Drug delivery system for one or more active ingredients

Abstract

A drug delivery system that includes an elongated inert support and at least two reservoirs containing a pharmaceutically active ingredient. The inert support has a number of wall segments that define at least two compartments arranged for accommodating the at least two reservoirs. The inert support is made of a material which prevents migration or diffusion of the active ingredient from one reservoir into the other or into the support. Since the drug delivery system is divided into compartments, one for each reservoir containing an active ingredient, the release rates of each active ingredient can be independently controlled or adjusted. This is due to the fact that there is no interaction between the active ingredients, and accordingly the active ingredients will not influence each other physically or chemically.

Claims

1. A drug delivery system comprising an elongated inert support and at least two reservoirs comprising an active medicament, wherein the elongated inert support has a longitudinal axis, is without an active medicament, and comprises a number of wall segments integrally formed into the inert support such that the wall segments and inert support constitute a single coherent unit defining and separating at least two compartments arranged longitudinally along the axis of the support, the at least two compartments displaced around the axis and arranged with one of the wall segments positioned between the at least two compartments for accommodating the at least two reservoirs, wherein the inert support and wall segments that constitute a single coherent unit are made of a material which substantially prevents migration or diffusion of active medicament from one reservoir into another reservoir or into the support, wherein each of the at least two reservoirs includes an outer surface through which the active medicament can diffuse or migrate into surroundings, wherein the outer surface of each of the at least two reservoirs does not extend beyond a perimeter formed about ends of the wall segments of the inert support, wherein the at least two compartments of the inert support are arranged for accommodating the at least two reservoirs without providing an interface between the at least two reservoirs, and for separating the at least two reservoirs chemically and physically, and wherein respective compartments of the inert support have a shape complementary to the at least two reservoirs and vice versa.

2. The drug delivery system according to claim 1, further comprising at least one rate-controlling membrane covering at least one reservoir or each of the at least two reservoirs.

3. The drug delivery system according to claim 2, further comprising at least one first reservoir covered by a first rate-controlling membrane and at least one second reservoir covered by a second rate-controlling membrane, wherein the first and second rate-controlling membranes each have a different permeability or thickness.

4. The drug delivery system according to claim 1, wherein the inert support is made of a first thermoplastic material, and wherein at least one compartment of the inert support is arranged such that the at least one compartment is wider at a base of the at least one compartment than at an opening of the at least one compartment, and wherein the elastic modulus of the drug delivery system is substantially defined by the elastic modulus of the inert support.

5. The drug delivery system according to claim 4, wherein the first thermoplastic material is selected from the group consisting of ethylvinylacetate (EVA), thermoplastic polyurethanes (TPUs), polyethylene (PE), polypropylene (PP), polyamide-imide (PAI), polyamide (PA), cross-linked polyethylene (PEX), thermoplastic elastomers (TPE), thermoplastic vulcanizates (TPVs), Polybutylene terephthalate (PBT), polyester, poly (ethylene terephthalate) (PET) and copolymers made with one or more of the foregoing materials.

6. A method of manufacturing a delivery system according to claim 1, which method comprises: providing an inert support having a number of wall segments defining at least two compartments along the support, wherein the inert support has a longitudinal axis and the at least two compartments are arranged longitudinally along and displaced around the longitudinal axis with one of the wall segments positioned between the at least two compartments, and placing one reservoir in each of the at least two compartments without providing an interface between reservoirs, wherein each reservoir defines an outer surface through which the active medicament can diffuse or migrate into surroundings and wherein the outer surface of each reservoir does not extend beyond the wall segments of the inert support.

7. The method according to claim 6, which further comprises placing at least one rate controlling membrane on at least one reservoir, wherein each reservoir or the at least one rate-controlling membrane is formed simultaneously.

8. The method according to claim 6, which is carried out by extrusion or injection moulding to obtain the delivery system, wherein the inert support, reservoirs and at least one membrane are extruded directly or by sequential extrusion, and further comprising curing or cooling steps after the providing of the support or placing of reservoirs.

9. The drug delivery system according to claim 1, wherein the wall segments are substantially plate-like structures arranged longitudinally along the axis with each one circumferentially extending from the axis.

10. The drug delivery system according to claim 1, wherein the inert support has a cross-section formed as an I, T, Y, H or X and comprises two, three, four or five wall segments to define two, three, four or five compartments.

11. The drug delivery system according to claim 1, wherein at least one reservoir that is present or that is an integral part of the support does not contain the active medicament.

12. The drug delivery system according to claim 1, wherein the active medicament is the same in at least two reservoirs or in all reservoirs.

13. The drug delivery system according to claim 1, wherein the delivery system has an annular, circular, oval or elliptical cross section with the perimeter providing a smooth outer surface without any extensions, projections or edges.

