A delivery vehicle for a silver ion source such as silver nitrate and the like, suitable for use in the treatment of menorrhagia, comprises a plurality of physiologically inert beads bearing a tissue cauterizing amount of a silver ion source. Preferably the beads are made of a physiologically inert polymer, ceramic or stainless steel. The silver ion source preferably is silver nitrate and can be substantially pure silver nitrate, or can comprise silver nitrate in combination with a physiologically tolerable binder or a diluent. Suitable binders include physiologically tolerable synthetic polymeric binders, polysaccharide binders, and the like. Diluents can include other salt materials such as potassium nitrate. The beads are useful in treating menorrhagia of a mammalian uterus. The beads can be delivered to the uterus via a catheter, and are distributed throughout the uterine cavity by uterine massage or like expedient. Silver ions are delivered to the endometrium and cause necrosis of the endometrial tissue. The silver ions remaining within the uterine cavity can then be neutralized with a sodium chloride solution delivered to the uterus e.g., by catheter, and the beads recovered from the uterus.

Description of the Invention

FIELD OF THE INVENTION

This invention relates generally to vehicles for delivering tissue necrosing agents. More specifically, the invention relates to inert beads having a silver ion releasing compound such as silver nitrate deposited thereon, and suitable for delivering a tissue cauterizing amount of silver ions to the endometrium of a mammalian uterus for the treatment of menorrhagia.

BACKGROUND OF THE INVENTION

Apparatus and methods for necrosing of the endometrium of a mammalian uterus, useful in treating excessive bleeding (menorrhagia) sterilization procedures, and cancer treatments, are known in the art. Thermal and cryogenic treatments have been utilized in such necrosing techniques and typically involve either the direct or indirect application of heat or cold to the tissue to be treated.

In addition to thermal and cryogenic treatments, methods involving application of caustic chemicals within the human body to treat menorrhagia, achieve sterilization and treat cancers also are known. The use of caustic chemicals as locally destructive agents has been attempted but has been limited by concerns about safety and control of the delivery of various agents as well as other shortcomings due to the methods of application, e.g., blind placement of a particular solid chemical. For example, as described by Babcock, W., Chemical Hysterectomy, Jnl. Obstet. & Gyn., Vol. 7, p. 693 (1924), application of gauze strips soaked in a saturated solution of zinc chloride to the uterine walls has reportedly been used to induce amenorrhea, to cause sterility, and to treat tumors. However this procedure has several disadvantages. The application of the gauze strips is a blind procedure, however. The zinc chloride soaked gauze is packed in the uterus until the practitioner feels the cavity is full. The strips are left in place for a predetermined length of time and then removed. Delivery to and removal from the uterine cavity of the caustic gauze strips necessarily entails substantial risk of infection and of contacting the vaginal walls wherein the caustic could damage the vaginal and other tissue that are not the target of the treatment. Accordingly, successful use of this methodology requires substantial skill and experience, limiting the availability of the procedure to women with access to highly trained medical personnel.

Use of caustic agents such as silver nitrate, zinc chloride and copper sulfate has been studied for use in chemical sterilization by chemically cauterizing the fallopian tubes. However, as discussed by Richart, R., Female Transcervical Sterilization, Chapter 3, Harper & Row (1983), even when massive tubal necrosis was achieved with the application of silver nitrate, a significant proportion of fallopian tubes remained open. When compositions for the sustained release of the caustic agents were employed it was found that control over the release of the caustic agents was insufficient to avoid unacceptable side effects. Additionally, use of strong caustic agents such as acids and alkalies would require the concomitant use of equally strong neutralizing agents whose use is also laden with risk. Use of such agents also puts the practitioner in the difficult position of titrating the neutralization of the caustic agent in the patient's uterus and Fallopian tubes.

Neuwirth describes a particularly effective method for treating menorrhagia, which involves administering a silver nitrate-containing paste to the uterine cavity and distributing the paste therein. See, e.g., U.S. Pat. Nos. 6,197,351; 6,187,346; 6,165,492; and 5,891,457; the relevant disclosures of which are incorporated herein by reference. The silver nitrate causes necrosis of the endometrium, which in turn stops excess uterine bleeding associated with menorrhagia. After treatment, the caustic silver nitrate is effectively neutralized by administering a solution of sodium chloride, usually physiologic saline, to the uterine cavity. Sodium chloride reacts with the silver nitrate to form insoluble (non-caustic) silver chloride. The silver chloride is then flushed out of the uterus along with any loose necrosed tissued present in the uterus.

