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WO1999022680A1 - Pessaire avec cartouche medicamenteuse - Google Patents

Pessaire avec cartouche medicamenteuse Download PDF

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Publication number
WO1999022680A1
WO1999022680A1 PCT/US1998/023346 US9823346W WO9922680A1 WO 1999022680 A1 WO1999022680 A1 WO 1999022680A1 US 9823346 W US9823346 W US 9823346W WO 9922680 A1 WO9922680 A1 WO 9922680A1
Authority
WO
WIPO (PCT)
Prior art keywords
pessary
cartridge
receptacle
vaginal
ring
Prior art date
Application number
PCT/US1998/023346
Other languages
English (en)
Inventor
Michael S. Wax
Matthew W. Hoskins
Original Assignee
Deschutes Medical Products, Inc.
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 Deschutes Medical Products, Inc. filed Critical Deschutes Medical Products, Inc.
Priority to EP98956493A priority Critical patent/EP1030629A4/fr
Priority to AU13007/99A priority patent/AU1300799A/en
Publication of WO1999022680A1 publication Critical patent/WO1999022680A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
    • A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
    • A61F6/08—Pessaries, i.e. devices worn in the vagina to support the uterus, remedy a malposition or prevent conception, e.g. combined with devices protecting against contagion
    • 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

Definitions

  • This invention is related to pessaries for use in the treatment of incontinence, uterine prolapse, and other conditions that may be caused by laxity of the pelvic musculature and pubococcygeal ligament.
  • Urinary incontinence is an inability to control voluntary urination. It can occur in a variety of clinical contexts, including stress incontinence and urge incontinence. Urge incontinence is an inability to control urine flow because of the sensation that the bladder is full when it is not. Stress incontinence is the involuntary loss of urine through an intact urethra, secondary to a sudden increase in intra-abdominal pressure, and in the absence of a bladder contraction. These types of incontinence will collectively be referred to as "incontinence" in this specification. Uterine prolapse is a downward displacement of the uterus so that the cervix extends into or through the vaginal orifice,
  • pessaries are instruments placed into the vagina to support the uterus, stabilize its position, and restore the intra- . pelvic anatomic relationships that provide continence.
  • Conventional pessaries come in many shapes, which are reviewed in Droegemueller and Sciarra, Gynecology and Obstetrics, Revised Edition 1992, chapter 39, which is incorporated by reference.
  • Conventional pessaries include the ring, lever, Gehrung, Gellhorn, doughnut and cube pessaries. They can provide both pelvic support and contraceptive action. Examples of these and other pessaries are shown in U.S. Patent Nos.
  • U.S. Patent No. 3,545,439 discloses a resilient ring shaped pessary made of an organopolysiloxane or other inert rubbery material, in which drugs are carried by the plastic material itself, and released into the vagina after placement of the device.
  • U.S. Patent No. 3,920,805 a nonmedicated core of the pessary is surrounded by a medicated coating of polymer, from which the drug is released.
  • U.S. Patent Nos. 3,854,480 and 3,948,254 disclose an intravaginal drug delivery system in which a solid inner drug-containing matrix is surrounded by an outer polymeric membrane that is insoluble in body fluids, but which allows diffusion of drug through the membrane into the vagina.
  • U.S. Patent Nos. 3,991,760 and 3,995,633 disclose annular intravaginal drug dispensers that contain a plurality of side-by-side enclosures that contain a liquid drug. The drug diffuses through the closed walls of the container to deliver an intravaginal dose of a spermicide or other solution.
  • U.S. Patent No. 3,896,819 discloses an intrauterine device that contains a drug within its walls, and allows controlled release of the drug through the walls into the intrauterine environment.
  • Yet another object is to provide such a pessary that combines the anatomic advantages of a pessary with a pharmaceutical treatment of incontinence, in a form that is convenient and reusable.
  • the pessary of the present invention in which the pessary is configured for retention within the vagina, and correction of uterine prolapse and incontinence.
  • the pessary includes a receptacle that opens on the surface of the pessary, and an insertable medication cartridge can be inserted into the surface receptacle with the cartridge in contact with the exterior of the pessary.
  • the cartridge can easily be loaded into the pessary for use, and removed after a period of time, once the medication has been delivered from the cartridge.
  • the cartridge is also easily replaced by the user, physician, or other health care provider, for reuse of the pessary.
  • the cartridge is, for example, a sustained release membrane that releases the medication over a period of days, at a substantially uniform rate, for example for at least about 30 days, or as long as 90 days.
  • the medication cartridge preferably comprises an estrogenic composition, such as estrogen, estrone, estradiol, or estriol, or esters thereof, which helps reverse vaginal atrophy that contributes to incontinence and prolapse.
