TARGETED DELIVERY OF PROGESTINS AND ESTROGENS VIA VAGINAL RING DEVICES FOR FERTILITY CONTROL AND HRT PRODUCTS

Abstract

A variety of different intravaginal drug delivery devices are described for the delivery of estrogens and progestins. The release rate of estrogens and progestins can be controlled by varying the matrix material or by the application of a thin coating. The intravaginal drug delivery devices may be composed of one or more individual compartments. By controlling various physical and chemical parameters, non-zero release rates of the estrogen or progestins may be achieved.

Claims

1. An intravaginal drug delivery device comprising: one or more compartments, each of the compartments comprising an estrogen and/or a progestin dispersed in a thermoplastic polymeric matrix; wherein the intravaginal drug delivery device provides the estrogen and/or the progestin according to a non-zero order release profile.

2. The device of claim 1, comprising: one or more uncoated compartments, the uncoated compartments comprising an estrogen and/or progestin dispersed in an uncoated thermoplastic polymeric matrix; and/or one or more coated compartments, the coated compartments comprising an estrogen and/or progestin dispersed in a coated thermoplastic polymeric matrix, wherein the coated thermoplastic polymeric matrix comprises a coating surrounding the coated thermoplastic polymeric matrix.

3. The device of claim 1, wherein the compartments have different sizes.

4. The device of claim 1, wherein the device comprises at least one compartment containing a progestin, and wherein the progestin is etonogestrel.

5. The device of claim 1, wherein the device comprises at least one compartment containing a progestin, and wherein the progestin is trimegestone.

6. The device of claim 5, wherein the device releases trimegestone in doses between 0.075 and 025 mg/day.

7. The device of claim 1, wherein the estrogen is ethinyl estradiol.

8. The device of claim 1, wherein the estrogen is estriol.

9. The device of claim 8, wherein the device releases estriol in doses between 0.05 and 0.75 mg/day.

10. The device of claim 8, wherein the device is configured such that estriol plasma levels of 50-200 pg/ml are achieved on day 1 of treatment

11. The device of claim 8, wherein the device is configured such that estriol plasma levels of 15-30 pg/ml are achieved on day 21 of treatment

12-14. (canceled)

15. The device of claim 1, wherein the thermoplastic matrix comprises an ethylene vinyl acetate copolymer.

16. The device of claim 1, wherein the thermoplastic matrix comprises one or more hydrophilic matrix materials.

17. The device of claim 1, wherein the thermoplastic matrix comprises an ethyl vinyl acetate copolymer and one or more hydrophilic matrix materials.

18. The device of claim 1, wherein the device has a substantially annular form.

19. The device of claim 1, wherein the device delivers an effective amount of the progestin and the estrogen for at least 21 days.

20. The device of claim 1, wherein the device comprises a progestin and an estrogen, and wherein the ratio of the release rate of the estrogen on day 1 to the release rate of the estrogen on day 21 is between 1.5 and 4.0, and wherein the ratio of the release rate of progestin on day 1 to the release rate of progestin on day 21 is between 1.5 and 4.0.

21. The device of claim 1, wherein the device comprises a progestin and an estrogen, and wherein the ratio of the release rate of the estrogen on day 1 to the release rate of the estrogen on day 21 is between 1.5 and 3.0, and wherein the ratio of the release rate of progestin on day 1 to the release rate of progestin on day 21 is between 1.5 and 3.0.

22. The device of claim 1, wherein the device comprises a progestin and an estrogen, and wherein the ratio of the release rate of the estrogen on day 1 to the release rate of the estrogen on day 21 is between 1.5 and 2.0, and wherein the ratio of the release rate of progestin on day 1 to the release rate of progestin on day 21 is between 1.5 and 2.0.

23. A method of producing a contraceptive state in a subject comprising positioning an intravaginal drug delivery device, as described in claim 1, in the vagina or uterus of a female.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Advantages of the present invention will become apparent to those skilled in the art with the benefit of the following detailed description of embodiments and upon reference to the accompanying drawings in which:

[0036] FIG. 1A depicts an in-vitro release profile of ethinyl estradiol from a reservoir type intravaginal ring;

[0037] FIG. 1B depicts an in-vitro release profile of etonogestrel from a reservoir type intravaginal ring;

[0038] FIG. 2A depicts an in-vitro release profile of ethinyl estradiol from a matrix type intravaginal ring;

[0039] FIG. 2B depicts an in-vitro release profile of etonogestrel from a matrix type intravaginal ring;

[0040] FIG. 3A depicts an in-vitro release profile of trimegestone from a matrix type intravaginal ring with 0.25% loading;

[0041] FIG. 3B depicts an in-vitro release profile of trimegestone from a matrix type intravaginal ring with 0.50% loading;

[0042] FIG. 4A depicts an in-vitro release profile of trimegestone from a reservoir type intravaginal ring with 1.053% core loading and 320 m skin thickness;

[0043] FIG. 4B depicts an in-vitro release profile of trimegestone from a reservoir type intravaginal ring with 1.053% core loading and 190 m skin thickness;

[0044] FIG. 4C depicts an in-vitro release profile of trimegestone from a reservoir type intravaginal ring with 0.90% core loading and 135 m skin thickness;

[0045] FIG. 5A depicts an in-vitro release profile of estriol from a matrix type intravaginal ring with 0.65% loading;

[0046] FIG. 5B depicts an in-vitro release profile of estriol from a matrix type intravaginal ring with 5% loading;

[0047] FIG. 5C depicts an in-vitro release profile of estriol from a matrix type intravaginal ring with 15% loading;

[0048] FIG. 5D depicts an in-vitro release profile of estriol from a matrix type intravaginal ring with 30% loading;

[0049] FIG. 6A depicts an in-vitro release profile of estriol from a matrix system of a segmented intravaginal ring (60% estriol loaded matrix segment length);

[0050] FIG. 6B depicts an in-vitro release profile of trimegestone from a reservoir system of a segmented intravaginal ring (1.053% core loading; 190 m skin thickness; 40% trimegestone segment length);

