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WO2018202574A1 - Système d'administration de médicament intravaginal, procédé de fabrication d'un tel système et son utilisation dans des thérapies gynécologiques et en contraception - Google Patents

Système d'administration de médicament intravaginal, procédé de fabrication d'un tel système et son utilisation dans des thérapies gynécologiques et en contraception Download PDF

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Publication number
WO2018202574A1
WO2018202574A1 PCT/EP2018/060854 EP2018060854W WO2018202574A1 WO 2018202574 A1 WO2018202574 A1 WO 2018202574A1 EP 2018060854 W EP2018060854 W EP 2018060854W WO 2018202574 A1 WO2018202574 A1 WO 2018202574A1
Authority
WO
WIPO (PCT)
Prior art keywords
inserts
drug
intravaginal
intravaginal ring
ring according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2018/060854
Other languages
English (en)
Inventor
Harri Jukarainen
Hakala RISTO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Oy
Original Assignee
Bayer Oy
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Oy filed Critical Bayer Oy
Publication of WO2018202574A1 publication Critical patent/WO2018202574A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes

Definitions

  • the present invention relates to the subject matter as characterized in the patent claims, in particular to an intravaginal ring system for drug delivery to a female human, wherein one or more drugs are contained i n one or more inserts embedded into a polymer based ring shaped inert carrier material and wherein the insert(s) are enclosed by a cylinder wall made of an inert material impermeable to the drag(s).
  • the invention further relates to a delivery systems with an improved release profile and low initial burst-effect.
  • the invention further relates to a method for manufacturing intravaginal rings according to the invention.
  • the invention further relates to the use of the delivery system in contraception and gynecological therapies.
  • Ring-shaped devices for controlled administration of drug substances into the vagina are known in the art for decades. Intravaginal rings are e.g.
  • IVR ' s described in the literature comprise a polymer matrix but no membrane or wall encasing said matrix (monolithic dosage form).
  • the IVR can be manufactured in accordance with standard techniques described in the art e.g. US 3,920,805, US 4,888,074, US 4,215,691, WO2010/058070.
  • vaginal ring which comprises a core of a polymeric material loaded with the drug substance, which is completely surrounded by a non-medicated sheath. Accordingly, the release of drug substances from such rings is dependent upon permeation (i.e., molecular dissolution and diffusion) of the core-loaded drag substance through the outer sheath.
  • the polymeric materials used in the construction of commercial vaginal rings have been limited to hydrophobic silicone elastomer and poly(ethylene-co- vinyl acetate) (PEVA) materials.
  • the initial burst effect is essentially caused by drug which has accumulated during the storage in the membrane.
  • the membrane acts as kind of depot in particular for drugs with a high solubility in the membrane material, as drug diffuses from the core material into the membrane and thus concentrates in the membrane, during storage and transportation period.
  • the "accumulated drug” is emitted from the membrane, in particular during the first 1 to 3 days after insertion, which leads to a higher drug release (so called “initial burst effect”).
  • Nuvaring® is stored at temperatures from 2-8 °C prior dispending it to the user (see package insert of Nuvaring® under "Storage"). But also for the end user storage in warm climate zones storing in a fridge is advisable.
  • WO 2013/110856 proposes to place an intermediate layer, made of an inert material such as e.g. Ti0 2 , between the drug containing core and the membrane material.
  • an intermediate layer made of an inert material such as e.g. Ti0 2
  • further improvement of the initial burst is an ongoing problem with a high medical need.
  • WO 2009/003125 (Warner Chilcott) discloses intravaginal drug delivery devices useful in the administration of pharmaceutically active water-soluble drugs or
  • the current invention differs not only with regard to the drugs to be delivered and the polymers used as drug carrier material for the inserts, it is further different as no sleeves (impermeable cylinder wall around the insert) are disclosed in the Warner Chilcott application.