14. The drug delivery system according to claim 1, wherein the inert support comprises either (a) at least one first retention means for securing at least one reservoir in a compartment or on a side surface of a wall segment that faces the at least one reservoir, (b) at least one second retention means in the form of a projection placed on an end-surface of one of the wall segments to close the at least one reservoir or to be placed upon a rate controlling membrane that is mounted upon the at least one reservoir.

15. The drug delivery system according to claim 1, wherein at least one reservoir or a rate-controlling membrane provided as a wall segment is made of a second thermoplastic material or a thermosetting polymeric material, wherein the second thermoplastic material is selected from the group consisting of cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate, ethyl cellulose, polyvinyl acetate (PVA), poly(ethylene-co-methyl acrylate), ethylene-vinyl acetate (EVA), poly(methyl methacrylate), thermoplastic vulcanizates (TPVs), thermoplastic polyurethanes (TPUs) and copolymers thereof; and wherein the thermosetting polymeric material is polydimethylsiloxane, a silicone polymer with functional phenyl-, fluoro-, chloro-, or butyl groups, or another pharmaceutical acceptable silicone material.

16. The drug delivery system according to claim 1, wherein the active medicament is an estrogenic steroid, a progestational steroid or another contraceptive agent, or is at least one spermicide, an antimicrobial agent or an anti-viral agent.

17. A delivery device comprising the delivery system according to claim 1 and being in the form of an implant, an intrauterine device or a vaginal ring, wherein drug delivery is inert.

18. An inert support that has a longitudinal axis, is without an active medicament, and comprises a number of wall segments integrally formed into the inert support such that the wall segments and inert support constitute a single coherent unit defining and separating at least two compartments arranged longitudinally along the axis of the support, the at least two compartments displaced around the axis and arranged for accommodating at least two reservoirs with one of the wall segments positioned between the at least two compartments, wherein the inert support and wall segments that constitute a single coherent unit are made of a material which substantially prevents migration or diffusion of an active medicament from one reservoir into another reservoir or into the support, wherein an outer surface of each of the at least two reservoirs does not extend beyond a perimeter formed about ends of the wall segments of the inert support, wherein the at least two compartments of the inert support are arranged for accommodating the at least two reservoirs without providing an interface between the at least two reservoirs, and for separating the at least two reservoirs chemically and physically, and wherein respective compartments of the inert support have a shape complementary to the at least two reservoirs and vice versa.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The invention will be explained in greater detail below, describing only exemplary embodiments of the delivery system according to the invention, in which

(2) FIG. 1 shows a perspective view perspective view of an elongated inert support, according to the present invention,

(3) FIG. 2 shows a section of an intravaginal ring according to a first embodiment of a delivery system according to the present invention,

(4) FIG. 3 is a cross-sectional view of the embodiment shown in FIG. 2 taken along the line III-III,

(5) FIG. 4 shows a cross-sectional view of a second embodiment of a delivery system according to the present invention,

(6) FIG. 5 shows a cross-sectional view of a third embodiment of a delivery system according to the present invention,

(7) FIG. 6 shows a cross-sectional view of a forth embodiment of a delivery system according to the present invention,

(8) FIG. 7 shows a cross-sectional view of a fifth embodiment of a delivery system according to the present invention,

(9) FIG. 8 shows a cross-sectional view of a sixth embodiment of a delivery system according to the present invention,

(10) FIG. 9 shows a cross-sectional view of a seventh embodiment of a delivery system according to the present invention,

(11) FIG. 10 shows a cross-sectional view of an eight embodiment of a delivery system according to the present invention,

(12) FIG. 11 shows a cross-sectional view of a ninth embodiment of a delivery system according to the present invention,

(13) FIG. 12 shows a cross-sectional view of a tenth embodiment of a delivery system according to the present invention,

(14) FIG. 13a, 13b, 13c, 13d schematically shows different cross sections of the inert support,

(15) FIG. 14 shows a first embodiment of a delivery device according to the present invention in the form of a section of an intravaginal ring, and

(16) FIG. 15 shows a second embodiment of a delivery device according to the present invention in the form of intrauterine device.

(17) FIG. 16a-16f shows six different ring designs according to the invention, and which has been used in experiments for determining the relate rates of active ingredients.

(18) FIG. 17a, 17b shows two conventional ring designs used as in the experiments for determining the relate rates of active ingredients.

DETAILED DESCRIPTION OF THE INVENTION

(19) The present invention relates to a drug delivery device e.g. in the form of an intravaginal ring or a hormone spiral, comprising a delivery system 1, having an elongated inert support and a number of reservoirs comprising a pharmaceutically active ingredient.

(20) FIG. 1 shows a perspective view of an elongated inert support 2, for use in the present invention. Said support has the form of an X and accordingly comprises four wall segments 4, defining four compartments 5 along the support. Said compartments are arranged for accommodating four reservoirs having an active ingredient, without providing an interface between said reservoirs.