[0051] FIG. 7 depicts a graph showing the concentration of Follicle Stimulating Hormone (FSH) for an etonogestrel and ethinyl estradiol containing intravaginal ring;

[0052] FIG. 8A depicts a graph showing mean plasma concentrations of estriol after single dose application for three different devices having different estriol delivery rates;

[0053] FIG. 8B depicts a graph showing mean plasma concentration vs. time curves for changes from baseline of FSH for three different devices having different estriol delivery rates;

[0054] FIG. 8C depicts a graph showing mean maturation index by cell types (parabasal, intermediate and superficial) for three different devices having different estriol delivery rates;

[0055] FIG. 9A depicts a graph showing mean plasma concentrations of estriol after single dose application for three different devices having different estriol and trimegestone delivery rates;

[0056] FIG. 9B depicts a graph showing mean plasma concentrations of trimegestone after single dose application for three different devices having different estriol and trimegestone delivery rates; and

[0057] FIG. 9C depicts a graph showing bleeding profile for women treated with an intravaginal device delivering estriol and trimegestone.

[0058] While the invention may be susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. The drawings may not be to scale. It should be understood, however, that the drawings and detailed description thereto are not intended to limit the invention to the particular form disclosed, but to the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present invention as defined by the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0059] It is to be understood the present invention is not limited to particular devices, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms a, an, and the include singular and plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a progestin includes one or more progestins.

[0060] As used herein, an intravaginal device refers to an object that provides for administration or application of an active agent to the vaginal and/or urogenital tract of a subject, including, e.g., the vagina, cervix, or uterus of a female.

[0061] In an embodiment, an intravaginal drug delivery device includes one or two or more compartments joined to each other. Each of the compartments includes an estrogen and/or a progestin. Each compartment may be an uncoated polymeric matrix that includes the active agent or a coated polymeric matrix that includes the active agent. A combination of coated and uncoated compartments may be combined to form a ring-shaped drug delivery device.

[0062] A variety of materials may be used as the matrix for the compartments. Generally, the compartments used in the intravaginal device are suitable for extended placement in the vaginal tract or the uterus. In an embodiment, a thermoplastic material is used to form the intravaginal drug delivery device. The thermoplastic material is nontoxic and non-absorbable in the subject. In some embodiments, the materials may be suitably shaped and have a flexibility allowing for intravaginal administration.

[0063] In a preferred embodiment, compartments of an intravaginal drug delivery device are formed from an ethylene vinyl acetate copolymer (EVA). A variety of grades may be used including grades having a low melt flow index, a high melt flow index, a low vinyl acetate content or a high vinyl acetate content. As used herein, EVA having a low melt flow index has a melt flow index of less than about 100 g/10 min as measured using ASTM test 1238. EVA having a high melt flow index has a melt index of greater than about 100 g/10 min as measured using ASTM test 1238. EVA having a low vinyl acetate content has a vinyl acetate content of less than about 20% by weight. EVA having a high vinyl acetate content has a vinyl acetate content of greater than about 20% by weight. The compartments of the intravaginal drug delivery device may be formed from EVA having a low melt flow index, a high melt flow index, a low vinyl acetate content or a high vinyl acetate content. In some embodiments, the thermoplastic matrix may include: mixtures of a low melt flow index and high melt flow index EVA or mixtures of low vinyl acetate content and high vinyl acetate content EVA.

[0064] In an embodiment, a combination of one or more suitable materials may be used to form the compartments. The material(s) may be selected to allow prolonged release of the active ingredients from the compartment. In addition, the concentration of the active agents, in combination with the matrix material may be selected to provide the desired release from the compartment. In some compartments, a coating may be applied to the matrix to yield reservoir systems to further control the release rate of the active ingredients. The coating may be formed from the same material, or a different material than the thermoplastic matrix used to form the compartment.

[0065] In one embodiment, the compartment may be composed of ethylene vinyl acetate copolymer in combination with the hydrophobic polymer hydroxy propyl cellulose.

[0066] In an embodiment, the active agents, for example the progestin and/or estrogen, are dispersed in the thermoplastic matrix to form a compartment. As used herein the term dispersed, with respect to a thermoplastic matrix, means that a compound is substantially evenly distributed through the polymer, either as a solid dispersion in the polymer or dissolved within the polymer matrix. The term particle dispersion, as used herein refers to a dispersion of the compound particles homogenously distributed in the polymer. The term molecular dispersion, as used herein refers to the dissolution of the compound in the polymer. For purposes of this disclosure, a dispersion may be characterized as a particle dispersion if particles of the compound are visible in the polymer at a magnification of about 100-fold under regular and polarized light. A molecular dispersion is characterized as a dispersion in which substantially no particles of the compound are visible in the polymer at a magnification of 100-fold under regular and polarized light.

[0067] In an embodiment, the intravaginal drug delivery device is used to produce a contraceptive state in a female mammal. The contraceptive state may be produced by administering an intravaginal drug delivery device that includes a progestin. In other embodiments, contraceptive state may be produced by administering an intravaginal drug delivery device that includes a progestin and an estrogen component.

[0068] Progestins include, but are not limited to, gestodene, ketodesogestrel, demegetone, desogestrel, drospirenone, levonorgestrel, megestrol, megestrol acetate, melengestrol, melengestrol acetate, nestorone, nomegestrol acetate, norgestimate, and promegestone.

[0069] A preferred progestin is trimegestone and a preferred estrogen is estriol.

[0070] The intravaginal delivery device can be in any shape suitable for insertion and retention in the vaginal tract without causing undue discomfort to the user. For example, the intravaginal device may be flexible. As used herein, flexible refers to the ability of an intravaginal drug delivery device to bend or withstand stress and strain without being damaged or broken. For example, an intravaginal delivery device may be deformed or flexed, such as, for example, using finger pressure, and upon removal of the pressure, return to its original shape. The flexible properties of the intravaginal drug delivery device are useful for enhancing user comfort, and also for ease of administration to the vaginal tract and/or removal of the device from the vaginal tract.