  • the medication cartridge may alternatively (or additionally) contain other hormonal drugs (e.g. progesterone or testosterone), or non-hormonal drugs, such as anti-microbials (metronidazole, clotrimazole), corticosteroids (e.g. dexamethasone), prostaglandins, or antineoplastics (such as tamoxifen or Taxol).
  • the vaginal pessary is ring-shaped, and the ring defines a receptacle that is shaped to retain the cartridge against inadvertent dislodgement, and the receptacle opens to an exterior surface of the ring.
  • the ring may be either hollow or solid, and is provided with an elongated recess on its exterior surface into which the cartridge fits, such that the cartridge is retained in the recess (for example by frictional engagement with the walls of the recess).
  • the ring comprises a local knob-like enlargement of the ring, and the receptacle is located in the knob-like enlargement.
  • the knob or enlargement may have a form fitting cartridge receptacle on its external surface to hold the cartridge in place.
  • the knob may be hollow and sufficiently large to hold the entire cartridge, and an opening to the hollow interior is closed by a drug permeable barrier that also allows vaginal fluids to enter the hollow interior.
  • the vaginal pessary may also be a cube pessary with an external receptacle for holding the cartridge.
  • the cube has suction members on each of its six faces, and the cartridge is lodged between two of the adjacent suction members.
  • the adjacent suction members form a funnel shaped opening between them, and that opening narrows to a constriction that is substantially the same width as the medicated cartridge, such that the cartridge can be lodged in the constriction without dislodgement.
  • the pessary may be a valve pessary, lever pessary, Hodge pessary or Gellhorn pessary.
  • the medicated cartridge is easily inserted into the pessary and removed from it after the medication has been dispensed, or after the level of drug dispensed from the cartridge has fallen below a preselected or desired level following a predetermined period of time.
  • the pessary provides anatomic support for the urethra to decrease stress incontinence, and dispenses medication (usually an estrogenic drug) directly into the environment where it will have the maximum effect in offsetting urogenital atrophy and decreasing stress incontinence.
  • the invention also includes a method of administering a pharmaceutical intravaginally by providing a pessary which is configured for retention within the vagina, for example around the cervix or behind the bladder.
  • the medicated cartridge is inserted into the receptacle with at least a portion of the cartridge exposed to the exterior of the pessary such that the vaginal fluids may contact the medicated cartridge.
  • the pessary is then inserted into the vagina in a position that provides support for the bladder, and in which vaginal fluids bathe the cartridge so that the medication is released into the vagina to provide therapeutic amounts of the medication locally to the pelvic structures.
  • the medicated pessary also provides a reliable daily dose of the drug, without having to rely on compliance with a daily oral medication regimen.
  • the medicated cartridge is a sustained release membrane that releases medication from the cartridge for a prolonged period of time, for example at least 30 days, or at least as long as 90 days.
  • the time course of drug release is predetermined, so that the pessary may be removed from the vagina when the dose of the drug is exhausted, or has reached sub-therapeutic levels (either locally or systemically).
  • the pessary is removed from the vagina, the cartridge is removed from the pessary and replaced with a new or recharged cartridge, and the pessary is again placed in the vagina.
  • the pessary is reusable, and only the medicated cartridge is replaced.
  • the cartridge is removed from the pessary, for example, by flexing the pessary to dislodge the cartridge.
  • the invention also includes a loading and removal tool for inserting the cartridge into and removing it from the pessary.
  • the tool has an elongated body with a spring-loaded pusher that engages the cartridge and loads it into the receptacle. Another portion of the tool has an edge with a recess complementary to a cross-sectional shape of the cartridge, such that the cartridge can snap into the recess, attach to the tool, and be removed from the pessary.
  • FIGs. 1A and IB are a plan view and a cross-sectional view of a ring pessary embodiment of the present invention in which a medicated cartridge is retained at least partially within a receptacle that opens to an exterior surface of the pessary.
  • FIGs. 2A and 2B are views similar to FIGs. 1A and IB, but showing another embodiment of the ring pessary in which the medicated cartridge snaps into an enlargement on the ring pessary.
  • FIGs. 3 A and 3B are views similar to FIGs. 1A and IB, but showing a torus shaped embodiment of the pessary.
  • FIG. 4 is a view similar to FIG. 1A, but showing a cube pessary.
  • FIG. 5 is a view of the pessary of FIG. 1 inserted in the vagina around the cervix.
  • FIG. 6 is a view of the pessary of FIG. 2 inserted in the vagina.
  • FIG. 7 is a view of the pessary of FIG. 3 inserted in the vagina.
  • FIG. 8 is a view of the pessary of FIG. 4 inserted in the vagina.
  • FIG. 9 is an enlarged, cross-sectional view of one embodiment of the medicated cartridge of the present invention.
  • FIG. 10 is a side elevational view of the tool for inserting the cartridge into the pessary, and removing it therefrom.