  • the sleeve is a key element to address the object of the current invention, in particular for hydrophobic drugs.
  • Vaginal rings with insertable drug containing cores are also disclosed in
  • WO 01/13780 discloses an apparatus (vaginal ring) for anesthetizing the cervical region of a female.
  • the anesthetic agent is placed in an inert biocompatible material which is placed in a depression of the vaginal ring.
  • the device is intended for an immediate release of the anesthetic. No sleeves are disclosed.
  • the present invention is directed to an intravaginal rin consisting of an inert carrier material (A) embedding at least one drug containing insert, wherein the insert(s) is (are) made of a biocompatible polymer material (B) (subsequently also called matrix material ) which is enclosed with a cylinder wall (sleeve) made of an inert material impermeable to the drug.
  • A inert carrier material
  • B biocompatible polymer material
  • matrix material subsequently also called matrix material
  • the cross sectional diameter of the inserts through which the release into the vaginal environment occurs can be covered by a membrane.
  • a preferred object of the invention is to provide an intravaginal delivery system with reduced drug load in particular at the end of the wearing period, to reduce manufacturing cost an environmental burdens caused by unspent drug washed-off when littered. [0023] It is a further object of the invention to provide an intravaginal delivery system with an improved release profile, namely with a reduced initial burst effect and an essentially constant drug release over the wearing period.
  • Another object of the invention is a process to manufacture such delivery systems, in particular intravaginal rings with an improved release profile.
  • a further object of the invention is the use of such delivery systems and intravaginal rings with an improved release profile in contraception and gynecological therapies in particular in endometriosis.
  • inert carrier material ethylene-vinyl acetate copolymer, polyethylene, polypropylene, polyurethane, polyvinylchloride, in general thermoplastic elastomers (TPE's), polydimethylsiloxane elastomers, polyurethane elastomers, polyurea elastomers or polyvinylchloride are used.
  • TPE's thermoplastic elastomers
  • polydimethylsiloxane elastomers polydimethylsiloxane elastomers
  • polyurethane elastomers polyurea elastomers or polyvinylchloride
  • biocompatible polymer (matrix) material (B) for the inserts in principle the same materials as for the inert carrier ring can be used. Preferred are polysiloxane elastomers or etinylvinylacetate (EVA) copolymers.
  • EVA etinylvinylacetate
  • an inert and impermeable material suitable for the cylinder wall which covers the inserts subsequently also called “sleeve”
  • any biologically compatible and essentially inert material metal, in particular silver, gold, stainless steel, nitinol (nickel -titanium alloy) or copper can used.
  • a biocompatible polymer, impermeable to the drug such as polyethylene (PE) or fluorinated polyolefins such as Teflon® can be used.
  • the insert can be of cylindrical or of barrel shape, whereby the barrel shape allows for a more stable fit in the punch hole of the surrounding inert carrier material/ring. Thus a firm, fixation of the inserts in the carrier material without utilization of a glue is possible.
  • inserts with a cylindrical shape can be firmly fixed without a glue if the cross-sectional diameter of the punch holes in the carrier material/ring is slightly smaller (up to 50 %, depending on insert outer diameter) as the cross sectional diameter of the inserts.
  • the elasticity of the carrier material is of relevance if a tight fixation without the use of additional adhesive or glue is desired.
  • materials with a higher elasticity such as silicones are usually more suitable for the carrier ring than thermoplastic polymers, at least if the use of an adhesive or glue for the fixation of the inserts in the carrier ring should be avoided.
  • the intravaginal ring can contain one or more inserts, dependent on the amount of substance needed. Also the diameter and material of the inserts can be adjusted according to the required amount of the substance and the physico- chemical properties of the drug.
