shows estradiol release for various IVRs. [Figure 9B] Figure 2 shows estradiol release for various IVRs.

[0076] The present invention is described with the assumption that the drug delivery system is a vaginal ring. However, this assumption should not be considered limiting and the system could simply have a different structure / design, such as an IUD (e.g., a hormonal spiral or an implant).

[0077] 1 shows a preferred embodiment of an intravaginal ring (IVR) 1 according to the present invention, in which the IVR comprises a reservoir design, i.e. the IVR comprises a core 2 made of a first polymeric material 3, which contains a first active ingredient 4, and a sheath 5 made of a second polymeric material 6, which contains a second active ingredient 7, the second active ingredient being dispersed and / or incorporated in the second polymeric material at a concentration of more than 10% by weight based on the weight of the sheath.

[0078] Example 1 To evaluate the effect of estradiol (E2) concentration in the core, progesterone (P4) concentration in the sheath, and the effect of sheath thickness on the release rates of estradiol and progesterone, respectively, a series of intravaginal rings (IVR) were prepared as follows.

[0079] Raw materials used in production JPEG2025506074000002.jpg73170

[0080] Process Scheme and Manufacturing Core / sheath fibers containing the APIs estradiol and progesterone were produced as shown in the following process flow for fiber production.

[0081] JPEG2025506074000003.jpg67170

[0082] Milled EVA and API were weighed according to the proportions detailed in Table 3. All four batches were mixed using the same mixing protocol. Compounding was done using a tight intermeshing 11 mm twin screw extruder (Thermo scientific twin screw extruder Pharma 11). In summary, the four batches were compounded according to Table 3 to produce active granules / pellets. The compounding set temperature for all batches is 90°C.

[0083] JPEG2025506074000004.jpg53170

[0084] Magnesium stearate (MgSt) was added to all batches to enhance the processing properties of the pellets in the co-extrusion process: 0.1 wt% MgSt was first added to the mixing bag containing the active pellets, which were then mixed by hand for approximately 3 minutes.

[0085] A co-extrusion line with a 5 mm die was used to produce 5 mm sheath / core fibers, comprising a single screw extruder 16 / 25 (D / L) (i.e., 16 is the diameter and 25 is the length, the diameter ratio is D / L) for the sheath and a single screw 25 / 25 (D / L) for the core.

[0086] The fibers produced contained the active ingredient in both the core and the sheath; furthermore, the sheath thickness was varied for each formulation, resulting in sheath thicknesses of 200 μm, 300 μm, and 400 μm for a fiber diameter of 5 mm (see Table 5).

[0087] Fiber properties (diameter and sheath thickness) were controlled by the melt pump speeds of Extruder 1 (sheath) and Extruder 2 (core) to produce 5 mm diameter fibers with the required sheath thickness. All fibers were extruded at 90°C-100°C. Melt pump speeds were calculated based on the pump capacity. The sheath thickness compared to the core can be seen in Figure 3 (AC batch) and Figure 4 (DC batch). For the AB batch (Figure 2), no boundary was visible. The melt pump speeds 1 and 2 for each batch are listed in Table 2.

[0088] JPEG2025506074000005.jpg82170 The melt pump volume for the sheath is 0.6 cm 3 and for the core it is 2.4 cm 3 It is.

[0089] After co-extrusion, the fibers are cut to lengths of 157 mm and then welded to form intravaginal rings (IVRs). The IVRs produced (for each batch) are listed in Table 3.

[0090] For the AB batch, the progesterone concentration loaded in the sheath is 5 wt %, and during extrusion the progesterone is completely dissolved, as expected. As a result of internal diffusion, the progesterone redistributes throughout the ring, and if no premature crystallization occurs, the progesterone concentration in the ring will be completely uniform once the ring is at equilibrium.

[0091] JPEG2025506074000006.jpg76170*The numbers 200, 300 and 400 represent sheath thicknesses of 200 μm, 300 μm and 400 μm, respectively.

[0092] Optical observation of fibers For each of batches AB200, AB300 and AB400, i.e., 0.39 wt% estradiol and 5 wt% progesterone, no clear boundary was observed between the core and the sheath (see Figure 2), whereas for the other batches, a clear boundary was observed (see Figures 3 and 4), because estradiol and progesterone were dissolved in EVA28 in the sheath and core, respectively.

[0093] The contrast (i.e., boundary) between the core and sheath is greatest for batches AC200, AC300, and AC400, which are loaded with dissolved estradiol (0.39 wt%) and crystalline progesterone (33.9 wt%) (compare with FIG. 3).

