WO2005006991A2

WO2005006991A2 - Device and method for fallopian tube occlusion

Info

Publication number: WO2005006991A2
Application number: PCT/IE2004/000098
Authority: WO
Inventors: Martin Gerard Caldwell; Donal Bermingham; Anne O'brien; Philip O'malley; Noeleen Swords; Kenneth Norman Broadley; James Coleman; Christopher Cummins
Original assignee: Chiroxia Limited; Henkel Loctite (Ireland) Limited
Priority date: 2003-07-18
Filing date: 2004-07-19
Publication date: 2005-01-27
Also published as: WO2005006991B1; WO2005006991A3

Abstract

A transcervical device and method for delivering an occluding compound to seal the fallopian tubes under direct visualization comprising a primary catheter carried optionally within a second catheter. The primary catheter carries on its distal end a plug to seal the fallopian tube entrance in preparation for the delivery of an occluding compound and said primary catheter having at its proximal end an actuator to mix and control the speed of delivery of the required amount of a mixed occluding compound delivered. The present invention further provides an occluding compound comprising cyanoacrylate. In a preferred embodiment, the composition comprises n-butyl cyanoacrylate, boron tri fluoride (polymerisation inhibitor), PMMA (thickener) and BHA.

Description

DEVICE AND METHOD FOR FALLOPIAN TUBE OCCLUSION

BACKGROUND OF THE INVENTION

Field of the Invention

The invention relates to a device and method for occluding the fallopian tubes of a female human or animal subject. In particular the present invention relates to a transcervical device for delivering an occluding compound in liquid form to the fallopian tubes.

Brief Description of Related Technology

Current world population is expected to double over the next thirty years. The effects of overpopulation are creating unsustainable ecological and economic effects. A safe, effective, low cost and reliable contraceptive method is desirable to assist and enhance birth control programs.

Today fallopian tubal sterilization is perhaps the most widely accepted form of female contraception. In excess of 135 million women have availed themselves of such form of sterilization. It is estimated that one billion women from a diverse range of socioeconomic groups and cultures will seek sterilization services over the next two to three decades.

In developing countries transabdominal procedures are the procedure of choice. In developed countries laparoscopic sterilization is the most commonly performed surgical procedure for permanent sterilization. At present, over 9 million such procedures are carried out each year worldwide with 750,000 in the United States alone. While highly efficient these sterilization methods are associated with substantial trauma and generally involve attendance at a hospital facility, general anesthesia and a stay over with the associated costs. Complications are also a known issue, which may include bleeding, bowel perforation, infection and cosmetic trauma. More recently transcervical sterilization has been the subject of much interest. This approach uses the female reproductive route as the means of access so avoiding incisional surgery. A further attraction is the ability to perform the procedure on an outpatient or office basis. In doing so it is envisaged the cost savings will be substantial. Additionally the procedure will be done with local or no analgesics and at greater convenience for the physician and patient.

Today various tubal occlusion methods have been used or proposed including mechanical, thermal and chemical techniques or a combination. In each case tissue damage is induced in the fallopian tube.

Examples of mechanical techniques include the OVABLOC™ and more recently the MIRENA COIL™ and the CONCEPTUS ESSURE™ device. In the case of the OVABLOC™ silicone is injected into each fallopian tube and forms a plug in situ. The MIRENA COBL™, which is a combination product, is a pre-formed tensioned T shaped frame that is placed at the head of the uterine cavity adjacent to the openings to the fallopian tubes. It is impregnated with a hormonal substance, levonorgestrel, which it releases to inhibit monthly growth of the lining of the uterus and normal sperm function. The MIRENA COIL™ is reversible and requires replacement after five years. The CONCEPTUS ESSURE™ is a metal coil pre-tensioned prior to insertion, which on insertion into the fallopian tube uncoils. With respect to the CONCEPTUS ESSURE™ and the OVABLOC™ devices the body reaction is an attempt to expel the obstruction which results in stenosis in the tube and leads over time to a permanent block achieved by a combination of the device and fibrotic growths. The CONCEPTUS ESSURE™ device being a preformed solid body inserted into the fallopian tubes gives rise to placement issues due to the need to insert a pre-tensioned metal coil at least 3-4 cm into each fallopian tube. Failure rates as high as 15% have been reported.