  • FIG. 11 is a schematic side view of the removal tool showing how it would be used to load the cartridges into the pessary.
  • FIG. 1 illustrates a first ring embodiment.
  • the pessary 10 is a solid, resilient annular ring 12 formed of an inert material that does not have any inflammatory effect on the urogenital structures in which it comes in contact.
  • Such materials may include biologically compatible, nontoxic, non-absorbable linear organosiloxanes (e.g. dimethylsiloxane) that have been converted to rubber by heat curing.
  • suitable materials include silicone rubbers, nylon, poly amide resin, polytetrafluoroethylene (PTFE or Teflon ), or polyesters or polyethyls, such as those shown in U.S. Patent No. 3,015,650.
  • the ring 12 is preferably made of a plastic that is flexible enough to allow the ring to be flexed, however it is not necessary that the plastic be permeable to the drug (such as estrogen) that is to be released from the pessary. Nor is it necessary that the matrix of the plastic ring be capable of carrying and dispensing the drug.
  • the drug is instead contained in an elongated medicated cartridge 14 that is carried in a receptacle 16 having a shape that is complementary to a portion of the cartridge 14.
  • the complementary shape of the receptacle 16 is sufficient to retain the cartridge 14 fixed in the receptacle until it is to be removed.
  • the cartridge 14 is longitudinally elongated with rounded ends, but has a circular transverse cross section.
  • the receptacle 16 is substantially the same length as cartridge 14, or slightly shorter to improve retention, and the receptacle has a transverse cross section that is substantially semi-circular.
  • the radius of the semicircular cross section of the receptacle 16 is slightly less than the radius of the cartridge 14 to provide tight engagement of the cartridge by the receptacle.
  • the material of which the cartridge is made may also have a high coefficient of friction, or a tacky texture (such as silastic material), to reduce accidental dislodgement of the cartridge from the receptacle.
  • the cartridge may be hollow, or have an outer shell that contains a solid or liquid core of medication to be dispensed by the pessary.
  • the cartridge is made of polysiloxane (as in U.S. Patent No. 3,545,439)
  • the drug is capable of permeating from the hollow interior of the cartridge, through the silastic material, and out of the cartridge.
  • the drug may be dispersed throughout the surface of the cartridge, and is released in a controlled fashion from the cartridge surface.
  • the cartridge incorporates a drug delivery system for releasing a drug at a controlled rate for a prolonged period of time.
  • a solid inner matrix of the cartridge has solid particles of drug dispersed throughout the matrix.
  • An outer polymeric membrane surrounds the inner matrix, and is insoluble in body fluids. Both the inner matrix material and the outer polymeric membrane are permeable to passage of the drug by diffusion, but drug release through the outer membrane is rate controlling to achieve a predictable, prolonged administration of the drug.
  • the inner matrix is polymethylsiloxane
  • the outer membrane is poly hydroxyethylmethacry late, gum rubber, silicone-carbonate copolymer, polyethylene, or ethylene-vinyl acetate copolymer.
  • the drug delivery member may be in the shape of a tube, rod, disc, sphere, ball, or elongated capsule.
  • the medicated pessary preferably carries an estrogen or a therapeutically equivalent estrogenic drug (including 17- -estradiol, ethinyl estradiol, and diethyl stilbesterol, estradiol 17-benzoate, estradiol 3-benzoate, estradiol 17- - cyclopentylpropionate, estradiol dipropionate, and ethinyl estradiol).
  • an estrogen or a therapeutically equivalent estrogenic drug including 17- -estradiol, ethinyl estradiol, and diethyl stilbesterol, estradiol 17-benzoate, estradiol 3-benzoate, estradiol 17- - cyclopentylpropionate, estradiol dipropionate, and ethinyl estradiol.
  • suitable drugs for use in therapy with the drug delivery system of the present invention include, without limitation: anti-infectives (such as penicillin, tetracycline, bacitracin, nystatin, and miconazole); anti-inflammatory drugs (such as hydrocortisone, cortisone, dexamethasone, fludinolone, triamcinolone, and prednisolone); androgenic steroids (such as testosterone and methyl testosterone); progestational agents (such as progesterone, 19-norprogesterone, norethindrone, megestrol, melengestrol, medroxyprogesterone, norethynodrel and 17- - hydroxyprogesterone); prostaglandins (such as PGE 1 ; PGE 2 , and PGF 2 ); and antineoplastic drugs (such as Taxol or methotrexate).
  • anti-infectives such as penicillin, tetracycline, bacitracin, ny
  • the cartridge In the embodiment in which the cartridge carries estrogen, it is designed to release 1 to 500 meg per day of estradiol. In alternative embodiments, it releases 0.1 to 20 mg progesterone (in the form of medroxyprogesterone acetate) daily, or 0.1 to 10 mg per day of andresteonedione or testosterone.
  • the medroxyprogesterone releasing cartridge may be manufactured as set forth in U.S. Patent No. 3,854,480, by mixing 25 parts by weight of the drug with polydimethylsiloxane (70 parts by weight; Dow Corning Silastic 382), and silicone oil (5 parts by weight; Dow Corning 360).