(21) The wall segments 4 are substantially plate like structures 6 each circumferentially extending from a common axis 7 of the support, and in the complete length of the supports axis. As the wall segments 4 are spaced apart, the compartments 5 are axially displaced and substantially arranged longitudinally along the axis, i.e. around the circumference of the axis 7, and extending in the length of the support.

(22) FIG. 2 shows a first embodiment of a delivery system 1 according to the present invention, comprising the inert support of FIG. 1 and four reservoirs 3; 3a, 3b, 3c, 3d. FIG. 3 is a cross-sectional view of the same embodiment, taken along the line III-III of FIG. 2. In said embodiment the four reservoirs 3a, 3b, 3c, 3d, have been attached to the support 2 shown in FIG. 1, one reservoir in each compartment 5. The reservoirs 3a and 3c comprises identical active ingredients, whereas the reservoirs 3b and 3d contains an individual active ingredient, i.e. the active ingredients in reservoirs 3b and 3d is not identical to each other or to the active ingredients in reservoirs 3a and 3c.

(23) As is evident from FIGS. 2 and 3, the reservoirs 3a, 3b, 3c, 3d are physically separated from each other, by means of the inert support 2, i.e. the active ingredients placed in the reservoirs cannot interact with each other, since the support prevents any contact between the reservoirs. Accordingly the release profile of the active ingredient in reservoir 3a will not be influenced by the presences of the active ingredients in reservoirs 3b, 3c and 3d, and vice versa. Each reservoir 3a, 3b, 3c, 3d will therefore in practice function as a single, separate delivery system. Accordingly, the release rates of each active ingredient can be independently controlled and/or adjusted.

(24) Furthermore, it is clear from FIGS. 2 and 3, that the reservoirs 3a, 3b, 3c, 3d does not extend beyond the wall segments of the inert support, i.e. that the reservoirs are held within the boundaries of the inert support 2, such that the reservoirs outer surface does not extend beyond the end surfaces of the wall segments. Accordingly, a drug delivery system is provided without any edges or similar noticeable transitions between the inert support and the reservoirs, such that a smooth surface can be obtained.

(25) In the following other preferred cross sections, which can be used in a delivery system 1 according to the invention, will be discussed. The same reference numbers will be used for identical parts.

(26) FIG. 4 shows a cross-sectional view of a second embodiment of a delivery system according to the present invention. Said embodiment also comprises four reservoirs 8; 8a, 8b, 8c, 8d but each reservoir contains an individual active ingredient. A rate-controlling membrane 9 further covers each reservoir. In the embodiment shown the rate-controlling membrane is identical for all reservoirs 8a, 8b, 8c, 8d, but each membrane 9 is separated from neighbouring membranes and reservoirs, by a small extension 10 made in the end-surface 4 of each wall segment 4. Said extensions 10 have a thickness corresponding to the thickness of the membranes 9, in order to provide a smooth surface of the system. The extensions 10 are preferably manufactured simultaneously with the inert support, and are therefore an integral part of the inert support 2.

(27) By using a rate-controlling membrane 9 the release of the active ingredient(s) to the surroundings is dependent upon permeation (i.e., molecular dissolution and subsequent diffusion) of the active ingredient(s) not only through the reservoir 8, but also through the rate-controlling membranes 9. Separation of the membranes by the extension 10 is further beneficial in order to prevent the active ingredient from diffusing and/or migrating through the membrane into one or more of the other reservoirs, e.g. if the membrane has a high permeability for one or more of the active ingredients.

(28) FIG. 5 shows a cross-sectional view of a third embodiment of a delivery system according to the present invention. In this embodiment, the respective reservoirs 3 corresponds to the reservoirs shown in FIGS. 2 and 3, i.e. reservoirs 3a and 3c comprises identical active ingredients, whereas reservoirs 3b and 3d contains an individual active ingredient. However, where the reservoirs in FIGS. 2 and 3 has surface areas that allows direct diffusion of the active ingredients into the surroundings, rate-controlling membranes 11b, 11d covers reservoir 3b and 3d, respectively. Thereby is provided a completely different release pattern for the same active ingredients, as for the embodiment shown in FIGS. 2 and 3. Accordingly, the release profile can be adjusted or controlled simply by changing a few parameter, i.e. by introducing rate-controlling membranes 11b, 11d for two reservoirs. It is evident based on the present application that further combinations easily can be made, e.g. by using more membranes, by using membranes for other reservoirs, etc.

(29) Small extensions 10 are made on the end-surface 4 of each wall segment 4, thereby preventing the active ingredients from diffusing and/or migrating through the respective membranes into the other reservoirs.

(30) FIG. 6 shows a cross-sectional view of a forth embodiment of a delivery system according to the present invention. In this embodiment the two reservoirs 12a and 12d comprises identical active ingredients, whereas reservoirs 12b and 12c contains individual active ingredient. One rate-controlling membrane 13 covers the entire longitudinal surface of the delivery system, but the thickness of the rate-controlling membrane 13b for reservoir 12b is larger than for the other three reservoirs, in order to reduce the release rate of the active ingredient in reservoir 12b.