[0071] In an embodiment, the intravaginal drug delivery device may be annular in shape. As used herein, annular refers to a shape of, relating to, or forming a ring. Annular shapes suitable for use include a ring, an oval, an ellipse, a toroid, and the like. The intravaginal drug delivery device may have a non-annular geometry.

[0072] In one embodiment, the intravaginal drug delivery device has a geometry in the form of a strand of geometrically shaped compartments linked together. For example, a plurality of hexagon shaped compartments may be linked to form a strand. Other geometrically shaped units including, but not limited to, squares, triangles, rectangles, pentagons, heptagons, octagons, etc. may be formed into strands. In some embodiment, mixtures of different geometrically shaped units may be joined to together in a strand. The strand of geometrically shaped units may be joined together to form ring-like structure.

[0073] In another embodiment, an intravaginal drug delivery device is in the shape of a half oval. A half oval device may be easier to manufacture than a full ring. In an embodiment, the half oval shape may allow a user to form a ring like structure before and/or after insertion. In another embodiment, an intravaginal drug delivery device may be in the shape of a hollow cylinder. Use of a hollow cylinder may allow easier insertion of the intravaginal delivery device. The hollow cylinder geometry may allow insertion of the intravaginal drug delivery device into the vaginal tract in a compressed form, which, upon deployment, expands inside the tract to improve the retention of the device. In another embodiment, an intravaginal drug delivery device may have a monolithic film geometry. Such a film may be formed or include, mucoadhesive substances to improve adhesion to the vaginal tract.

[0074] The intravaginal drug delivery device may be manufactured by any known techniques. In some embodiments, therapeutically active agent(s) may be mixed within the thermoplastic matrix material and processed to the desired shape by: injection molding, rotation/injection molding, casting, extrusion, or other appropriate methods. In one embodiment, the intravaginal drug delivery device is produced by a hot-melt extrusion process.

[0075] In one embodiment, a method of making an intravaginal drug delivery device includes: [0076] a. forming a mixture of a thermoplastic polymer and the active agent; [0077] b. heating the thermoplastic polymer/active agent mixture such that at least a portion of the thermoplastic polymer is softened or melted to form a heated mixture of thermoplastic polymer and active ingredient; [0078] c. permitting the heated mixture to cool and solidify as a solid mass, [0079] d. and optionally, shaping the mass into a predetermined geometry.

[0080] For purposes of the present disclosure a mixture is softened or melted by applying thermal or mechanical energy sufficient to render the mixture partially or substantially completely molten. For instance, in a mixture that includes a matrix material, melting the mixture may include substantially melting the matrix material without substantially melting one or more other materials present in the mixture (e.g., the therapeutic agent and one or more excipients). For polymers, a softened or melted polymer is a polymer that is heated to a temperature at or above the glass transition temperature of the polymer. Generally, a mixture is sufficiently melted or softened, when it can be extruded as a continuous rod, or when it can be subjected to injection molding.

[0081] The mixture of the thermoplastic polymer and the active agent can be produced using any suitable means. Well-known mixing means known to those skilled in the art include dry mixing, dry granulation, wet granulation, melt granulation, high shear mixing, and low shear mixing.

[0082] Granulation generally is the process wherein particles of powder are made to adhere to one another to form granules, typically in the size range of 0.2 to 4.0 mm. Granulation is desirable in pharmaceutical formulations because it produces relatively homogeneous mixing of different sized particles.

[0083] Dry granulation involves aggregating powders with high compressional loads. Wet granulation involves forming granules using a granulating fluid including either water, a solvent such as alcohol or water/solvent blend, where this solvent agent is subsequently removed by drying. Melt granulation is a process in which powders are transformed into solid aggregates or agglomerates while being heated. It is similar to wet granulation except that a binder acts as a wetting agent only after it has melted. The granulation is further achieved following using milling and/or sieving to obtain the desired particle sizes or ranges. All of these and other methods of mixing pharmaceutical formulations are well-known in the art.

[0084] Subsequent or simultaneous with mixing, the mixture of thermoplastic polymer and the active agent is softened or melted to produce a mass sufficiently fluid to permit shaping of the mixture and/or to produce melding of the components of the mixture. The softened or melted mixture is then permitted to solidify as a substantially solid mass. The mixture can optionally be shaped or cut into suitable sizes during the softening or melting step or during the solidifying step. In some embodiments, the mixture becomes a homogeneous mixture either prior to or during the softening or melting step. Methods of melting and molding the mixture include, but are not limited to, hot-melt extrusion, injection molding and compression molding.

[0085] Hot-melt extrusion typically involves the use of an extruder device. Such devices are well-known in the art. Such systems include mechanisms for heating the mixture to an appropriate temperature and forcing the melted feed material under pressure through a die to produce a rod, sheet or other desired shape of constant cross-section. Subsequent to or simultaneous with being forced through the die the extrudate can be cut into smaller sizes appropriate for use as an oral dosage form. Any suitable cutting device known to those skilled in the art can be used, and the mixture can be cut into appropriate sizes either while still at least somewhat soft or after the extrudate has solidified. The extrudate may be cut, ground or otherwise shaped to a shape and size appropriate to the desired oral dosage form prior to solidification, or may be cut, ground or otherwise shaped after solidification. In some embodiments, an oral dosage form may be made as a non-compressed hot-melt extrudate. In other embodiments, an oral dosage form is not in the form of a compressed tablet.

[0086] Injection molding typically involves the use of an injection-molding device. Such devices are well-known in the art. Injection molding systems force a melted mixture into a mold of an appropriate size and shape. The mixture solidifies as least partially within the mold and then is released.

[0087] Compression molding typically involves the use of a compression-molding device. Such devices are well-known in the art. Compression molding is a method in which the mixture is optionally preheated and then placed into a heated mold cavity. The mold is closed and pressure is applied. Heat and pressure are typically applied until the molding material is cured. The molded oral dosage form is then released from the mold.