[0094] The contrast (i.e., boundary) is lower when both APIs are present in crystalline form, i.e., in the case of an IVR containing 10 wt. % estradiol and 33.9 wt. % progesterone (in addition to the dissolved API fraction) (as seen in Figure 4 for DC200, DC300, and DC400).

[0095] The sheath / core systems observed generally exhibited a centered / concentrated geometry (see Figures 3 and 4).

[0096] The release rates of estradiol and progesterone for the prepared IVRs are shown in Table 4 (estradiol data), Table 5 (progesterone data), and corresponding Figures 5-9.

[0097] JPEG2025506074000007.jpg255170JPEG2025506074000008.jpg255170JPEG2025506074000009.jpg255170JPEG20255060740 00010.jpg255170JPEG2025506074000011.jpg255170JPEG2025506074000012.jpg255170JPEG2025506074000013.jpg255170

[0098] JPEG2025506074000014.jpg255170JPEG2025506074000015.jpg255170JPEG2025506074000016.jpg255170JPEG2025506074000017.jpg255170 JPEG2025506074000018.jpg255170JPEG2025506074000019.jpg255170JPEG2025506074000020.jpg255170JPEG2025506074000021.jpg255170

[0099] The results from Tables 4 and 5 are discussed in more detail below.

[0100] Estradiol and progesterone release during prepared IVR IVR containing 0.39% estradiol and 5% progesterone (AB batch) with various sheath thicknesses The release of estradiol and progesterone from IVRs obtained from batches containing 0.39% by weight estradiol and 5% by weight progesterone (i.e., AB200, AB300, and AB400) is shown in Figures 5A and 5B.

[0101] As is evident from the figure, progesterone release increases with increasing sheath thickness: in all cases the daily release is less than 1 mg per day after 10 days.

[0102] Since estradiol is present in the AB batch at low concentration (0.39 wt%), it dissolves in the ring. Since the sheath and core are made of the same polymer for the AB200, AB300 and AB400 batches (see FIG. 10) (no partitioning), the equilibrium estradiol concentration is uniform and therefore not affected by the sheath thickness. However, a slight effect is seen in FIG. 5B. This is expected due to the fact that a small amount of progesterone crystals increases the effective diffusion path, but only slightly.

[0103] Thus, it is clear that the low concentration (5% by weight) of progesterone in the sheath has no or only a very limited effect on the release rate of estradiol in the core.

[0104] Progesterone release depends on the concentration of estradiol in the core. A comparison of the release rate of progesterone in the sheath depending on the concentration of estradiol and the thickness of the sheath is shown in Figures 6A, 6B and 6C.

[0105] As is evident from the figure, the release of progesterone in the IVR with 33.9% by weight progesterone in the sheath is much higher compared to the IVR with 5% by weight progesterone in the sheath.

[0106] However, as can be seen from the data in Figures 6A, B, and C, it can also be concluded that estradiol does not affect progesterone release if it is present in a dissolved state, i.e., at a relatively low estradiol concentration (0.39% by weight), and / or in a crystalline state, i.e., at a relatively high estradiol concentration (10% by weight). Note that rings containing crystalline estradiol also contain estradiol in a dissolved state, likely at or near saturation concentrations.

[0107] For example, in FIG. 6A, IVRs AC200 (0.39% estradiol by weight) and DC200 (10% estradiol by weight) have substantially identical release profiles, and the same is seen for AC300 (0.39% estradiol by weight) and DC300 (10% estradiol by weight) in FIG. 6B, and AC400 (0.39% estradiol by weight) and DC400 (10% estradiol by weight) in FIG. 6C.

[0108] Effect of sheath thickness on progesterone release As shown in FIG. 7, increasing the thickness of the sheath allows for sustained delivery of progesterone.

[0109] Daily progesterone release (for the same sheath thickness) from both AC and DC batches is the same until the depletion phenomenon becomes significant for each sheath thickness. For DC200 (AC200), the effect of depletion on IVR is seen as early as day 7, whereas for DC300 (AC300), this occurs on days 12-13. Although only data for the DC200 batch are shown in Figure 7, these data are identical for each AC batch.

[0110] Effect of sheath thickness on estradiol release As can be seen from Figures 8A, B and C, the presence of progesterone in the sheath reduces the daily release of estradiol.

[0111] This effect is less pronounced when the sheath thickness is thin, e.g., 200 μm, as in the AB and AC IVRs, where estradiol (0.39 wt %) is primarily dissolved in the core (see FIG. 8A).