Delivery of silver nitrate as a paste, as described by Neuwirth, requires some degree of care to ensure that the paste does not come into prolonged contact with tissues that are not in need of cauterization such as the Fallopian tubes. There exists, therefore, a need for improved vehicles for a more precise delivery of silver nitrate to the uterine cavity to implement chemical cauterization of the endometrium. The present invention provides such improved delivery vehicles.

SUMMARY OF THE INVENTION

A delivery vehicle for a silver ion releasing compound such as silver nitrate suitable for tissue necrosis, e.g., for use in the treatment of menorrhagia, comprises a plurality of physiologically inert beads bearing a tissue necrosing amount of a solid silver ion releasing composition. The beads can be composed of any physiologically inert material such as a polymer, a ceramic or stainless steel. The solid silver ion releasing composition can be a water-soluble inorganic silver salt, a water-soluble organic silver salt, and the like water-soluble oxidizing agent. A preferred water soluble inorganic silver salt is silver nitrate, which can be administered as substantially pure silver nitrate, as silver nitrate in combination with a physiologically tolerable binder or a diluent. A preferred water-soluble organic silver salt is silver acetate, and the like, alone or in combination with a physiologically tolerable binder or diluent. Suitable binders include physiologically tolerable synthetic polymeric binders, polysaccharide binders, and the like. Diluents can include other water soluble salts such as potassium nitrate, and the like.

The beads are preferably substantially spherical in shape and have an average diameter in the range of about 1 to about 6 millimeters, more preferably about 2 to about 4 millimeters. Preferably the beads are substantially uniform in size.

Preferably each bead carries a composition containing at least about 20 milligrams, more preferably about 50 milligrams to about 150 milligrams of a silver ion releasing compound such as silver nitrate, silver acetate, and the like, per bead.

The beads carrying a silver ion releasing composition are useful in treating menorrhagia of a mammalian uterus. The beads are delivered to the uterus via a catheter, and are distributed throughout the uterine cavity by uterine massage or like manipulation. Silver ions are delivered to the endometrium and cause necrosis of the endometrial tissue as well as some of the myometrium. The silver ions remaining within the uterine cavity can thereafter be neutralized, usually with a sodium chloride solution delivered to the uterus by catheter. Thereafter the beads are recovered from the uterus, for example, by suction, by flushing, by mechanical removal, or the like expedient.

SUMMARY OF THE INVENTION

A delivery vehicle for a silver ion releasing compound such as silver nitrate suitable for tissue necrosis, e.g., for use in the treatment of menorrhagia, comprises a plurality of physiologically inert beads bearing a tissue necrosing amount of a solid silver ion releasing composition. The beads can be composed of any physiologically inert material such as a polymer, a ceramic or stainless steel. The solid silver ion releasing composition can be a water-soluble inorganic silver salt, a water-soluble organic silver salt, and the like water-soluble oxidizing agent. A preferred water soluble inorganic silver salt is silver nitrate, which can be administered as substantially pure silver nitrate, as silver nitrate in combination with a physiologically tolerable binder or a diluent. A preferred water-soluble organic silver salt is silver acetate, and the like, alone or in combination with a physiologically tolerable binder or diluent. Suitable binders include physiologically tolerable synthetic polymeric binders, polysaccharide binders, and the like. Diluents can include other water soluble salts such as potassium nitrate, and the like.

The beads are preferably substantially spherical in shape and have an average diameter in the range of about 1 to about 6 millimeters, more preferably about 2 to about 4 millimeters. Preferably the beads are substantially uniform in size.

Preferably each bead carries a composition containing at least about 20 milligrams, more preferably about 50 milligrams to about 150 milligrams of a silver ion releasing compound such as silver nitrate, silver acetate, and the like, per bead.

The beads carrying a silver ion releasing composition are useful in treating menorrhagia of a mammalian uterus. The beads are delivered to the uterus via a catheter, and are distributed throughout the uterine cavity by uterine massage or like manipulation. Silver ions are delivered to the endometrium and cause necrosis of the endometrial tissue as well as some of the myometrium. The silver ions remaining within the uterine cavity can thereafter be neutralized, usually with a sodium chloride solution delivered to the uterus by catheter. Thereafter the beads are recovered from the uterus, for example, by suction, by flushing, by mechanical removal, or the like expedient.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

As used herein, the term "necrosis" and grammatical variations thereof means death of cells in a tissue. The term "chemical necrosis" and grammatical variations thereof means necrosis resulting from contact with a caustic chemical agent. The terms "physiologically inert" and "physiologically tolerable" as used herein and in the appended claims in references to materials or chemical components of the delivery vehicles of the present invention mean that the material or chemical component does not produce an adverse physiological reaction to the patient when present in the uterine cavity of the patient. Adverse physiological reactions include, for example, allergic and other systemic reactions, local inflammation not attributable to the silver nitrate, and the like.