[0088] The final step in the process of making intravaginal drug delivery device is permitting the mixture to solidify as a solid mass. The mixture may optionally be shaped either prior to solidification or after solidification. Solidification will generally occur either as a result of cooling of the melted mixture by different methods (air, water bath) or as a result of curing of the mixture however any suitable method for producing a solid dosage form may be used.

[0089] When combining compartments to form an intravaginal drug delivery device, individual compartments may be joined directly together or may be coupled to each other through a spacer formed form a thermoplastic matrix material. The spacer may be formed from the same thermoplastic material used to form the compartments, or may be formed from a different material. The spacer, in some embodiments, does not include any active agents.

[0090] Through the use of different compartments in the drug delivery device, the device releases the active ingredients such that each of the released active ingredients has a different non-zero order release kinetic profile, and the amounts of active ingredients released are not constant but rather changing over time. Such release profiles are especially useful in the field of contraception and menopause management.

[0091] In one embodiment, a combination of compartments is selected to create release profiles that mimic hormone profiles of regular female cycle, with estrogen being more dominate in the first half, and progestin being more dominate in the second half of the cycle. In some embodiments, compartments may be selected to enable delivery of high concentrations of a progestin, which is responsible for ovulation inhibition, from the first day of treatment to avoid further growth of the leading follicle that has grown in the hormone free interval between two cycles. The timing of the delivery of the appropriate amounts of progestin with the appropriate estrogen ensures a good bleeding profile.

[0092] In another preferred embodiment the estrogen is estriol and the progestin is trimegestone. In another preferred embodiment the estrogen is ethinyl estradiol and the progestin is etonogestrel.

[0093] Since estriol is a natural estrogen, its use is especially desirable since it offers significant advantages over synthetic estrogens (e.g., ethinyl estradiol and estradiol) when it comes to safety in indications like contraception and menopause management. Some of the advantages of estriol are: (a) lack of hepatic estrogenicity; (b) no stimulatory effect on breast tissue; (c) less induction of bleeding episodes than estradiol in postmenopausal women.

[0094] Estriol, however, offers a significant challenge when it comes to securing therapeutic plasma levels over the whole cycle based on the short half-life, the low solubility in thermoplastic polymers and the high doses that need to be delivered daily based on the lower intrinsic activity of estriol compared to estradiol and ethinyl estradiol. There are just three vaginal ring products releasing estrogenic compounds on the market: NUVARING, releasing 0.015 mg ethinyl estradiol per day; FEMRING, releasing 0.0075 mg estradiol per day; and ESTRING, releasing 0.05 to 0.1 mg estradiol acetate per day. It is noteworthy to mention, that for accomplishing a daily release of 0.1 mg estradiol, the ESTRING device uses a more lipophilic prodrug of estradiol, namely the estradiol 3-acetate.

[0095] In one embodiment, an intravaginal drug delivery system includes one or more compartments, each of the compartments including progestin and/or estrogen embedded in a thermoplastic polyethylene vinyl acetate copolymer. The progestin and/or estrogen may be either fully dissolved or in a crystalline stage. Each compartment may be an uncoated matrix of thermoplastic polyethylene vinyl acetate copolymer with the active agent(s) dispersed throughout the core. In some embodiments, a compartment may be a coated matrix having a thermoplastic polyethylene vinyl acetate copolymer covering the core.

[0096] The individual compartments, may be welded together to form a ring shaped drug delivery system by using a thermoplastic polymer spacer to link the compartments together. The spacers may be formed from a polyethylene vinyl acetate copolymer capable of inhibiting the exchange of estrogens and progestins from one compartment to the other.

[0097] One significant advantage of the intravaginal drug delivery devices described herein is that targeted release profiles can be generated by either: varying the size of the compartments (e.g., the length); varying the loading of active agents (e.g., the progestin or estrogen); adding a coating material to the compartment; or using a combination of any of these modifications.

[0098] Release kinetics identify the drug release process via mathematical models to drug release process (the amount of drug release per unit time). Release kinetics can also be defined by the ratio of active agent released on Day 1 to active agent release on the last day of administration (Day 21 or Day 28). For supersaturated systems where co (initial concentration at to) is above the c.sub.s (saturation concentration), release can also be fitted using the Korsmeyer-Peppas equation, where the drug fraction dissolved at a time, equivalent to active agent release, as a function of time is plotted. The diffusional exponent n of the power law and thereby, the drug release mechanism from different polymeric controlled delivery systems for different geometries (thin films, spheres or cylinders) can be determined via the slope of the linear regression fit. The release kinetics follows zero order release (Case-II transport), when the drug release is constant over time (ratio of releases Day 1 to Day 28 is 1) and independent of concentration. For cylinders, a diffusional exponent n of 0.89 or above indicates Case-II Transport and hence, zero order release.

[0099] The target release kinetics of a non-zero order release is provided for Day 1/Day 21 (or Day 28) ratios between 1.5 and 4.0. In the Korsmeyer-Peppas equation, non-zero order or anomalous transport (a combination of Case-II transport and Fickian diffusion) is achieved when the diffusional exponent n is between 0.89 and 0.45. A diffusional exponent of 0.45 indicates Fickian diffusion.

[0100] In preferred embodiments, the compartments include an active agent as a substantially uniform dispersion within a thermoplastic matrix. In alternative embodiments the distribution of the active agent within the thermoplastic matrix can be substantially non-uniform. One method of producing a non-uniform distribution of the active agent is through the use of one or more coatings of water-insoluble or water-soluble polymers. Another method is by providing two or more mixtures of polymer or polymer and the active agent to different zones of a compression or injection mold. These methods are provided by way of example and are not exclusive.

[0101] In practice, for a human female, an annular intravaginal drug delivery device has an outer ring diameter from 35 mm to 70 mm, from 35 mm to 60 mm, from 45 mm to 65 mm, or from 50 mm to 60 mm. The cross-sectional diameter may be from 1 mm to 10 mm, from 2 mm to 6 mm, from 3.0 mm to 5.5 mm, from 3.5 mm to 4.5 mm, or from 4.0 mm to 5.0 mm.