(31) A similar situation is shown for the fifth embodiment in FIG. 7. In said embodiment each of the four reservoirs 14, i.e. 14a, 14b, 14c, and 14d comprises an individual active ingredient, and each reservoir is further covered by an individual rate-controlling membrane 15a, 15b, 15c, and 15d. Each rate-controlling membrane has an individual permeability, which can be obtained by e.g. using different materials for the membrane, by varying the degree of cross linking, by using block copolymers and/or by varying the relative amounts of the different blocks materials.

(32) Another option is to adjust the thickness of the respective membranes, either alone or in combination with the above. As can be seen in the FIG. 7, membrane 15c is thicker than membrane 15a and 15b, which has an identical thickness, but still thinner than membrane 15d, which is the thickest membrane in the present embodiment. It will be understood by a person skilled in the art, that membranes with different thickness can control the release rates, as the active ingredient will have to travel a longer distances using a thick membrane than a thinner membrane.

(33) Each reservoir will define a surface area, i.e. an outer surface 16 through which the active ingredients can diffuse/migrate into the membrane and further into the surrounding environment. Accordingly the size of said surface area will influence the release profile of a respective active ingredient.

(34) As can be seen in FIG. 7, the surface area 16c and 16d of the reservoirs 14c and 14d, i.e. the reservoirs with the thick membranes is smaller than the surface area 16a and 16b, of the reservoirs 14a and 14b, having thinner membranes. Since it is generally desired to provide a circular cross section having a relatively smooth surface, the thicker the membrane, the smaller the surface area will be in practice. Accordingly it will be easy to adjust the release profile, such that one active ingredient e.g. the active ingredient in reservoir 14d, can be released to the surroundings in an ever smaller concentration than the other active ingredients in reservoirs 14a, 14b, and 14c. Thus, again minor or small adjustments to the overall system will alter the release profile significantly.

(35) FIG. 8 shows a cross-sectional view of a sixth embodiment of a delivery system according to the present invention, and the structure corresponds in reality to the embodiment shown in FIG. 4, with the modification that all four reservoirs 17 are identical, and contains the same/identical active ingredient. This solution is advantageous from a production-point of view, since the same supports can be used for several embodiments. In this way the support functions as a universal support, which can be loaded with one or more active ingredients and where each active ingredient is released at a controlled rate. Accordingly, the need to provide an individual inert support designed for a specific application is eliminated.

(36) A cross-sectional view of a seventh embodiment according to the present invention is shown in FIG. 9. Said embodiment differs from the above embodiments in that a single uniform membrane 18 covers the inert support 2 and in that one of the reservoirs 19c, does not contain any active ingredients. In the present embodiment, reservoir 19c without active ingredient, has been added to the inert support when the inert support was manufactured, i.e. one of the compartments was filled with the same material as the remaining of the inert support during the extrusion, such that said reservoir in reality became part of the inert support, i.e. only three compartments was provided for receiving reservoirs. However, this can of course also be achieved by placing a reservoir without active ingredients in said compartment later. Furthermore, more than one compartment can be filled with the same material as the inert support.

(37) The purpose of incorporating one or more reservoirs without active ingredient into the delivery system according to the invention is to provide further alternative for altering and/or adjusting the release profile of the system even further. However, this can also be relevant if specific ratio of the active ingredients can be achieved more economically in this way, or if a higher degree of stiffness/rigidity of the inert support is required.

(38) A single membrane 18 having uniform thickness covers the entire circumference of the inert support 2 and the reservoirs 19a, 19b,19c. Accordingly, the membrane 18 will hold all the reservoirs securely in place. Such an embodiment is very simple and inexpensive, and can also be relevant when the active ingredient in e.g. reservoir 19a and 19d, cannot diffuse in a substantial degree via the membrane into the reservoir 19b, which contains a different active ingredients.

(39) In some situation it can be problematic to maintain the reservoirs in the correct position in the compartment 5, simply because the materials do not adhere securely to each other during manufacture or use. One way of providing a safe and effective adherence of the reservoirs to the support is shown in FIG. 10 in which the side surfaces 20 of the wall segments 4 facing the reservoir 21a, 21b, 21c, and 21d comprises a number of first retention means 22, in the form of barbs 22 and circular projections 22. Said first retention means are made as an integral part of the inert support, however they can also be placed on the relevant side surfaces after the support has been provided e.g. by gluing or melting said first retention means to the support.

(40) It must be noted that if a single membrane covers the system completely as in the embodiments shown e.g. in FIGS. 6 and 9, then said membrane will retain the reservoirs in place, and the need for retention means may be less significant.