[0112] When estradiol is present in the core in crystalline form (eg, 10 wt %), as in the DC batches, the maximum release threshold is defined by the sheath thickness loaded with progesterone crystals (see Figures 8A, B and C).

[0113] In addition to dissolved progesterone preventing the release of estradiol (see FIG. 5), the presence of progesterone in crystalline form also affects the release of estradiol (see FIG. 8).

[0114] As can be seen from Figures 9A and B, the presence of estradiol in crystalline form, i.e., DC batches with 10% estradiol by weight, allows for sustained release of estradiol from the IVR at a zero order release rate for 28 days.

[0115] The slight increase in estradiol release after 14 days may be the result of two physical phenomena: the presence of progesterone in the sheath as crystals tends to increase the diffusion length (i.e., decrease the average release rate), and the depletion of crystals in the sheath allows faster diffusion through the holes in the sheath. At this point, the space originally occupied by progesterone is left with an empty porous matrix (holes), which may be empty or may be filled with water due to water ingress. This means that the ring is permeated or the crystals are dense near the outer surface of the IVR.

[0116] Thus, the space originally occupied by the progesterone steroid leaves an empty porous matrix which may fill with water upon ingress of water and / or leave empty holes, which is believed to provide the free passage of estradiol and thus the desired zero order release profile.

[0117] Increasing the sheath thickness decreases the release rate of estradiol embedded in the core: increasing the sheath thickness from 200 to 400 μm reduces the average daily release of estradiol on day 24 from 409.14 μg to 226.64 μg (for DC400 and DC200, respectively).

[0118] Experiments were performed with EVA28 (EVA 28% by weight), which acted like a rate-controlling sheath. Similar results are expected with other EVAs preferred according to the invention, such as ethylene-vinyl acetate polymers with vinyl acetate content of 24%, 33%, or 40% by weight.

[0119] When the cores are loaded with 10% estradiol by weight, the presence of progesterone limits / modulates the release rate of estradiol, resulting in a zero order release rate for estradiol over the 28 day treatment period.

[0120] Therefore, based on the experimental data, it can be concluded that the progesterone crystals loaded in the sheath play the role of a rate-controlling sheath at the VA content tested. Without being bound by theory, it is believed that in this regard, progesterone acts as a filler and controls the release of estradiol in the core. It is believed that the reduction in the presence of progesterone steroid in the sheath facilitates the diffusion of water into the sheath, leaving an empty porous matrix and / or empty pockets / holes and / or the sheath collapses, thereby ensuring the desired zero-order release profile for the estrogen steroid. Such a zero-order release was obtained with the DC batch (10 wt. % estradiol in the core, 33.9 wt. % progesterone in the sheath) (see FIG. 9B).

[0121] By using a drug delivery system (e.g., an intravaginal ring) according to the present invention, the inventors have found that it is possible to achieve independent and optimal release of two active ingredients, i.e., an estrogen steroid and a progesterone steroid, without the need for complex assembly of components and without the need for sophisticated multi-layer extrusion techniques.

[0122] The drug delivery system according to the invention is simple in design and inexpensive, making it equally suitable for use in private and medical or hospital settings.

[0123] Modifications and combinations of the above principles and designs are contemplated as falling within the scope of the present invention.

Claims

1. A drug delivery system (1), comprising: a core (2) comprising a first polymeric material (3) and a first active ingredient (4); a sheath (5) comprising a second polymeric material (6) and a second active ingredient (7), the second active ingredient (7) being dispersed and / or incorporated in the second polymeric material at a concentration of at least 10% by weight based on the weight of the sheath (5); A drug delivery system (1).

2. 2. The drug delivery system (1) of claim 1, wherein the second active ingredient (7) is dispersed and / or incorporated in the second polymeric material (6) at a concentration of at least 15% by weight, preferably at least 20% by weight, even more preferably at least 25% by weight.

3. 3. The drug delivery system (1) according to claim 1 or 2, wherein the second active ingredient (7) is dispersed and / or incorporated in the second polymeric material (6) in particulate, e.g. crystalline, form.

4. 4. The drug delivery system (1) of any one of claims 1 to 3, wherein a second active ingredient (7) is dispersed and / or incorporated in the second polymeric material (6) at a concentration below the permeation threshold of said second active ingredient in the sheath (5).

5. 5. The drug delivery system (1) according to any one of claims 1 to 4, wherein the second active ingredient (7) is dispersed and / or incorporated in the second polymeric material (6) at a concentration of 40% by weight or less, preferably 35% by weight or less, based on the weight of the sheath (5).