  • the inserts are preferably arranged in a symmetrical order, e.g. in an angle of 180° is preferred if two inserts, respectively an angle of 120° is preferred if three inserts are included.
  • the insert design offers also the easy option to combine different drugs, e.g. a progestin and an estradiol, if the ring should be used for contraception, or a combination of a progestin and a therapeutic active substance, such as a nonsteroidal anti-inflammatory agent (NSAID) or an aromatase inhibitor.
  • NSAID nonsteroidal anti-inflammatory agent
  • an aromatase inhibitor such as a nonsteroidal anti-inflammatory agent (NSAID) or an aromatase inhibitor.
  • NSAID nonsteroidal anti-inflammatory agent
  • the insert design according to the invention allows for an easy adjustment of the release by e.g. using different polymer materials for the inserts.
  • the inserts may be covered with a membrane material.
  • This membrane material can be brought up by a simple dipping process, where the insert (covered by the metal sleeve) is dipped into a liquid solution of the membrane material or a monomer of the membrane material which is subsequently cured.
  • the ends of the insert having the active pharmaceutical ingredient (API) loaded matrix inside can be coated with dipping, spraying, paintbrush or flexoprint means.
  • Another possibility is to dip the insert without sleeve and subsequently insert the half-finished inserts into the sleeve either before or after curing.
  • the different inserts containing the different drugs can be covered with different or no membrane material, to adjust the drug release.
  • the membrane can be applied to the preassembled IV , by swelling a membrane tube, e.g. in cyclohexane, and slipping the swollen tube over a rod of the inert carrier material (A) which contains already the inserts.
  • silicones such as poly(disubstituted siloxanes) where the substituents are lower alkyl, preferably alkyl groups of 1 to 6 carbon atoms, or phenyl groups, wherein said alkyl or phenyl can be substituted or unsubstituted, are preferred.
  • a widely used and preferred polymer is curable poly(dimethylsiloxane) (PDMS).
  • siloxane-based polymers comprising either 3,3,3 trifluoropropyl groups attached to the si l icon atoms of the siloxane units (fluoro-modified polysiloxanes) or poly(alkylene oxide) groups, wherein said poly(alkylene oxide) groups are present as alkoxy- terminated grafts or blocks linked to the polysiloxane units by silicon-carbon bonds or as a mixture of these forms.
  • Polysiloxanes and modified polysiloxane polymers are described for example in EP 0652738 B l , WO 00/29464 and WO 00/00550.
  • PEO-b-PDMS polyethylene oxide block- polydimethylsiloxane copolymer
  • the inserts can be prepared in different ways. The easiest way is to mix the compound with the biocompatible, inert polymer material (B) and to inject this mixture into the sleeve. Mixture and injection for thermoplastic polymer materials (B) can occur by heating the polymer up to a temperature which makes the polymer sufficiently
  • liquid(viscous) if the polymer material is a silicon based material, mixing and injection can be done with the monomer as starting material or a partially polymerized monomer, which is completely cured after mixing with the drug and injection into the sleeve.
  • an adhesive or glue the following materials can be used: All medical grade silicone adhesives such as Silastic Adhesive Type A (from Dow Corning), MED3-4213 silicone adhesive (from NuSil ) or P-DERM silicone gel adhesive (from Polymer Science). Selection of a suitable glue is dependent of the selected insert and sleeve material to ensure a stable connection between the insert and the surrounding sleeve.
  • All medical grade silicone adhesives such as Silastic Adhesive Type A (from Dow Corning), MED3-4213 silicone adhesive (from NuSil ) or P-DERM silicone gel adhesive (from Polymer Science). Selection of a suitable glue is dependent of the selected insert and sleeve material to ensure a stable connection between the insert and the surrounding sleeve.
  • the sleeve of the insert is of barrel shape, an improved fixation in the inert carrier material (A) of the ring is possible.
  • the holes in the carrier material (A) should be also in barrel shape to ensure a form-lock fixing.
  • the sleeve respectively the cylinder material is of utmost importance to fulfill the object of the invention, namely the reduction of the total amount of drug in the intravaginal ring.
