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EP-4129300-B1 - GEOMETRICALLY COMPLEX INTRAVAGINAL RINGS, SYSTEMS AND METHODS OF MAKING THE SAME

EP4129300B1EP 4129300 B1EP4129300 B1EP 4129300B1EP-4129300-B1

Inventors

  • BENHABBOUR, Soumya Rahima
  • JANUSZIEWICZ, Rima
  • MECHAM, SUE J.

Dates

Publication Date
20260506
Application Date
20170323

Claims (15)

  1. A geometrically complex intravaginal ring (IVR), the IVR comprising: a three dimensional ring structure comprising a body forming an inner diameter and an outer diameter; a plurality of geometrically shaped unit cells, the unit cells comprising a macroscopic and/or microscopic architecture forming geometric shapes, wherein the plurality of geometrically shaped unit cells together form the body of the ring structure, wherein the IVR contains void volumes, wherein said void volume is regularly or irregularly distributed continuously or in discrete volumes, wherein the IVR has a volume fraction of 0.1 to 0.9 compared to their solid counterparts; and an active compound; wherein the macroscopic architecture and/or microscopic architecture of the geometrically shaped unit cells is configured to control a loading capacity of the active compound within or on the IVR, a diffusion rate of the active compound from the IVR, a surface area of the IVR, a fractional volume of the IVR, and/or a mechanical property of the IVR.
  2. The geometrically complex IVR of claim 1, wherein the IVR comprises one or more types of geometrically shaped unit cells, wherein each type of geometrically shaped unit cell varies in size, shape, configuration, surface area and/or three dimensional geometry; and/or wherein the loaded fractional volume is calculated based on Equation 2: Volume Fraction × Loading wherein the Volume Fraction is calculated based on Equation 1: Geometric Complexity by Volume Fraction : Volume of IVR with Void Spaces Volume of Solid IVR < 1
  3. The geometrically complex IVR of any of claims 1 to 2, wherein the outer diameter, inner diameter, and/or a cross-section of the body can vary throughout the three dimensional ring structure.
  4. The geometrically complex IVR of any of claims 1 to 3, wherein a shape, size, and/or surface area of the IVR is fabricated by 3D printing; and wherein the active compound is incorporated into the IVR during or after 3D printing.
  5. The geometrically complex IVR of claim 4, wherein the 3D printing used in fabrication comprises continuous liquid interface production (CLIP).
  6. The geometrically complex IVR of any of claims 4 to 5, wherein the active compound is incorporated into the IVR after 3D printing by coating, absorption, infusion, or adsorption of active compound onto the IVR.
  7. The geometrically complex IVR of any of claims 4 to 6, further comprising providing a gel-like compound, wherein the gel-like compound is incorporated into the IVR after 3D printing by filling a void volume of the IVR.
  8. The geometrically complex IVR of any of claims 1 to 7, wherein the active compound is captured inside one or more nanoparticles incorporated into the IVR.
  9. The geometrically complex IVR of any of claims 1 to 3, wherein a shape, size, and/or surface area of the body of the IVR is produced by a foaming method or by a die-cut method.
  10. The geometrically complex IVR of any of claims 1 to 9, wherein the IVR is configured to control the rate and/or duration of diffusion of the active compound from the IVR, wherein the active compound is released from the IVR for an extended period of time, optionally 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 days or more; and/or wherein the active compound comprises a therapeutic compound selected from an antiviral, antiretroviral, microbicide, contraceptive, antibiotic, hormone, pre-exposure prophylaxis, small molecule drug, macromolecule drug, biopharmaceutical, biologics, chemotherapeutic, other pharmaceutical compound, and combinations thereof.
  11. The geometrically complex IVR of any of claims 1 to 10, further comprising an additive selected from the group consisting of a pore-forming agent, a plasticizer, a stabilizer, a filler and combinations thereof, wherein the pore-forming agent comprises one or more of PEG 3000, PEG 6000, PEG 8000, hydroxypropyl cellulose, PVP 10000 , and PVA 10000 , wherein the pore-forming agent is configured to create aqueous diffusion pathways for a drug molecule over time.
  12. The geometrically complex IVR of any of claims 1 to 11, wherein the plurality of unit cells comprise a resin formulation, wherein the resin formulation comprises additives configured to influence drug solubility, viscosity, porosity, stability, or mechanical properties of the body of the IVR during processing, or configured to influence surface properties, swelling, stability, or mechanical properties during packaging, storage, or use, and/or wherein the IVR is configured to release two or more active compounds simultaneously or iteratively and at a predetermined rate and/or duration.
  13. The geometrically complex IVR of any of claims 1 to 12, wherein the IVR is configured for HIV pre-exposure prophylaxis (PrEP), HIV treatment, contraception, and/or prevention of sexually transmitted diseases (STDs), or wherein the IVR is configured for treatment of infections, optionally wherein the infections are selected from the group consisting of urinary tract infections, cystitis, and chlamydia, or wherein the IVR is configured for treatment of diseases and cancers, optionally wherein the cancers are selected from the group consisting of cervical cancer, ovarian cancer and uterine cancer, or wherein the IVR is configured for treatment of infectious diseases, optionally wherein the infectious diseases are selected from the group consisting of bacterial, fungi, viral or parasites, or wherein the IVR is configured for hormone therapy, collection of cervicovaginal lavage samples, vaccine development, preterm birth and/or infertility.
  14. Geometrically complex intravaginal ring (IVR) for use in a method of one or more of: - HIV pre-exposure prophylaxis (PrEP), HIV treatment, contraception, and/or prevention of sexually transmitted diseases (STDs), infections, optionally wherein the infections are selected from the group consisting of urinary tract infections, cystitis, and chlamydia, - cancers, optionally wherein the cancers are selected from the group consisting of cervical cancer, ovarian cancer, and uterine cancer, - promotion of reproductive fertility, and - prevention of premature birth, and wherein the method comprises placing the IVR intravaginally in the subject in need of treatment, whereby the subject is treated, and wherein said IVR is as defined in any of claims 1-13.
  15. The geometrically complex intravaginal ring (IVR) for use according to claim 14, wherein the active compound comprises a therapeutic compound selected from an antiviral, antiretroviral, microbicide, contraceptive, antibiotic, hormone, pre-exposure prophylaxis, small molecule drug, macromolecule drug, biopharmaceutical, chemotherapeutic, and combinations thereof.