  • stannous octoate curing catalyst (0.25 part by weight) and the mixture is injected into a polyethylene tube having an inside diameter of 0.125 inch. After curing for 30 minutes, the silicone rubber matrix is removed from the tube and cut to a length of 12 mm. The matrix is then placed within a 15 mm polyethylene tube having an inside diameter of 0.125 inch and an outside diameter of 0.157 inch. The tube ends are sealed using PTFE plugs and cyanoacrylate adhesive.
  • a cartridge that releases estrogen could, for example, have 2 mg of estradiol in the polydimethylsiloxane matrix.
  • the amount of estrogen (or other drug) can be varied depending on the drug level desired, and depending on whether systemic or merely local, intra-pelvic therapeutic drug levels are desired.
  • the cartridge would be similar to that shown in FIG. 9, in which particles of the estrogen P are dispersed within the polydimethylsiloxane matrix M, which forms the core of the cartridge 14.
  • the resulting cartridge 14 is preferably semi-rigid and elastomeric, so that it can be forced into receptacle 16 and retained within the receptacle until it is desired to remove it.
  • One way to remove the cartridge is to flex ring 12 to deform the receptacle 16, which pops the cartridge out of the receptacle.
  • a removal instrument such as a forceps can be used to remove the cartridge from the receptacle.
  • the pessary is inserted in known fashion into the vagina, and is preferably placed around the uterine cervix (FIG. 5) with a portion 18 of the ring in the posterior fornix, and an opposing portion of the ring adjacent the bladder. In this position, the pessary provides additional physical support to the uterus and bladder, and diminishes stress incontinence. The prolonged release of estrogen directly to the affected tissues also provides superior pharmaceutical therapy for this condition.
  • the ring is removed from the vagina, the cartridge displaced from the ring by flexing the ring or using the tool shown in FIGS. 10 and 11, and a new loaded cartridge is inserted into the receptacle.
  • the pessary 10 is then reinserted into the uterus, and this procedure is repeated (at 30-90 day intervals) as long as needed.
  • FIG. 2 A second embodiment of the pessary is shown in FIG. 2, in which the solid ring 30 has an enlarged cartridge holder 32 with a receptacle 34 which is shown in cross section to have a shape complementary in shape and size (but slightly smaller) than cartridge 14.
  • the holder 32 has a circular cross section (like ring 30), but holder 32 has a diameter that is about twice the diameter of ring 30.
  • the pessary of FIG. 2 is shown in place around the uterine cervix in FIG. 6.
  • FIG. 3 A third embodiment of the pessary is shown in FIG. 3, in which the pessary 40 is in the shape of a torus 42 (hollow donut) that presents a concavity 44 on its face.
  • the concavity conforms to about half of the cartridge 46, and is configured to allow the cartridge 14 to snap into the concavity by applying digital pressure to the cartridge 14 when it is in place over the concavity 44.
  • the pessary 40 is shown in place around the uterine cervix in FIG. 7, providing support to the uterus and bladder.
  • FIG. 4 A fourth embodiment of the pessary is shown in FIG. 4, in which a cube pessary 50 is shown.
  • a cube pessary has six faces, each face of which presents an identical suction member 52 (three of which are shown in FIG. 4).
  • the suction members project slightly from the cube, and form complementary funnel shaped recesses 54 between the suction members, that narrow to a constriction 56 that can be configured to hold the medication cartridge 14 between the raised suction members.
  • a receptacle 60 is recessed into the exterior surface of the cube to hold the cartridge 14. In this position, the cartridge is exposed to the intravaginal environment, where it is bathed in vaginal fluids that transport the medication from the cartridge 14 to the uterus, vaginal walls, urethra, and other anatomic structures that benefit from its therapeutic effects.
  • FIGS. 10 and 11 A tool for inserting and removing the cartridge 14 from a pessary 42 is shown in FIGS. 10 and 11.
  • the tool includes a substantially rectangular body 100 having a longitudinal slot 102 and a transverse slot 104, wherein the slots 102, 104 are oriented perpendicular to one another.
  • a spring loaded trigger 106 extends through longitudinal slot 102, and carries a push member 108 that is normally spring-biased in the direction of arrow 110. However the spring bias can be overcome by pushing the trigger 106 in the direction of arrow 112, to displace a cartridge 14 and insert it into the receptacle 44 of pessary 42 that is aligned with the tool 100.
  • the cartridges can be carried by a package strip 114 with an aluminum foil backing that is perforated by the movement of cartridge 14 through it.
  • the cartridge When the drug carried by cartridge 14 is expended, the cartridge can be removed from pessary 42 using the tool 100, which has a crescent shaped removal tip at one corner of the tool. A free leading edge 120 of the tool 100 is wedged between cartridge 14 and the receptacle 44 to pry the cartridge out of the receptacle 44. The opposite end of the tool can then be used to insert a new cartridge from a package 114 into the receptacle 44.
  • the cartridge of the present invention may be discarded when spent, or it can be refilled with the drug and placed back into the cartridge.
  • the illustrated embodiments are only examples of the invention and should not be taken as a limitation on the scope of the invention. Rather, the scope of the invention is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