  • the sleeve material is impermeable to the drug, to avoid that the drug diffuses from the drug containing biocompatible polymer material (B) into the surrounding inert carrier material (A) of the ring. This is key as an u tides i red diffusion would reduce the drug concentration/load in the insert (material B) which would negatively impact the release and would at the same time increase the burst phenomena.
  • vaginal ring dosage form is furthermore preferred, where a treatment over a longer time period, up to several weeks, is desired and also in cases where bioavailability of the drug (compared e.g. to oral or transdermal dosage forms) should be improved.
  • progestins such as chlormadinone acetate (CMA), norgestimate (NGM), norelgestromin (NGMN), norethisterone (NET) /
  • norethisterone acetate NETA
  • etonogestrel 3-keto-desogestrel
  • NOMAc nomegestrol acetate
  • demegestone promegestone
  • DRSP drospirenone
  • MPA medroxyprogesterone acetate
  • CCA cyproterone acetate
  • trimegestone TMG
  • levonorgestrel LNG
  • norgestrel NG
  • desogestrel DSG
  • GSD gestodene
  • DNG dienogest
  • levonorgestrel LNG
  • DSG gestodene
  • DNG dienogest
  • levonorgestrel LNG
  • desogestrel DSG
  • GSD gestodene
  • DNG dienogest
  • levonorgestrel LNG
  • desogestrel DSG
  • GSD gestodene
  • DNG dienogest
  • levonorgestrel LNG
  • the inserts can also contain estrogens or therapeutic drugs such as aromatase inhibitors or nonsteroidal anti-inflammatory agents (NSAID) either as mono therapy or in combination with the a.m. progestins.
  • NSAID nonsteroidal anti-inflammatory agents
  • CEEs conjugated equine estrogens
  • ethinylestradiol and estrogen or their esters such as estradiol valerate or benzoate.
  • aromatase inhibitor selective aromatase inhibitors such as anastrozole
  • anastrozole (Arimidex ® ), exemestane (Aromasin ® ), fadrozole (Afema ® ), formestane (Lentaron ® ), letrozole (Femara ® ), pentrozole, vorozole (Rivizor ® ) and pharmaceutical acceptable salts thereof are suitable, whereby anastrozole ( ⁇ ) is preferred.
  • NSAID non-selective Cox inhibitors as well as selective Cox 2 inhibitors are equally suitable in the context of this invention.
  • Preferred are meloxicam, piroxicam, naproxen, celecoxib, diclofenac, tenoxicam, nimesulide, lornoxicam and indomethacin, of which indomethacin is particularly preferred.
  • Intravaginal rings according to the invention are useful for contraception and therapy i n particular for the treatment of endometriosis.
  • API active ingredient
  • the extmdate was cut to desired length (e.g. 5 mm).
  • This rod was then either; a) Inserted inside an impermeable silver sleeve with tight fitting or b) first coated with a glue and then inserted to the silver sleeve, after which the
  • the inert vaginal carrier ring was prepared through injection molding of heat curable silicone elastomer into a mold containing toroidal cavity with an outer diameter (OD) of 55 mm and an inner diameter (ID) of 43 mm.
  • OD outer diameter
  • ID inner diameter
  • This toroid was punched with holes (2) that were 2 mm in OD and the inserts (3 mm. in OD, 5 mm in length) were simply pushed inside.
  • Fig. 1 shows photo of such inert carrier ring with 2 punched holes.
  • Fig. 2 shows the carrier ring with empty inserts.
  • Fig. 3 a ring with silicon filled inserts.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Inorganic Chemistry (AREA)
  • Reproductive Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nanotechnology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un anneau intravaginal constitué d'un matériau de support inerte (A) intégrant au moins un insert contenant un médicament, le ou les inserts étant constitués d'un matériau polymère biocompatible (B) qui est entouré d'une paroi cylindrique (manchon) constituée d'un matériau inerte imperméable à la traînée pour réduire la quantité de substance de traînée inutilisée à la fin de la période d'usure et réduisant ainsi la charge environnementale lorsque l'anneau intravaginal (IVR) est éliminé.
PCT/EP2018/060854 2017-05-04 2018-04-27 Système d'administration de médicament intravaginal, procédé de fabrication d'un tel système et son utilisation dans des thérapies gynécologiques et en contraception Ceased WO2018202574A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17169419 2017-05-04
EP17169419.3 2017-05-04