(41) A cross sectional view of an eight embodiment according to the present invention is shown in FIG. 11. Said embodiment is also arranged for securing the four reservoirs 23a, 23b, 23c, 23d, and the four identical membranes 24 in place. In this embodiment the support 2 comprises at least one second retention means 25, for securing the reservoirs 23 and the rate-controlling membranes 24 to the inert support 2. The second retention means is a projection 25 in the form of a fraction of a circle, placed on the end-surface 26 of at least one of the wall segments 4.

(42) As can be seen in FIG. 11 the projections 25 partly covers the reservoirs 23a, 23b, 23c, 23d and the membranes 24, in such a way that all elements are held securely in place. The projection covers the membranes 24 in varying degrees, thereby providing an additional way of adjusting the release rates of the different active ingredient in the respective reservoirs. In the embodiment shown, the surface area 25c of the membrane though which active ingredient is allowed to diffuse/migrate is larger for reservoir 23c having one active ingredient, than for the identical reservoirs 23a, 23b, 23d accommodating a different active ingredient. Thereby is provided a further means for adjusting the release rate of the active ingredients in the system according to the invention.

(43) Furthermore, the section 27 of the wall segment 4 spanning the membrane, will function as the extension 10, described under FIG. 4, FIG. 5 and FIG. 8, i.e. said section will effectively separate the membranes, preventing any active ingredient from entering the other reservoirs though the membranes.

(44) Another way of ensuring that the rate-controlling membranes 9a,9b,9c,9d are effectively and securely held in place is to add third retention means 28 to the membranes, such that they is arranged for being embedded into the end-surfaces of the wall segments, as shown in FIG. 12.

(45) The above embodiments of the delivery system according to the invention, have all been described with a support in the form of an X, having four compartments and accordingly four reservoirs, as shown schematically in FIG. 13a. However as is evident from FIGS. 13b, 13c, and 13d, the support can also have cross-sections in the form of an I, Y, or T, receptively. The person skilled in the art will understand that the support in principal can have any cross-sectional design, and that said inert support can have any preferred number of compartments, as long as the support is arranged for preventing any interference between the reservoirs.

(46) The choice of desired cross-section of the inert support will in any given case depend on the desired ratio of delivery rates of the active ingredient in the reservoirs 29. In this way the present invention resides in a unique means of delivering one, and preferably two or more, active ingredient(s) simultaneously to an environment at a specified ratio of delivery rates.

(47) It is also clear from the figures that the reservoirs of the shown embodiments are held within the boundaries of the inert support 2, such that the reservoirs outer surface does not extend beyond the end surfaces of the wall segments.

(48) In the embodiments shown in FIGS. 13a, 13b, 13c and 13d, the reservoirs 29 are all made of the same material having the same active ingredients, however this can easily be adjusted based on the present application, and must not be constructed as limiting. Similar the membrane 30, which is shown as a single membrane, can be divided into one or more individual membranes, depending one the desired release profile.

(49) It will be understood by a person skilled in the art based on the above invention, that the parameters of the reservoirs and/or the rate controlling membranes can be varied singly or in combination, and further variations may also be incorporated, such as the length of the respective reservoir and the size of the delivery device.

(50) Control of the delivery rates of the active ingredient in the delivery system according the invention, is thus transferred to a number of easily adjustable parameters, which provide a full range of flexibility and variation, rather than relying on the quantities, concentrations, and ratios of the active ingredients or polymers alone. Thereby is obtained a very effective and inexpensive drug delivery system, in which the active ingredients are released in a more controlled manner than hitherto known.

(51) The above embodiments for delivery systems can be used as a drug delivery device, either alone or in combination with other parts of a delivery device.

(52) In a preferred embodiment the drug delivery device is an intravaginal ring, a segment 31 of which is shown in FIG. 14. The cross sectional design of said segment, corresponds to the embodiment shown in FIG. 4. Said segment has been provided using sequential extrusion, i.e. the support, reservoirs and membranes are extruded in separate extrusion steps, with appropriate curing/cooling steps in-between. Thereby is provided long filaments that can be cut at appropriate lengths into segments 31 for forming the vaginal ring. The two ends of the segments 32 and 32 are thereafter assembled; by connecting them to each another e.g. by gluing or melting; thereby providing a desired vaginal ring structure. In FIG. 14 the segment has been slightly bend and is in the process of being assembled. It will be understood by a person skilled in the art, that during assembly of the ring, corresponding reservoirs are matched in order to prevent migration/diffusion of active ingredients from one reservoir to other reservoirs.

(53) Alternatively, the filaments can be cut into appropriate length for combination with a part of a T-frame, in order to provide a IUD 33, as shown in FIG. 15. Here a segment e.g. the segment 31 shown in FIG. 14 is placed between an upper portion 34 and a lower portion 34 of a conventional T-frame, providing the final IUD.

EXAMPLES

(54) In order to compare the release profiles of a drug delivery system according to the invention with a conventional drug delivery system, six drug delivery systems according to the invention with six different cross sectional designs were constructed, and compared with two conventionally drug delivery systems of two designs. Two units of each system were manufactured, all in the form of vaginal rings.