[0102] The release rate can be measured in vitro using compendial methods, e.g., the USP Apparatus Paddle 2 method, or a rotational incubation shaker. The active agent(s) can be assayed by methods known in the art, e.g., by HPLC or UPLC.

[0103] In some embodiments of the present invention, active agent(s) is/are released from the intravaginal device for up to about 1 month or about 28 days after administration to a female, for up to about 25 days after administration to a female, for up to about 21 days after administration to a female, for up to about 15 days after administration to a female, for up to about 10 days after administration to a female, for up to about 7 days after administration to a female, or for up to about 4 days after administration to a female.

[0104] Each individual compartment may release an active agent at a steady rate. As used herein, a steady rate is a release rate that does not vary by an amount greater than 70% of the amount of active agent released per 24 hours in situ, by an amount greater than 60% of the amount of active agent released per 24 hours in situ, by an amount greater than 50% of the amount of active agent released per 24 hours in situ, by an amount greater than 40% of the amount of active agent released per 24 hours in situ, by an amount greater than 30% of the amount of active agent released per 24 hours in situ, by an amount greater than 20% of the amount of active agent released per 24 hours in situ, by an amount greater than 10% of the amount of active agent released per 24 hours in situ, or by an amount greater than 5% of the amount of active agent released per 24 hours in situ.

[0105] In some embodiments, the active agent is trimegestone with a compartment steady release rate of active agent in situ of about 80 g to about 200 g per 24 hours, about 90 g to about 150 g per 24 hours, about 90 g to about 125 g per 24 hours, or about 95 g to about 120 g per 24 hours.

[0106] In some embodiments, the active agent is estriol with a compartment steady release rate of active agent in situ of about 50 g to about 800 g per 24 hours, about 100 g to about 500 g per 24 hours, about 150 g to about 300 g per 24 hours.

[0107] The release kinetics and drug release profile can be impacted by selecting the type of system. Reservoir systems are designed to yield zero order release kinetics (Case-II transport), whereas matrix systems provide either Fickian diffusion (drug release proportional to surface and drug loading) or anomalous transport (combination of Fickian diffusion and Case-II transport). For reservoir systems, release rates can be modulated by the skin thickness and type of polymer used. EVA copolymers with high vinyl acetate (VA) content show reduced crystallinity and hence, increased permeability, whereas EVA polymers with low VA content yield increased crystallinity and hence, reduced permeability.

[0108] In some embodiments, the active agent is released according to a non-zero order release, where the ratio of active agent release Day 1 to Day 21/28 is in the range of 1.5-4.0, more specifically, the ratio is in the range of 1.5-3.0, even more specifically, in the range of 1.5-2.0.

[0109] In some embodiments, the active agent is released according to anomalous transport (a combination of Case-II transport and Fickian diffusion). This refers to a diffusional exponent (in the Korsmeyer-Peppas Equation) for cylinders of 0.89-0.45.

[0110] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1Vaginal Ring Releasing Etonogestrel and Ethinyl Estradiol, Reservoir System

Premix Preparation:

[0111] Ethinyl estradiol and etonogestrel loaded powder blends are prepared by dry blending the active agents and the polymer ethylene vinyl acetate using different blending techniques (e.g., tumble blending) and blending parameters, yielding a powder blend where the active agent is homogeneously distributed in the blend.

Co-Extrusion:

[0112] The ethinyl estradiol and etonogestrel loaded ethylene vinyl acetate is co-extruded at low throughput ranges of <3 kg/h using a twin screw extruder for the drug loaded core material and a single screw extruder for the drug free ethylene vinyl acetate with lower VA content. The target skin thickness of 110 m can be achieved via single screw extruder speeds of <10 rpm. The obtained co-extrudate (reservoir system) is subsequently cooled to yield co-axial fibers with an outer diameter of 4.0 mm and a pre-defined skin thickness. The co-extrudate diameter and sphericity may be controlled in-line using a multiple laser head system.

[0113] Ring Closure:

[0114] The ethinyl estradiol and etonogestrel loaded reservoir strands are cut into segments of 154 mm either manually or using a semi-automated system prior to being shaped to the vaginal ring via a welding step (e.g., hot air welding, injection molding) inside a ring-shaped mold with a single or multiple cavities of 4.0 mm cross-sectional diameter and 54 mm outer diameter. As welding material, the drug free ethylene vinyl acetate, serving as the core polymer, is used. The obtained rings are then stored at 5 C.

Example 2Vaginal Ring Releasing Etonogestrel and Ethinyl Estradiol, Matrix-Matrix System

Premix Production:

[0115] Etonogestrel and ethinyl estradiol loaded powder blends are mixed by dry blending 7 parts of ethinyl estradiol and 40 parts of etonogestrel and 953 parts of hydroxy propyl cellulose using different blending techniques (e.g., tumble blending) and blending parameters, yielding a powder blend where the active agents are homogeneously distributed in the blend.

First Extrusion:

[0116] In a first extrusion step, the drug loaded cellulose powder blend is processed via hot melt extrusion using a twin screw extruder and subsequent cooling to yield strands with an outer diameter of around 2.5 mm, which are then pelletized via strand granulation to obtain drug loaded polymer pellets.

Second Extrusion:

[0117] In a second extrusion step, the drug loaded cellulose-based polymer pellets are further processed via hot melt extrusion in a twin screw extruder with ethylene vinyl acetate. This can be achieved by either blending the drug loaded cellulose pellets with the ethylene vinyl acetate in a ratio of >90 parts EVA and <10 parts drug loaded cellulose pellets and subsequent hot melt extrusion or by simultaneous processing of the drug loaded pellets and the ethylene vinyl acetate via split feeding and hot melt extrusion to strands with an outer diameter of around 2.5 mm and subsequent granulation of the extruded strands.