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  • Health & Medical Sciences (AREA)
  • Reproductive Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

Selon cette invention, un pessaire (10) destiné au traitement du prolapsus utérin et de l'incontinence contient une cartouche médicamenteuse (14) diffusant une dose de médicament de manière stable et continue. Le médicament est, de préférence, un oestrogène qui, combiné au pessaire, limite l'incontinence en augmentant le tonus de l'appareil génito-urinaire. Le pessaire (10) peut avoir la forme d'un anneau, d'un tore ou d'un cube. Il comporte un réceptacle (16) se présentant comme un enfoncement de la surface du pessaire, ouvert vers l'extérieur. La taille et la forme de la cartouche (14) sont complémentaires dudit réceptacle (16) enfoncé; cependant, la cartouche peut être un peu plus grande que le réceptacle, de manière à permettre d'enfoncer la cartouche (14) dans ledit réceptacle où elle reste pour une période prolongée pendant laquelle le médicament est diffusé. On peut retirer la cartouche (14) de manière sélective, par exemple, en la pliant ou en utilisant un instrument spécial; ainsi peut-on insérer dans le réceptacle une cartouche neuve ou rechargée. L'invention concerne également un instrument muni d'une détente à ressort et servant à insérer des réceptacles dans le réceptacle du pessaire.
PCT/US1998/023346 1997-11-03 1998-11-02 Pessaire avec cartouche medicamenteuse WO1999022680A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP98956493A EP1030629A4 (fr) 1997-11-03 1998-11-02 Pessaire avec cartouche medicamenteuse
AU13007/99A AU1300799A (en) 1997-11-03 1998-11-02 Pessary with medicated cartridge