(55) Construction of Vaginal Rings

(56) Inert Support

(57) The inert support/skeleton of the rings according to the invention, were made of a thermoplastic materials, selected from low density polyethylene (LDPE) obtainable from Celanese Corporation, ethylvinylacetate 9% vinyl acetate (EVA 9% VA), obtainable from Celanese Corporation and ethylvinylacetate 18% vinyl acetate (EVA 18% VA) obtainable from Arkema.

(58) The LDPE skeleton was extruded at 130? C., the EVA 9% VA skeleton was extruded at 110? C., and the EVA 18% VA skeleton was molded.

(59) Reservoir

(60) The reservoirs of the rings according to the invention were made of the polydimethylsiloxanes, MED4-4420 or MED5-6382 obtainable from NuSil Technology LLC. Each reservoir contained a single pharmaceutical active ingredient (API) selected from ethinylestradiol (obtainable from Bayer Pharma AG), levonorgestrel (obtainable from Chemo Group, Spain), and drospirenone (obtainable from Sterling S.p.A.).

(61) MED4-4420 is a platinum catalyzed, addition cure silicone system, and MED5-6382 is a tin catalyzed, condensation cure system.

(62) The respective active ingredients are uniformly suspended as particles throughout the polymer and the reservoirs are matrix systems (monolithic system).

(63) Membrane

(64) The membranes used in the rings according to the invention were made of the polydimethylsiloxanes, MED4-4420 or MED5-6382 obtainable from NuSil Technology LLC. The membranes did not contain any active ingredients.

(65) Ring Construction

(66) The rings according to the invention, ring 1-6, were manufactured by sequential extrusion of the reservoirs onto the skeleton, and when relevant also the membrane, followed by cutting the extruded string in 160 mm sections. The ring form were obtained by melting the ends together (using EVA 18% VA). The joint of ring 2-6 was covered with the same polydimethylsiloxane that was used as an outer layer and/or membrane.

(67) The rings 7-8 that were of the conventional kind had a drug containing core covered by a membrane, and were manufactured using conventional techniques i.e. by first molding the inner ring and then the membrane was overmolded in two steps. Cores and membranes were made of a material identical to the reservoirs and membranes used for the rings according to the invention. The temperatures used are the same as for the rings according to the invention.

(68) All rings were cured at 60? C. for about 1 hour.

(69) Design

(70) The cross-sectional views of the rings 1-6, are shown in FIG. 16a-16f respectively, and the cross-sectional views of conventional ring designs for ring 7 and 8, are shown in FIG. 17a and b.

(71) Ring 1 is shown in FIG. 16a. The inert support 2, has an overall H-shape providing two compartments 35 which is designed such that the both compartments are wider at the base, (i.e closest to the longitudinal axis of the inert support) than at the opening, (i.e. at the surface area not in contact with the inert support). In this way the reservoirs 36a, 37a can easily be retained in the compartment, without any additional means.

(72) Each compartment has a width b of 1.5 mm at the base and a width b of 1.0 mm at the opening. The depth h of the compartment is 2.0 mm. The skeleton and string diameter x is 5 mm, and accordingly the device has the same cross-sectional diameter.

(73) The first reservoir, 36a contains 5 w/w % ethinylestradiol in MED5-6385 and the second reservoir 37a contains 20 w/w % drospirenone in MED4-4420.

(74) Ring 2 is shown in FIG. 16b, and has the same skeleton profile as ring 1. As for ring 1, the first reservoir 36b contains 5 w/w % ethinylestradiol in MED5-6382 whereas the second reservoir 38b contains 5 w/w % levonorgestrel in MED5-6382. An 0.5 mm layer 39 of MED5-6382 with 20% drospirenone covers the entire ring. Said layer 39, will both function as a membrane layer for the active ingredients placed in the reservoirs 36b and 38b, and as a drug-containing layer.

(75) Ring 3 is shown in FIG. 16c, and has the same skeleton profile as ring 1 and 2. As for ring 2, the first reservoir 36c contains 5 w/w % ethinylestradiol in MED5-6382 and the second reservoir 38c contains 5 w/w % levonorgestrel in MED5-6382. A 0.5 mm membrane 40 of MED5-6382 covers the entire ring. Between the skeleton/reservoirs construction and the membrane 40, is placed a 0.5 mm drug containing layer 39 of 20 w/w % drospirenone in MED5-6382. Said layer 39, will function both as a membrane layer for the active ingredients placed the reservoirs 36c and 38c, and as a drug-containing layer.