Injection Molding:

[0118] The ethinyl estradiol and etonogestrel loaded hydroxy propyl cellulose pellets, embedded into the ethylene vinyl acetate copolymer, are shaped via injection molding using a single or multiple cavity ring shaped mold to yield a ring shaped device of 4.0 mm cross-sectional diameter and 54 mm outer diameter. Sufficient tensile strength is obtained by applying optimized injection molding parameters.

Washing Step:

[0119] A final washing step is applied to reduce the burst effect, i.e., the amount of active ingredients released during the first days of ring application via depleting the outer regions of the rings. As washing agent, different types of solvents or solvent mixtures may be applied. The extent of active ingredients washed out and hence, the extent of the burst effect is controlled by the different washing parameters (e.g., type and volume of washing agent, washing time, temperature). The washed rings are finally rinsed with water and subsequently dried prior to being packed into individual sachets.

Example 3Trimegestone Vaginal Ring, Matrix System

Premix Preparation:

[0120] Trimegestone loaded powder blends containing 0.25% and 0.50% trimegestone are prepared by dry blending the active agent and ethylene vinyl acetate using different blending techniques (e.g., tumble blending) and blending parameters, yielding a powder blend where the active agent is homogeneously distributed in the blend.

Extrusion:

[0121] In a matrix extrusion step, the drug loaded premix is processed via hot melt extrusion using a twin screw extruder. The melt temperature was around 100 C. The extrudate was subsequently cooled at ambient temperature to solidify the melt and yield drug loaded matrix strands of 4.0 mm outer diameter. The co-extrudate diameter and sphericity may be controlled in-line using a multiple laser head system.

Ring Closure:

[0122] The drug loaded matrix fibers are cut into segments of 154 mm either manually or using a semi-automated system prior to being shaped to the vaginal ring via a welding step (e.g., hot air welding, injection molding) inside a ring-shaped mold with a single or multiple cavities of 4.0 mm cross-sectional diameter and 54 mm outer diameter. As welding material, the drug free ethylene vinyl acetate is used. The obtained rings are then stored at 5 C.

Example 4Trimegestone Vaginal Ring of Different Skin Thickness, Reservoir Systems

Premix Preparation:

[0123] Trimegestone loaded powder blends containing identical loadings in the core (=1.053%) are prepared by dry blending the active agent and the polymer ethylene vinyl acetate using different blending techniques (e.g., tumble blending, high shear blender) and blending parameters, yielding a powder blend where the active agent is homogeneously distributed in the blend.

Co-Extrusion:

[0124] The trimegestone loaded ethylene vinyl acetate is co-extruded using a twin screw extruder for the drug loaded core material and a single screw extruder for the drug free ethylene vinyl acetate with a lower VA content (12%). The single screw extruder speed is adjusted to screw speed in order to yield the target skin thickness. By running the single screw extruder at low screw speeds of <5 rpm, a skin thickness of 135 m can be achieved. Doubling the single screw extruder speed produces a skin thickness of 190 m, and by a further screw speed increase of above 20 rpm, an increased skin thickness of 320 m can be produced. The obtained co-extrudate is subsequently cooled to yield co-axial fibers with an outer diameter of 4.0 mm and the distinct skin thicknesses of 135 m, 190 m and 320 m. The co-extrudate diameter and sphericity may be controlled in-line using a multiple laser head system.

Ring Closure:

[0125] The trimegestone loaded reservoir fibers are cut into segments of 154 mm either manually or using a semi-automated system prior to being shaped to the vaginal ring via a welding step (e.g., hot air welding, injection molding) inside a ring-shaped mold with a single or multiple cavities of 4.0 mm cross-sectional diameter and 54 mm outer diameter. As welding material, the drug free ethylene vinyl acetate, serving as the core polymer, is used. The obtained rings are then stored at 5 C.

Example 5Estriol Vaginal Ring, Matrix System

Premix Preparation:

[0126] Estriol loaded powder blends of different loadings (in the range of 0.625% to 30% w/w) are prepared by dry blending the active agent and the high VA content ethylene vinyl acetate, using different blending techniques (e.g., tumble blending, active blending via high shear forces) and blending parameters, yielding a powder blend where the active agent is homogeneously distributed in the blend.

Extrusion:

[0127] In a matrix extrusion step, the drug loaded premix is processed via hot melt extrusion using a twin screw extruder and subsequent cooling at ambient temperature to yield drug loaded matrix strands of 4.0 mm outer diameter. The temperature configuration is slightly adapted depending on the drug loading and hence, the resulting melt viscosity to achieve a stable extrusion process and spherical extrudates.

Ring Closure:

[0128] The drug loaded matrix fibers are cut into segments of 154 mm either manually or using a semi-automated system prior to being shaped to the vaginal ring via a welding step (e.g., hot air welding, injection molding) inside a ring-shaped mold with a single or multiple cavities of 4.0 mm cross-sectional diameter and 54 mm outer diameter. As welding material, the drug free ethylene vinyl acetate is used. The obtained rings are then stored at 5 C.

Example 6Estriol/Trimegestone Vaginal Ring, Segmented (Matrix/Reservoir) System

[0129] Combining Estriol with Trimegestone Containing Segments and Ring Closure:

[0130] Estriol loaded segments, prepared according to Example 3, are cut into segments of 92 mm (60% of the full ring). Trimegestone containing co-extrudates of 190 m, prepared according to Example 5, are cut into segments of 60 mm (corresponding to 40% of the full ring). Cutting is done either manually or using a semi-automated system. The two segments are then joined in 2 subsequent welding steps (e.g., hot air welding, injection molding) inside a ring-shaped mold with a single or multiple cavities to yield one or multiple vaginal rings of 4.0 mm cross-sectional diameter and 54 mm outer diameter. As welding material, the drug free ethylene vinyl acetate, serving as the carrier for the matrix and the core polymer for the reservoir system, is used. The welding material serves the purpose of forming a ring, but can also act as a barrier to prevent the active agents from migration. This is achieved by selecting polymers with reduced VA content or no VA such as LDPE, that show higher crystallinity and hence, a lower and/or no permeability. Thereby, the welding material can act as barrier to avoid diffusion of the active ingredient from one segment into the other. The obtained rings are then stored at 5 C.