The induction of scarring by lasers, cryosurgery, hot water and electrocautery are known technologies. These methods have been shown to have a high failure rate with associated complications including bowel perforation and excessive bleeding. In particular electrocautery methods have been found to result in limited tissue damage so as to allow for regeneration.

Methods seeking to damage the tissue at the ostium have suffered from a failure to accommodate the curvature of the target site and the thickness of the tissue at the ostium and intramural segments of the tube.

In a number of cases the introduction of chemicals into the tubes are used as sclerosing agents to induce scarring thus promoting occlusion. In the past, these agents have included methylcyanoacrylates, iodine, sodium morrhuate, ethanol, quinacrine and tetracycline. Concerns over biosafety and biocompatibility have acted as a bar to the wide-spread use of these agents.

U.S. Patent No. 3,822,702 (Bolduc et al) and U.S. Patent No. Re. 29,207 discloses a fluid dispensing instrument for introducing a tissue adhesive into both canals of the fallopian tubes. The instrument comprises a probe, an expandable balloon assembly to displace the lower portion of the uterine cavity and a dispenser to discharge the tissue adhesive into the uterine cavity above the balloon assembly. The adhesive is forced from the uterine cavity into the canals by the expansion of the balloon and subsequently polymerizes when it reacts with the moisture in the tissue of the fallopian tubes and thereby occludes the canals. Reference is also made to U.S. Patent No. 3,875,939 (Bolduc et al) relating to a single stroke dispensing method for use with the above system.

U.S. Patent No. 6,096,052 (Callister et al.) discloses a sterilization device for occluding a reproductive tract or lumen to prevent the passage of reproductive cells through the tract, fallopian tubes, or body lumen. The device comprises a tubular member and a mesh member which is permeable to allow for tissue ingrowth which produces a tissue impregnated mesh occluding the fallopian tubes.

A similar type device is disclosed in U.S. Patent No. 6,432,116 and which can be placed in the fallopian tubes by means of a catheter. Other background information is available in U.S. Patent Nos. 3,887,112 (Bolduc et al); 3,948,259 (Bolduc et al.); 3,972,331 (Bolduc et al.); 4,124,134 (Bolduc et al); 4,109,654 (Bolduc et al.); 4,119,098 (Bolduc et al.); 4,160,446 (Barrington); 4,601,698 (Moulding); 4,509,504 (Brundin); 4,547,188 (Bolduc); 4,245,623 (Erb); 5,469,867 (Schmitt); 5,826,584 (Schmitt); 6,042,590 (Sporrir); 6,066,139 (Ryan); 4,126,134 (Bolduc et al); 5,698,189 (Rowe); 6,309,384 Bl (Harrington); 5,935,137 (Saudat et al.); 4,136,695; 5,698,189 (Rowe); 4,264,577 (Zimmerman) 5,303,719 (Wilk); 6,245,090 (Gilson); 4,700,701 (Montaldi); 3,805,767 (Erb); 5,891,457 (Neuwirth); 4,606,336 (Zeluff); 6,176,240 Bl (Nikolchev); 4,795,438 (Kensey); 4,416,660 (Dafoe) and 5,095,917 (Vancaillie); and International Patent Publication Nos. WO 83/00011 (AB Medline) and WO 81/00701 (Population Research Corp).

Most, if not all, of the above patent specifications discuss various techniques of depositing or implanting an occluding compound, a plug or other blocking element within or adjacent to the fallopian tubes.