(76) Ring 4 is shown in FIG. 16d. In this ring the inert support 2 has the shape of a U-form 41 with two legs 41, providing a first and second compartment 42a and 42b, respectively. The first compartment 42a has a width b of 1 mm, the second compartment 42b has a width b of 2.8 mm. The total width x of the skeleton is 3.8 mm, and the total skeleton height h is 2.5 mm. Each leg 41 has a width z of 0.5 mm and a height h of 1 mm. In the present case the first compartment 42a is filed to a thickness of 0.2 mm with a first reservoir 36d containing 5 w/w % ethinylestradiol in MED5-6382 and, and the second compartment 42b is filed to a thickness of 0.6 mm with a second reservoir 37b containing 20 w/w % drospirenone in MED5-6382. Thus, none of the compartments are filled completely, as is also evident from the figure. In order to provide a smooth surface of the ring design, an outer membrane 43 is provided. Said membrane is arranged such that it fills the gaps and grooves in the skeleton with the reservoirs. Accordingly, the membrane will be thicker in some places than others, thereby controlling the release rate.

(77) Ring 5 is shown in FIG. 16e. In this ring the inert support 2 has the shape of a filled X, providing four identical compartments 44. The total width and height x of the skeleton is 5 mm and each compartment 44, has a maximum depth d of 0.70 mm. The distance y between the compartments are 2.8 mm. In the present case one compartment 44a is filed with a first reservoir 36e containing 5 w/w % ethinylestradiol in MED5-6382 and, and three compartments 44b,44c,44d are filed with identical reservoirs 37e containing 20 w/w % drospirenone in MED5-6382. An outer membrane 45 is provided, said membrane is arranged such that smooth surface of the ring design is obtained.

(78) Ring 6 is shown in FIG. 16f, and has an inert support identical to the support of ring 4 shown in FIG. 16d, with the modification that no reservoir is present in the first compartment 42a, and that the addition cure silicone, MED4-4420, is used in both reservoir and membrane.

(79) Ring 7 is shown in FIG. 17a, said ring comprises a core 46 of 5 w/w % ethinylestradiol in MED5-6382 having a diameter of 3 mm, covered by a membrane 47 of MED5-6382, providing a total diameter of the string of 6 mm.

(80) Ring 8 is shown in FIG. 17b, said ring comprises a core 46 of 5 w/w % levonorgestrel in MED5-6382 having a diameter of 3 mm, covered by a membrane 47 of MED5-6382, providing a total diameter of the string of 6 mm

(81) Ring Composition

(82) The respective rings made according to the invention has the composition shown in table 1, and the conventional rings had the composition shown in table 2.

(83) TABLE-US-00001 TABLE 1 Skeleton Skeleton Reservoir Membrane String diameter Ring Material Design number API and reservoir material material (mm) 1 EVA 9% VA H-form 2 20 w/w % drospirenone in MED4-4420 n/a 5 5 w/w % Ethinylestradiol in MED5-6382 2* EVA 9% VA H-form 2 5 w/w % levonorgestrel in MED5-6382 MED5-6382 6 5 w/w % Ethinylestradiol in MED5-6382 3** EVA 9% VA H-form 2 5 w/w % levonorgestrel in MED5-6382 MED5-6382 7 5 w/w % Ethinylestradiol in MED5-6382 4 LPDE U-form with 2 20 w/w % drospirenone in MED5-6382 MED5-6382 5 legs 5 w/w % Ethinylestradiol in MED5-6382 5 EVA 18% VA X-form 4 20 w/w % drospirenone in MED5-6382 MED5-6382 6 5 w/w % Ethinylestradiol in MED5-6382 6 LPDE U-form with 1 20 w/w % drospirenone in MED4-4420 MED4-4420 5 legs **Ring 2 contains a drug containing layer of 20 w/w % drospirenone in MED5-6382, covering the skeleton/reservoirs. **Ring 3 contains a drug containing layer of 20 w/w % drospirenone in MED5-6382, placed between the skeleton/reservoirs, and the membrane.

(84) TABLE-US-00002 TABLE 2 Core String diameter Membrane diameter Ring API and core material (mm) material (mm) 7 5 w/w % Ethinylestradiol in 3 MED5-6382 6 MED5-6382 8 5 w/w % levonorgestrel in 3 MED5-6382 6 MED5-6382
Drug Release

(85) In vitro release experiments of the active ingredients in the rings were conducted with a typical dissolution test for vaginal rings. The samples were submerged in a glass flask containing 400 ml water medium subjected to shaking of 130 rpm at 37? C., for 14 days. The water medium was exchanged every day except day 4, 5, 11 and 12 (i.e. no change of medium on Saturdays and Sundays). Samples were withdrawn after appropriate time periods, and the concentration of the active ingredients was determined with an HPLC method.

(86) The release rates of the active ingredients of ring 1-8 is shown in table 3 (mean value of two identical rings) for day 1, 2, 7 and 14.