In Vitro Release Rates

Methods

[0131] For in vitro dissolution testing, a rotational incubator operated at 370.5 C. is used. The type of dissolution medium, its volume and the incubator rotational speed are selected to provide sink conditions. Samples of 1 mL are withdrawn every 240.5 h (and multiples thereof) over 21 or 28 days, the medium is replaced every 240.5 h (and multiples thereof) by fresh media and the samples are analyzed for the drug content via (ultra) high performance liquid chromatography (UPLC/HPLC). The results of the tests on the rings of Examples 1-8 are depicted in FIGS. 1-8.

[0132] FIGS. 1A and 1B show the release profiles of a reservoir system, where etonogestrel is supersaturated. FIG. 1A gives the release rate of ethinyl estradiol during dissolution testing of the ring formed according to Example 1. FIG. 1B shows the release rate of etonogestrel during dissolution testing of the ring produced according to Example 1. The ratio of the ethinyl estradiol release rates day 1 to day 21 is 1.40, for etonogestrel, the ratio of the release rates d1/d21 is 1.50, indicating zero order release. Data fitting in the zero order release model yields a diffusional exponent n of 0.93 for ethinyl estradiol and 0.91 for etonogestrel, indicating zero order release rates.

[0133] FIG. 2 shows the release rates of ethinyl estradiol and etonogestrel from a ring formed in Example 2, where the two actives are embedded in a hydrophilic carrier, which is further embedded in an EVA with high VA content. FIG. 2A shows the release rate of ethinyl estradiol during dissolution testing produced according to Example 2. FIG. 2B shows the dissolution profile of etonogestrel during dissolution testing of the ring formed according to Example 1, where etonogestrel is supersaturated in the core. The ratio of the ethinyl estradiol release rates on day 1 to day 21 is 1.90, for etonogestrel the ratio of the release rates d1/d21 is 3.03. Data fitting in the zero-order release model yielded diffusional exponents of n=0.89 for ethinyl estradiol, indicating zero-order release, and n=0.80 for etonogestrel.

[0134] Generally, trimegestone can also be formulated into both, a matrix and a reservoir system. Matrix formulations containing trimegestone in an EVA carrier with high VA content according to Example 3 were tested with core loadings of 4.3 mg (=0.25%) and 8.6 mg (=0.50%). FIG. 3A shows the release rates of the matrix system with 0.25% trimegestone, FIG. 3B depicts the release of a 0.50% loaded matrix system.

[0135] The daily release of trimegestone increases with increasing drug loading. For both drug loadings, the release of trimegestone highly exceeds the target release values for the intended application, and more than 50% of the incorporated trimegestone is already released within one week, attributed to the formation of a solid dispersion comprising amorphous trimegestone, which is obviously highly diffusive in the EVA. The diffusional exponent n for this matrix systems is 0.37 and 0.47 for the 0.25% and 0.50% loadings, respectively. This suggests that the simple matrix approach is not applicable and a skin needs to introduced in order to tailor (i.e., decrease) the TMG release. The dissolution was therefore ended after 7 days. The diffusion coefficient of trimegestone is similar regardless of the VA content of the EVA polymer. Permeability of trimegestone is similar for EVA with high VA contents, but lower for EVA with low VA content (by a factor of 10). However, the solubilities are different and are significantly lower for low VA content EVAs, hence its permeability is decreased for lower VA contents due to its decreased solubility in the polymer, leading to reservoirs systems as delivery concept for trimegestone to achieve the target therapeutic release rates.

[0136] The release rates in the reservoir system can be modulated via the skin thickness. For low VA skin types and skin thicknesses of 190 m and 320 m, manufactured according to Example 4, zero order release was achieved with n=0.90 and d1/21 ratio of 1.62 for IVRs with 320 m and n=0.89, d1/d21=2.43 for 190 m skin thickness. FIG. 4A shows the release profile of a reservoir system (1.053% core loading according to Example 4) for a skin thickness of 320 m, FIG. 4B depicts the release profiles of trimegestone for a reservoir IVRs (1.053% core loading) with 190 m skin thickness.

[0137] When the skin thickness was decreased to 135 m, data fitting showed anomalous transport (combination of Case-II and Fickian diffusion) as the underlying mechanism, with a diffusional exponent n of 0.76 for this formulation. FIG. 4C depicts the release profiles of trimegestone for a reservoir IVRs (1.053% core loading) with 135 m skin thickness.

[0138] FIGS. 5A-5D show the release rate of estriol during dissolution testing of the matrix ring formed according to Example 5 for the investigated drug loadings, FIG. 5A shows the release profile for the 0.65% Estriol, FIG. 5B for the 5% Estriol loading, FIG. 5C for the 15% Estriol, and FIG. 5D for the 30% Estriol. Independent upon the loading, the release rates of these matrix type systems follow Fickian diffusion, and the diffusional exponent n ranges between 0.48 and 0.53, showing anomalous transport. All ratios of release rates d1/d21 are between 5.84 and above 10 for the tested estriol loadings. Achieving meaningful release rates of estriol from a reservoir ring is not feasible due to its physicochemical properties (low solubility in EVA with high VA contents, low permeability in EVA with low VA content).

[0139] The estriol matrix system and the trimegestone reservoir system can be combined to a segmented ring as described in Example 6. FIGS. 6A and 6B show the release rates of such a segmented IVR. In FIG. 6A, the release rate of estriol from the matrix segment (30% loading; 60% segment length) is shown, FIG. 6B shows the trimegestone release from a reservoir segment (40% segment length) during dissolution testing of the segmented IVR. The release rates are proportional to the segment lengths, thereby a zero-order release is achieved for the reservoir type segment releasing trimegestone, whereas estriol is formulated into a matrix system. The ratio d1/d21 is 7.4 and 2.5 for the estriol release from the matrix and the trimegestone release from the reservoir segment, respectively.