The present invention provides a vehicle suitable for delivering a silver ion source such as silver nitrate and the like to the uterine cavity of a patient suffering from menorrhagia to chemically necrose the endometrium. The delivery vehicle comprises a plurality of physiologically inert beads bearing a solid silver ion source. The solid silver ion source adheres firmly to the beads, but the beads readily release a silver ion bearing composition when the beads come into contact with the moist endometrium of the uterus. The solid silver ion source can be coated on the external surface of a bead, or can be present at least partially within a porous bead.

Preferably the beads are substantially spherical in shape and have an average diameter in the range of about 1 to about 6 millimeters, more preferably about 2 to about 4 millimeters.

The beads can be made of any physiologically inert material which can meet governmental regulatory requirements, such as United States Food and Drug Administration requirements for medical devices received within the uterine cavity. The bead can be composed of a physiologically inert polymer such as polystyrene, polyethylene, polypropylene, nylon, polyethyleneterephthalate (PET), polyurethane, ethylene/vinyl acetate copolymers, and the like. Alternatively the beads can be made of a physiologically inert ceramic or of stainless steel. The beads can be perforated, spongiform, porous, or non-porous. Porous beads can be polymeric foam beads, such as polypropylene foam or polyethylene foam beads, or can be beads having machined pores or perforations, molded pores, and the like. Preferably the beads are nylon, polystyrene or polypropylene beads, more preferably having a specific gravity of less than 1 so that the beads can be readily removed from the uterine cavity after treatment by flushing with a saline solution or like expedient. Perforations or grooves in the beads, when present, can increase the loading of a silver ion releasing compound, such as silver nitrate, carried by the beads. For example, the beads can include one or more through perforations which can be filled with a silver ion releasing composition. Alternatively, the beads can have cavities or pits in the surface of the beads to hold additional silver ion source therein. Reticulated polyurethane beads are also suitable.

The silver ion delivery vehicles of the present invention can be manufactured by a variety of methods known in the art. For example, the beads can be coated with a molten silver nitrate composition, such as substantially pure silver nitrate, or a mixture of silver nitrate and up to about 25 weight percent of a diluent such as potassium nitrate, preferably no more than about 20 weight percent potassium nitrate, more preferably no more than about 5 percent by weight potassium nitrate. The molten silver nitrate composition can be deposited on the beads by spraying, for example, by spraying a molten silver nitrate composition onto a fluidized bed of beads. The beads also can be coated by combining the beads with a molten silver nitrate composition in a rotating kiln, a pin blender, and the like. Pure silver nitrate melts at a temperature of about 212.degree. C. When a molten silver nitrate composition is deposited on a bead, preferably the bead has a softening temperature or a melting point above the melting point of the silver nitrate composition.

Alternatively, an aqueous composition containing a silver ion source such as a water-soluble inorganic silver salt, e.g., silver nitrate, silver sulfate, silver perchlorate, silver permanganate, and the like, or a water soluble organic silver salt, e.g., silver acetate, silver lactate monohydrate, and the like, together with a binder can be deposited on the beads and dried to provide silver ion delivery vehicles of the present invention. The aqueous composition can be a paste or a fluid containing a thickening binder (e.g., a dextran and the like), such as are described in U.S. Pat. No. 6,197,351 to Neuwirth, the relevant disclosures of which are incorporated herein by reference. Other suitable binders include any physiologically tolerable binder, such as synthetic polymeric binders and thickeners (e.g., poloxamer polymers, carbomer polymers, polyvinylpyrrolidone, and the like), gelatin, hardened gelatin, polysaccharides (e.g., dextrans, microcrystalline cellulose, methylcellulose, xanthan gum, guar, gum, and the like), and like thickening and binding agents, so long as they are of a grade suitable for use in intrauterine preparations. Pharmaceutically acceptable binders, carriers, diluents, disintegrants, and the like are described in Remington's Pharmaceutical Sciences, 14th Ed., Mack Publishing Co., pp. 1650-1653 (1970), the relevant disclosures of which are incorporated herein by reference to the extent pertinent.