(87) TABLE-US-00003 TABLE 3 Drug Drospirenone Ethinylestradiol Levonorgestrel (?g/day) (?g/day) (?g/day) Day 1 2 7 14 1 2 7 14 1 2 7 14 Ring 1 951 441 265 185 473 260 142 97 n.a. n.a. n.a. n.a. Ring 2 6677 6304 5561 4556 65 36 37 37 13 8.2 11 9.6 Ring 3 826 751 839 846 61 33 31 32 15 8.4 9.3 8.8 Ring 4 94 43 48 49 69 36 29 26 n.a. n.a. n.a. n.a. Ring 5 370 316 331 315 101 89 89 85 n.a. n.a. n.a. n.a. Ring 6 136 61 65 64 n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. Ring 7 n.a. n.a. n.a. n.a. 334 236 227 206 n.a. n.a. n.a. n.a. Ring 8 n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. 58 51 55 54

(88) Desired release rates of the used active ingredients will always depend on the intended use. As an example could the release rate be: 15 ?g/day for ethinylestradiol, 20 ?g/day for levonorgestrel, and between 500-2000 ?g/day for drospirenone. These release rate must not be construed as limiting, and the desired release rate will among others depend on the desired use of the delivery system. The present examples shown that the drug release rates using a delivery system according to the invention can be chosen within a wide range. However, it will be understood that the release rate of the active ingredients easily can be adjusted according to the invention, e.g. by using different thickness of membranes, and/or different shape and size of the respective reservoirs. The present examples are not intended to resemble usable intravaginal rings, but only to demonstrate that the invention provides the possibility of easily controlling and adjusting the release rate of several active ingredients in a single system.

(89) Ring 1 does not have a membrane or outer layer, and accordingly the drug release rate from the reservoirs drops over time as expected with a matrix design. It must however be stressed that the drop in drug release is less pronounced compared to a conventional monolithic matrix design due to the geometry, i.e. when the drug depletes the diffusion path increases as with the monolithic design but the area does not decrease as much as it would with a conventional monolithic matrix design.

(90) It is further evident from the results for ring 2, that the addition of an outer layer provides a close to constant drug release profile for the two reservoirs. The typical burst effect on day 1 and the fact that the drug release rates drops slowly when the drug depletes is expected. However, the release of ethinylestradiol for ring 2 has much lower release rate compared to the conventional design exemplified by ring 7. Levonorgestrel for ring 2 has also a much lower drug release rate compared to the conventional design exemplified by ring 8.

(91) This lower drug release rate using the ring designs according to the invention is highly desirable and very difficult to obtain using the conventional design, as is evident when comparing the release rates of the two conventional rings with ring 2.

(92) The addition of an additional layer between the skeleton/reservoirs and the membrane, does not only provide an additional drug but also a thicker membrane, since the membrane of the two reservoirs consists of the combination of the drospirenone layer and the membrane. Compared to ring 2 the ethinylestradiol and levonorgestrel releases through a thicker membrane/layer in ring 3 and consequently has slightly lower drug release rate. The drospirenone from the intermediate layer also releases with close to constant drug release rate as expected from a reservoir design.

(93) Ring 4 is an example of a ring with two reservoirs with different surface area. The compartment have straight walls and the membrane secures that the reservoirs are kept in place. As expected the drospirenone releases much slower in ring 4 compared to ring 3 due to the smaller surface area and also due to the thicker membrane.

(94) Ring 5 is an example of a ring with four compartments. One is filled with an ethinylestradiol matrix and three with drospirenone matrixes. Ethinylestradiol releases faster compared to ring 2, 3 and 4 as expected due to the larger surface area of the ethinylestradiol matrix. The release rate of drospirenone is placed between ring 3 and 4 as expected due to the size of the drospirenone matrix surface area.

(95) Ring 6 is an example of a ring with addition cure silicone as compared to ring 4 that contain condensation cure silicone. The drug release rate is as expected in the same magnitude for ring 4 and 6.

(96) Ring 7 and 8 is example of traditional reservoir design of vaginal rings. They are made with a size to resemble and to fairly compare with ring 1 to 6. It is easy to see that those rings have much faster drug release and is not suitable to achieve the slower drug release that can be obtained with the present invention.

(97) The analytical drug release results show that widely different drug release can be obtained using the drug delivery system according to the invention. The main benefits are: Controlled drug release, especially to achieve slow drug release with a long duration. Suitable for combining several drugs and control the drug release independently for the different drugs by having separate compartments. Complex profile of the skeleton is easy to achieve by extruding the skeleton. (Retention design in ring 1 is expensive to mold but easy to extrude).

(98) In the above the invention has been described with the assumption that the drug delivery device is either a vaginal ring or a hormone spiral. However, this assumption is not to be construed as limiting, and the delivery device can just as easily have a different structure/design, or be a different kind of device, e.g. a single-rod subdermal implant. Using the specific construction of the delivery system according to the invention, it is possible to provide drug delivery devices, e.g IVRs and IUDs capable of providing sustained delivery of one or more active ingredient in a substantially zero order release profile. Such drug delivery devices, has an inexpensive design, and can therefore be used equally well both privately and in medical or hospital facilities.

(99) Modifications and combinations of the above principles and designs are foreseen within the scope of the present invention.