Description

TECHNICAL FIELD Disclosed herein are geometrically complex intravaginal rings, systems and methods of making the same. Geometrically complex intravaginal rings with tunable and enhanced drug release, which in some embodiments can be fabricated by 3D printing technologies, are also disclosed. BACKGROUND Despite decades of research an estimated 36.9 million people were living with HIV and about 2.0 million people were newly infected with the virus in 2014 globally [1]. Thus, it is imperative that effective HIV prevention tools are developed and rapidly implemented. Oral pre-exposure prophylaxis (PrEP) with the daily pill TRUVADA® is an effective prevention intervention for HIV acquisition, particularly when adherence is high [2-5]. However, oral PrEP trials utilizing daily dosing of antiretrovirals (ARVs) have yielded disparate efficacy results (0-83%), attributed to unpredictable tissue drug penetration and variable adherence [6]. Additionally, HIV and other sexually transmitted infections occur via the female genital tract (FGT); however, conventional treatment and prevention strategies involve oral administration of drugs. Most of these therapeutic strategies have failed as a result of high liver metabolism of orally administered drugs before being absorbed into the systemic circulation and reaching the FGT. Increasing the administered dose is not always a viable option due to severe systemic toxicity. Therefore, local drug delivery via the vagina could in some cases be the ideal strategy for treatment of infections or disease affecting the FGT. Innovations recently introduced into the field of systemic PrEP are long acting (LA) formulations of ARVs that stably release drugs over many weeks [7, 8]. Intravaginal rings represent a sustained-release approach to microbicide delivery and are one strategy to improve adherence and drug delivery. This is particularly important considering the fact that more than 50% of those infected with HIV are women with heterosexual transmission as the main route of infection [9]. The field of HIV PrEP is in desperate need for new technologies that utilize efficient and cost effective engineering to manufacture devices with high patient adherence and long acting delivery of antiretroviral drugs. Current technologies utilize either traditional injection molding or hot-melt extrusion to manufacture intravaginal rings (IVRs). An inherent drawback with these processes is the effect of the high temperatures and pressures on drug or biologic's stability and dispersion within the resin during fabrication. These technologies are limiting in many ways including a) the choice of starting materials (i.e. Polydimethylsiloxane (PDMS), ethylene-vinyl acetate (EVA), or polyurethane (PU)), b) minimal and restricted complexity of design, c) limited range of drug diffusion rate due to simple IVR design (e.g. conventional matrix IVR), and d) complex stepwise processes to produce multi-purpose IVRs. The field of HIV PrEP also needs new devices that can 1) release drugs over longer periods of time (>30 days), 2) enhance efficacy in preventing against HIV transmission, and 3) can integrate two or more drugs to prevent HIV and other STDs as well as unwanted pregnancies. The development of multipurpose prevention could be ground breaking, as there are no approved products that use two drugs to simultaneously address multiple indications (e.g. HIV and unwanted pregnancies) and potential drug resistance. Developing effective multipurpose IVRs has proven to be challenging due to differences in drug properties and target release rates, mandating the investigation of customized IVR designs. Therefore, there is an unmet need for IVR technologies that have the potential to provide precise and tunable control over the drug release rates for as long as several months. WO 2016/116502 A1 discloses an intrauterine delivery system comprising non-steroidal anti-inflammatory and a progestogenic compound, containing anti-inflammatory active compound in the frame material and wherein the progestogenic compound is contained in a silicon based reservoir attached to the frame, wherein the frame consist of a thermoplastic material. US 2009/0004246 A1 discloses an intravaginal drug delivery device comprising a device body comprising a hydrophobic carrier material having at least one channel defining at least one opening to the exterior of said device body. WO 2015/013716 A1 discloses customized implants containing customized curvature-constrained internal channels that fit securely, minimize air gaps, and precisely guide treatment sources through internal printed channels to accurately reach tumors and minimize damage to healthy tissue. SUMMARY This summary lists several embodiments of the presently disclosed subject matter, and in many cases lists variations and permutations of these embodiments. This summary is merely exemplary of the numerous and varied embodiments. Mention of one or more representative features of a g