In one preferred coating method, the silver nitrate-containing composition can be an aqueous composition comprising silver nitrate and a polymeric binder such as polyvinylpyrrolidone, and the like. The composition can be applied to the beads in any suitable manner. Preferably, the composition is applied as a uniform coating having a relatively smooth surface structure and a relatively constant thickness. For example, the composition may be applied to the beads by utilizing a pneumatic spray gun, by dipping, and the like expedients. Ideally, spraying is continuous, with substantially concurrent drying so that the beads do not become too moist (overly wet) and stick together. The freshly sprayed silver nitrate coating is dried as quickly as possible to avoid agglomeration of the beads. Other suitable methods include the use of fluidized-bed processes to coat the beads with a silver nitrate composition. Modified coating drums (e.g., cylindrical horizontally rotating units with a perforated wall) are also suitable for coating the beads with silver nitrate.

In another preferred embodiment, solid silver nitrate, as a powder or as fine crystals, can be added as a filler to a polymer melt, optionally with a blowing agent, during the bead-making process. Beads of silver nitrate filled polymer can then be extruded to form a silver nitrate delivery vehicle comprising a porous bead with silver nitrate dispersed therein. Preferably the bead is water swellable or water permeable, so that silver nitrate in the interior of the bead can be released when the beads are in contact with the endometrium in the uterus. Alternatively, an aqueous silver nitrate solution can be imbibed into a preformed, porous, water swellable or water permeable polymer bead.

FIG. 1 (see Original Patent) is a cross-sectional view of a silver nitrate delivery vehicle 10, comprising a polymeric bead 12, such as a polypropylene or polystyrene bead, having a layer 14 of silver nitrate dispersed in polyvinylpyrrolidone deposited on the surface of bead 12. FIG. 2 (see Original Patent) is a cross-sectional view of a silver nitrate delivery vehicle 20 comprising a porous polymeric bead 22 having silver nitrate 24 within the pores of bead 22.

Porous beads preferably have an open cell structure and are composed of a hydrophilic polymer which is water permeable such as nylon or polyurethane, for example, or have surfaces that are hydrophilic.

Blowing agents that can be used to form porous polymeric materials are well known in the art. Suitable blowing agents and methods of manufacturing foamed polymeric materials are described in Frados, Plastics Engineering Handbook of the Society of Plastics Industry, Inc., Chapter 20, Van Nostrand Reinhold Co., New York, pp. 499-599 (1976). Suitable blowing agents include, for example, chemical blowing agents such as azobisisobutyronitrile, azodicarbonamide, and the like; and gases such as carbon dioxide, nitrogen, and the like.

The plurality of beads delivered to the uterus includes a sufficient quantity of silver ions to produce the level of endometrial necrosis desired by the clinician performing the treatment. The released silver ions (Ag.sup.+) react in the cells with moieties such as proteins, sulfides, chlorides, and the like that are vital to cell metabolism and thus initiate necrosis. Preferably a sufficient number of beads is administered to the uterine cavity to provide a total quantity of silver ions in the range of about 25 mg/cm.sup.2 to about 150 mg/cm.sup.2 of endometrium, preferably about 50 mg/cm.sup.2 to about 100 mg/cm.sup.2 of endometrium.

For a human uterine cavity of normal size, preferably about 15 to about 25 silver ion bearing beads having an outside diameter of about 2 to about 4 millimeters are introduced at one time. More preferably about 20 such beads are introduced into the uterine cavity at a time.

In the case of silver nitrate, preferably each bead can release an amount of silver nitrate in the range of about 20 to about 150 milligrams, more preferably about 50 to about 150 milligrams.

Another aspect of the present invention is a method of treating menorrhagia comprising the steps of administering to the uterine cavity of a patient suffering from menorrhagia a plurality of physiologically inert beads bearing a tissue cauterizing amount of a solid silver ion source such as silver nitrate and the like; massaging the uterus to distribute the beads therein; maintaining the beads in contact with the endometrial lining of the uterus for a time period sufficient to necrose the endometrial tissue; flushing the uterine cavity with an aqueous saline solution to neutralize the silver ions present in the uterine cavity; and recovering the beads from the patient's uterus in any convenient manner.

Claim 1 of 16 Claims

1. A delivery vehicle for silver nitrate for use in the treatment of menorrhagia and comprising a plurality of separate, pbysiologically inert beads bearing a tissue necrosing amount of silver nitrate coated on the surface of each bead, the beads having an average diameter in the range of about 1 to about 6 millimeters.

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