Publications (1)

Publication Number Publication Date
WO2018202574A1 true WO2018202574A1 (fr) 2018-11-08

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PCT/EP2018/060854 Ceased WO2018202574A1 (fr) 2017-05-04 2018-04-27 Système d'administration de médicament intravaginal, procédé de fabrication d'un tel système et son utilisation dans des thérapies gynécologiques et en contraception

Country Status (1)

Country Link
WO (1) WO2018202574A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020172065A1 (fr) * 2019-02-19 2020-08-27 Particle Sciences Inc. Dispositifs d'administration de médicament compartimentés
WO2021101998A1 (fr) 2019-11-18 2021-05-27 Daré Bioscience, Inc. Dispositifs anneaux intravaginaux

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920805A (en) 1971-12-09 1975-11-18 Upjohn Co Pharmaceutical devices and method
US4215691A (en) 1978-10-11 1980-08-05 Alza Corporation Vaginal contraceptive system made from block copolymer
US4292965A (en) 1978-12-29 1981-10-06 The Population Council, Inc. Intravaginal ring
EP0050867A1 (fr) 1980-10-28 1982-05-05 Schering Aktiengesellschaft Vaginalring
US4888074A (en) 1987-07-22 1989-12-19 Dow Corning France S.A. Therapeutic rings
EP0652738B1 (fr) 1992-07-31 1997-04-09 Leiras Oy Equipement pour entourer d'une enveloppe une tige de medicament
WO1998004220A1 (fr) 1996-07-31 1998-02-05 The Population Council, Inc. Anneau vaginal a noyau inserable contenant un medicament
WO2000000550A1 (fr) 1998-06-30 2000-01-06 Leiras Oy Membrane ou matrice permettant de reguler la vitesse de permeation des medicaments
WO2000029464A1 (fr) 1998-11-12 2000-05-25 Leiras Oy Nouvelle membrane ou matrice permettant de controler la penetration de medicaments
WO2001013780A2 (fr) 1999-08-26 2001-03-01 Fei Technologies, Inc. Appareil et procede permettant d'anesthesier la region cervicale d'une femelle
WO2009003125A1 (fr) 2007-06-26 2008-12-31 Warner Chilcott Company,Inc. Dispositifs d'administration intravaginale de medicament permettant la liberation de macromolecules et de medicaments hydrosolubles
WO2010058070A1 (fr) 2008-11-19 2010-05-27 Bayer Schering Pharma Oy Système d'administration intravaginal et son procédé de fabrication
WO2013110856A1 (fr) 2012-01-23 2013-08-01 Bayer Oy Système d'administration de médicament

Patent Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3920805A (en) 1971-12-09 1975-11-18 Upjohn Co Pharmaceutical devices and method
US4215691A (en) 1978-10-11 1980-08-05 Alza Corporation Vaginal contraceptive system made from block copolymer
US4292965A (en) 1978-12-29 1981-10-06 The Population Council, Inc. Intravaginal ring
EP0050867A1 (fr) 1980-10-28 1982-05-05 Schering Aktiengesellschaft Vaginalring
US4888074A (en) 1987-07-22 1989-12-19 Dow Corning France S.A. Therapeutic rings
EP0652738B1 (fr) 1992-07-31 1997-04-09 Leiras Oy Equipement pour entourer d'une enveloppe une tige de medicament
WO1998004220A1 (fr) 1996-07-31 1998-02-05 The Population Council, Inc. Anneau vaginal a noyau inserable contenant un medicament
WO2000000550A1 (fr) 1998-06-30 2000-01-06 Leiras Oy Membrane ou matrice permettant de reguler la vitesse de permeation des medicaments
WO2000029464A1 (fr) 1998-11-12 2000-05-25 Leiras Oy Nouvelle membrane ou matrice permettant de controler la penetration de medicaments
WO2001013780A2 (fr) 1999-08-26 2001-03-01 Fei Technologies, Inc. Appareil et procede permettant d'anesthesier la region cervicale d'une femelle
WO2009003125A1 (fr) 2007-06-26 2008-12-31 Warner Chilcott Company,Inc. Dispositifs d'administration intravaginale de medicament permettant la liberation de macromolecules et de medicaments hydrosolubles
US20090004246A1 (en) * 2007-06-26 2009-01-01 David Aaron Woolfson Intravaginal drug delivery devices for the delivery of macromolecules and water-soluble drugs
WO2010058070A1 (fr) 2008-11-19 2010-05-27 Bayer Schering Pharma Oy Système d'administration intravaginal et son procédé de fabrication
WO2013110856A1 (fr) 2012-01-23 2013-08-01 Bayer Oy Système d'administration de médicament

Non-Patent Citations (1)

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Title
KARL MALCOLM ET AL: "Vaginal rings for delivery of HIV microbicides", INTERNATIONAL JOURNAL OF WOMEN'S HEALTH, vol. 4, 1 January 2012 (2012-01-01), pages 595 - 605, XP055114358, ISSN: 1179-1411, DOI: 10.2147/IJWH.S36282 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020172065A1 (fr) * 2019-02-19 2020-08-27 Particle Sciences Inc. Dispositifs d'administration de médicament compartimentés
WO2021101998A1 (fr) 2019-11-18 2021-05-27 Daré Bioscience, Inc. Dispositifs anneaux intravaginaux
EP4061354A4 (fr) * 2019-11-18 2023-12-20 Daré Bioscience, Inc. Dispositifs anneaux intravaginaux

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