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6400797P 1997-11-03 1997-11-03
US60/064,007 1997-11-03

Publications (1)

Publication Number Publication Date
WO1999022680A1 true WO1999022680A1 (fr) 1999-05-14

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PCT/US1998/023346 WO1999022680A1 (fr) 1997-11-03 1998-11-02 Pessaire avec cartouche medicamenteuse

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EP (1) EP1030629A4 (fr)
AU (1) AU1300799A (fr)
WO (1) WO1999022680A1 (fr)

Cited By (25)

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WO2009109966A1 (fr) * 2008-03-04 2009-09-11 Elan Ziv Support vaginal pour la libération contrôlée de substances
WO2010086681A1 (fr) * 2009-01-29 2010-08-05 Fondazione Ircss Dispositif intra-cervical pour la libération locale de médicaments dans le traitement locorégional du cancer du col de l'utérus
EP2567680A1 (fr) * 2011-09-09 2013-03-13 VivoSensMedical GmbH Pessaire annulaire souple
WO2015073177A1 (fr) * 2013-10-10 2015-05-21 Therapeuticsmd, Inc. Compositions pharmaceutiques à base d'estradiol pour insertion vaginale et méthodes associées
WO2015198104A1 (fr) 2014-06-28 2015-12-30 Laboratorios Andromaco S.A. Pessaire de cerclage contenant de la progestérone à libération prolongée, soutenue et continue, utile pour la prévention de l'accouchement prématuré
US9248285B2 (en) 2012-06-09 2016-02-02 Fempulse, Llc Devices and methods for stimulating nerves
US9381351B2 (en) 2012-06-09 2016-07-05 Fempulse, Llc Devices and methods for stimulating nerves
EP3060179A1 (fr) * 2013-10-22 2016-08-31 Therapeuticsmd, Inc. Compositions pharmaceutiques à base d'estradiol pour insertion vaginale et méthodes associées
US9775864B2 (en) 2013-01-31 2017-10-03 Ams Research Corporation Vaginal laxity therapy utilizing cell-based bulking compositions
US10004584B2 (en) 2006-07-10 2018-06-26 First Quality Hygienic, Inc. Resilient intravaginal device
US10098894B2 (en) 2014-07-29 2018-10-16 Therapeuticsmd, Inc. Transdermal cream
US10206932B2 (en) 2014-05-22 2019-02-19 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10219884B2 (en) 2006-07-10 2019-03-05 First Quality Hygienic, Inc. Resilient device
US10258630B2 (en) 2014-10-22 2019-04-16 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10675288B2 (en) 2011-11-23 2020-06-09 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10888516B2 (en) 2012-12-21 2021-01-12 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
WO2021111385A3 (fr) * 2019-12-06 2021-08-26 Prathima Chowdary Pessaire à anneau vaginal à libération prolongée de traitement de l'atrophie, de la cystite et du prolapsus utérovaginal
US11103516B2 (en) 2011-11-23 2021-08-31 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations

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AU1300799A (en) 1999-05-24
EP1030629A4 (fr) 2001-09-05

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