Example 7Ovulation Inhibition Study of Etonogestrel/Ethinyl Estradiol (Example 2)

[0140] In a single center, open label clinical trial performed in 2 phases (pre-treatment and treatment), the vaginal ring of Example 1 was investigated in 39 women over two cycles separated by 7 treatment days. Primary efficacy parameter was ovarian activity, measured by transvaginal ultrasound according to the Hoogland and Skouby score and pituitary hormones like FSH as surrogate marker for efficacy.

[0141] Table 1 shows the Hoogland and Skouby scores obtained during clinical trials of the vaginal ring of Example 2. The results show excellent control of the follicle sizes for all women with more than 80% of women showing no or minor follicle growth (Hoogland score 1 and 2).

TABLE-US-00001 TABLE 1 Hoogland and Skouby scores of an etonogestrel/ethinyl estradiol vaginal ring (according to Example 2). Score 6 5 4 3 2 1 Missing N Treatment treatment cycle N [%] N [%] N [%] N [%] N [%] N [%] N [%] total Test treatment cycle 1 0 0.00 0 0.00 2 5.13 0 0.00 7 17.95 30 76.92 0 0.00 39 treatment cycle 2 0 0.00 0 0.00 8 20.51 1 2.56 14 35.90 15 38.46 1 2.56 39 Total 0 0.00 0 0.00 10 12.82 1 1.28 21 26.92 45 57.69 1 1.28 78

[0142] FIG. 7 shows the concentration of Follicle Stimulating Hormone (FSH) overtime during clinical trials of the vaginal ring of Example 2. The figure shows an overlay of individual profiles of FSH concentration per time point (visit) during treatment cycle 1 and 2 under treatment with the vaginal ring of Example 1 following a 21-day application+7 days treatment-free break per cycle (PPS). Insertion of the vaginal ring in the second treatment cycle is marked by a vertical red line between visit 12 and 13.

Example 8Mean Plasma Concentration Study of Estriol

[0143] In a single center, open-label, randomized (allocation to treatment), balanced, parallel-group trial with single dose application the following three vaginal rings were tested in postmenopausal women for 21 days. [0144] Device 1: a vaginal ring, formed according to Example 5, having a 5% estriol loading, and having a nominal estriol delivery rate of 0.125 mg/day. The ring was administered by vaginal application in 10 women. [0145] Device 2: a vaginal ring, formed according to Example 5, having a 15% estriol loading, and having a nominal estriol delivery rate of 0.250 mg/day. The ring was administered by vaginal application in 10 women. [0146] Device 3: a vaginal ring, formed according to Example 5, having a 30% estriol loading, and having a nominal estriol delivery rate of 0.500 mg/day. The ring was administered by vaginal application in 10 women.

[0147] FIG. 8A depicts the mean plasma concentration vs. time curves of estriol during a single vaginal application of 1 vaginal ring of Device 1 (Test 1), Device 2 (Test 2), and Device 3 (Test 3) over 21 days.

[0148] FIG. 8B depicts the mean plasma concentration vs. time curves for changes from baseline of FSH during single vaginal application of a single vaginal ring of Device 1 (Test 1), Device 2 (Test 2), and Device 3 (Test 3) over 21 days.

[0149] FIG. 8C depicts mean maturation index by cell types (maturation values) over time during single vaginal application of 1 vaginal ring of Device 1 (Test 1), Device 2 (Test 2), and Device 3 (Test 3) over 21 days.

Example 9Mean Plasma Concentration Study of Estriol and Trimegestone

[0150] In a single center, open-label, randomized (allocation to treatment), balanced, parallel-group trial with single dose application the following three vaginal rings were tested in fertile women for 21 days. [0151] Device 1: a vaginal ring, formed according to Example 6, having a 30% estriol loading, an estriol segment length of 60%, a 1.90% trimegestone core loading with a 320 um skin thickness, and having a nominal delivery rate of 0.400 mg/day for estriol and a nominal delivery rate of 0.050 mg/day for trimegestone. The ring was administered by vaginal application in 10 women. [0152] Device 2: a vaginal ring, formed according to Example 6, having a 15% estriol loading, an estriol segment length of 60%, a 1.90% trimegestone core loading with a 195 um skin thickness, and having a nominal delivery rate of 0.300 mg/day for estriol and a nominal delivery rate of 0.095 mg/day for trimegestone, vaginal application in 10 women. [0153] Device 3: a vaginal ring, formed according to Example 6, having a 5% estriol loading, an estriol segment length of 60%, a 1.90% trimegestone core loading with a 135 um skin thickness, and having a nominal delivery rate of 0.209 mg/day for estriol and a nominal delivery rate of 0.137 mg/day for trimegestone, vaginal application in 10 women.

[0154] The mean trimegestone plasma levels and mean estradiol plasma levels were analyzed in women. FIG. 9A depicts the mean plasma concentration vs. time curves of estriol during a single vaginal application of 1 vaginal ring of Device 1 (Test 1), Device 2 (Test 2), and Device 3 (Test 3) over 21 days.

[0155] FIG. 9B depicts the mean plasma concentration vs. time curves of trimegestone during a single vaginal application of 1 vaginal ring of Device 1 (Test 1), Device 2 (Test 2), and Device 3 (Test 3) over 21 days.

[0156] FIG. 9C depicts the bleeding profile under treatment of Test 3 (Device 3), the vaginal ring with a delivery rate of 0.209 mg/day for estriol and 0.137 mg/day for trimegestone.

[0157] Most women under Test 3 had a good bleeding control during treatment with few bleeding and spotting episodes during treatment and a predictable initiation of bleeding after the ring has been removed.

[0158] In this patent, certain U.S. patents, U.S. patent applications, and other materials (e.g., articles) have been incorporated by reference. The text of such U.S. patents, U.S. patent applications, and other materials is, however, only incorporated by reference to the extent that no conflict exists between such text and the other statements and drawings set forth herein. In the event of such conflict, then any such conflicting text in such incorporated by reference U.S. patents, U.S. patent applications, and other materials is specifically not incorporated by reference in this patent.

[0159] Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.