BACKGROUND OF THE INVENTION 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, Most patients with clinically significant stress incontinence or uterine prolapse are women who have given birth several times. Pregnancy, labor, and delivery may damage the normal supports of the uterus, bladder neck and proximal urethra. In addition, continence deteriorates with increasing age, even in women who have not borne children, because intra-urethral pressure decreases after menopause due to atrophy of urogenital structures in the absence of premenopausal blood levels of estrogen. Stress incontinence is believed to occur when the proximal urethra drops below the pelvic floor because of pelvic relaxation. Once the pelvic muscles have relaxed, an increase in intra-abdominal pressure (such as occurs during coughing) can overcome urethral resistance to urine flow, and inadvertent leakage of urine from the urethra can occur.

The number of postmenopausal women is increasing dramatically because of the increasing life span of the population throughout the world. As a result, the incidence of stress incontinence is also increasing significantly. The increasing

age of the world population is also increasing the incidence of other types of incontinence. In spite of its prevalence, however, treatments for incontinence have been somewhat inadequate. One of the most common responses to this condition is simply to use absorbent pads, which help contain the inadvertent urine flow. This approach has not met with widespread satisfaction.

Another treatment has been to use pessaries, which 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. 3,683,904; 3,773,042; 3,866,613; 3,871,368; 4,307,716; 4,516,570; 4,579,110; 4,669,478; 4,724,832; 4,823,814; 4,888,074; 5,014,722; 5,065,772; 5,224,494; 5,355,896; 5,603,685; 5,611,768; European Patent No. 636 355 A1 and 084 755; DE 3700239 A1; UK 1,452,262, Canadian Patent 970641; and French Patent 72.29071.

Pessaries have also been used to deliver drugs intravaginally. An example is U. S. Patent No. 3,545,439, which 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. In 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.

Although many attempts have been made to provide a pessary that is suitable for intravaginal administration of drugs such as estrogen, none of them have been sufficiently suitable to attain widespread acceptance. The medicated pessaries of the prior art that have had the drug incorporated into the matrix of the pessary have required replacement after the drug is released from the matrix.

None of the pessaries have been easily reusable, or they have suffered from an inability to reliably release a sustained, steady dose of the drug into the vagina.

It is therefore an object of this invention to provide a pessary that is suitable for placement in the vagina to relieve the symptoms of incontinence and uterine prolapse.

Another object of the invention is to provide such a pessary that will release a sustained dose of medication intravaginally.

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.

SUMMARY OF THE INVENTION The foregoing objects are achieved by 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. However, 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).

In specifically disclosed embodiments, 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). Alternatively, 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. Alternatively, 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. In yet other embodiments, the pessary may be a valve pessary, lever pessary, Hodge pessary or Gellhorn pessary. In each of these

embodiments, 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. Sufficient amounts of the medication may be released to achieve therapeutic serum levels of the drug (such as estrogen or progesterone) but an advantage of the invention is that local release of the drug in the vagina may achieve desired physiologic effects without therapeutic systemic blood concentrations of the drug. Hence the advantages of drug or hormonal treatment of stress incontinence may be achieved, without exposing the patient to the attendant risks of systemic estrogen supplementation.

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). After this predetermined period of time, 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. Hence 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.

The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description of a preferred embodiment which proceeds with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS FIGs. 1A and 1B 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 1B, but showing another embodiment of the ring pessary in which the medicated cartridge snaps into an enlargement on the ring pessary.

FIGs. 3A and 3B are views similar to FIGs. 1A and 1B, 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 enlarged9 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.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS A first embodiment of the medicated pessary 10 of the present invention is shown in FIG. 1, which 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. Other suitable materials include silicone rubbers, nylon, polyamide 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. In FIG. 1, for example, 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. In one embodiment in which 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. In other embodiments, the drug may be dispersed throughout the surface of the cartridge, and is released in a controlled fashion from the cartridge surface.

One particularly suitable embodiment of the cartridge is shown in U. S.

Patent No. 3,854,480 (assigned to Alza Corporation), which patent is incorporated by 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, and the outer membrane is polyhydroxyethylmethacrylate, 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). However 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,, PGE2, and PGF2); and antineoplastic drugs (such as Taxol or methotrexate).

In the embodiment in which the cartridge carries estrogen, it is designed to release 1 to 500 mcg 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). To this well stirred mixture is added a 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. Alternatively (or

additionally), a removal instrument (such as a forceps) can be used to remove the cartridge from the receptacle.

In use, 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.

After the drug has been released from the cartridge over an extended period of time, 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.

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. As shown in cross section in FIG. 2, 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.

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.

A fourth embodiment of the pessary is shown in FIG. 4, in which a cube pessary 50 is shown. As is known, 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. However, in the disclosed embodiment, 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.

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.

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.

In view of the many possible embodiments to which the principles of our invention may be applied, it should be recognized that 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.