6. 6. The drug delivery system (1) according to any one of claims 1 to 5, wherein the first active ingredient (4) is dispersed and / or incorporated and / or dissolved in the first polymeric material (3) at a concentration of more than 5% by weight based on the weight of the core (2), preferably at a concentration of at least 10% by weight based on the weight of the core, preferably at a concentration of at least 15% by weight based on the weight of the core, and even more preferably at a concentration of at least 20% by weight based on the weight of the core.

7. 7. The drug delivery system (1) according to any one of claims 1 to 6, wherein at least one first active ingredient (4) is dispersed and / or incorporated in the first polymeric material (3) in particulate form, e.g. in crystalline form.

8. 8. The drug delivery system (1) according to any one of claims 3 to 7, wherein the particles of the second active ingredient (7) and optionally the particles of the first active ingredient (4) have a particle size, determined by laser diffraction, of between 3 μm and 40 μm, preferably between 8 μm and 24 μm, even more preferably between 10 μm and 24 μm.

9. 7. The drug delivery system (1) according to any one of claims 1 to 6, wherein the first active ingredient (4) is dissolved in the first polymeric material (3) at a concentration below the saturation concentration of said first active ingredient at 25°C.

10. The drug delivery system (1) according to any one of claims 1 to 9, wherein the first polymeric material (3) and / or the second polymeric material (6) is at least one inert thermoset or thermoplastic elastomer, such as ethylene-vinyl acetate (EVA) copolymer, low density polyethylene, polyurethane, and styrene-butadiene copolymer.

11. The drug delivery system (1) according to any one of claims 1 to 10, wherein the first polymeric material (3) is an ethylene-vinyl acetate copolymer having a vinyl acetate content of 26-40% by weight, preferably around 28%, 33% or 40% by weight.

12. The drug delivery system (1) according to any one of claims 1 to 11, wherein the second polymeric material (6) is an ethylene-vinyl acetate copolymer having a vinyl acetate content of 12-28% by weight, preferably having a vinyl acetate content of between 14-24% by weight, for example approximately 20% by weight.

13. 13. The drug delivery system (1) according to any one of claims 1 to 12, wherein the first active ingredient (4) and the second active ingredient (7) are selected from hormones, steroids, spermicides, antibacterial agents, antiviral agents and combinations of said active ingredients.

14. 14. The drug delivery system (1) of claim 13, wherein the steroid is a contraceptive, such as an estrogen steroid and / or a progesterone steroid.

15. 15. The drug delivery system (1) according to claim 13 or 14, wherein the first active ingredient (4) is a first contraceptive, such as estradiol, and the second active ingredient (7) is a different contraceptive, such as progesterone.

16. The drug delivery system (1) according to any one of claims 1 to 15, wherein the sheath is an outer layer of the drug delivery system (1).

17. The drug delivery system (1) according to any one of claims 1 to 16, wherein the thickness of the sheath (5) is between 0.05 mm and 3 mm, preferably between 0.05 mm and 2 mm, more preferably between 0.1 mm and 2 mm, even more preferably between 0.1 mm and 0.6 mm.

18. The drug delivery system (1) according to any one of claims 1 to 17, wherein the cross-sectional diameter of the core (2) is between 2 and 8 mm, more preferably between 3 and 6 mm, even more preferably around 4 mm.

19. 19. A method for producing a drug delivery system according to any one of claims 1 to 18, comprising the steps of: a. providing a core (2) comprising a first polymeric material (3) and a first active ingredient (4); b. providing a sheath (5) comprising a second polymeric material (6) and a second active ingredient (7), the second active ingredient (7) being dispersed and / or incorporated in the second polymeric material at a concentration of at least 10% by weight based on the weight of the sheath (5); c. Co-extruding the core (2) and sheath (5) into a fiber. A method comprising:

20. 20. The method of claim 19, further comprising a cooling step of cooling the provided drug delivery system to a temperature below 20°C to effect crystallization of one second active ingredient (7) in the second polymeric material (6).

21. 21. The method of claim 20, wherein the cooling step occurs immediately after step c.

22. 22. The method according to any one of claims 19 to 21, wherein the fibres obtained in step c are cut and / or shaped into drug delivery devices.

23. 23. A dual drug delivery device comprising the drug delivery system of any one of claims 1 to 18 or obtained by the method of any one of claims 19 to 22, wherein the dual drug delivery device is in the form of an implant, an intrauterine device or a vaginal ring.

24. Use of a drug delivery system according to any one of claims 1 to 18, or a dual drug delivery device according to claim 23, to provide a substantially zero order release rate for at least one first active ingredient (4) over a treatment period of at least 15 days, preferably at least 30 days, even more preferably at least 90 days.

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