U.S. Patent No. 5,530,037 (McDonnell et al.) discloses a curable cyanoacrylate adhesive composition for medical or veterinary uses which is sterilized in liquid form by gamma irradiation. After irradiation the cyanoacrylate monomer is left in a substantially ungelled state.

U.K. Patent Specification No. GB 2 201 685 discloses a composition for occlusion of ducts and cavities of the human body. The composition disclosed incorporates an alpha- cyanoacrylate dimethylsulphoxide, dimethylketone and an iodine-containing radiopaque organic acid, or mixtures of such acids. Examples of the ducts and cavities for occlusion are blood vessels, bronchi, cysts, abscesses and dental canals.

International Patent Publication No. WO 92/09651 discloses a polycyanoacrylate foam made by mixing a cyanoacrylate monomer, a liquid foaming agent and a polymerization initiator. The mixture simultaneously polymerises and foams. The foaming agent is usually an organic compound with a boiling point not higher than 100°C, miscible with the monomer but not a solvent for the polymer. The monomer is said to be any 2- cyanoacrylate ester compatible with the composition.

International Patent Publication No. WO 00/44287 discloses a composition comprising of a monomer component comprised of an alkyl cyanoacrylate and at least one inhibitor, and a second component comprised of a resultant aggregate structure formed from an alkyl cyanoacrylate monomer, an alkyl esterified fatty acid and an opacificant agent where said composition is useful for filing an existing space, e.g., the lumen of a blood vessel, a space created by a transiently placed external device, e.g., a catheter or like device, a space created by a procedure, e.g., an excision or implantation of an object, e.g., a stent. The composition is also useful for adhering tissue to tissue, or adhering tissue to a device. The composition has the property of polymerizing when it comes in contact with an anionic environment, or when it is deployed in situ in an existing space.

International Patent Publication No. WO 99/43380 discloses methods for gynecologic embolization with a fluid embolic composition which in situ in the blood vessel forms a coherent solid mass.

International Patent Publication No. WO 00/72821 discloses therapeutic microfoams as a sclerosing agent in blood vessels. The foam comprises polidocanol or sodium tetradecyl sulphate dispensed in a physiological accepted gas and is dispensed from an aerosol. A method and device for producing the foam are also disclosed.

In "Effect of Methyl Cyanoacrylate Tissue Adhesive on the Human Fallopian Tube and Endometrium" J. of Obstetrics and Gynaecology of the British Commonwealth. 79, 1028- 39 (1972), it is disclosed that when the liquid tissue adhesive methyl 2-cyanoacrylate polymerized on the endometrium and fallopian tube lining a temporary localized histotoxic effect occurred. The authors suggest that the transcervical technique of instillation described using a modified Foley catheter with a tip cut off surrounded by a 5ml balloon and having a polythene tube passed up inside the catheter and fixed with polystyrene cement offers a method of permanent sterilization in women comparable in ease to the insertion of an intrauterine contraceptive device. Robert S. Neuwirth et al., "An outpatient approach to female sterilization with methylcyanoacrylate", Am. J. of Obstetrics and Gvnecology, 136, 951-956 (1980), discusses the use of methylcyanoacrylate as a tissue adhesive which can be delivered transcervically to the fallopian tubes by means of a FEMCEPT™ device. Robert S. Neuwirth et al, Am. J. of Obstetrics and Gvnecology- 145, 948-954 (1983) reports on trials with the FEMCEPT™ method of female sterilization and experience with a radiopaque version of methylcyanoacrylate.

Despite the state of the technology, there exists a need for a simple to use, reliable, cost effective sterilization device and method devoid of any significant complications or side effects.

Fallopian Tube Anatomy and Physiology

Fallopian tubes have a complex anatomy and physiology. They are paired, hollow, seromuscular organs that extend from the superior-lateral aspect of the uterine fundus to the ovaries. The mucosa is thrown into folds that project into the lumen. The height and complexity of the folds vary among the segments of the tube. The mucosa is composed of an epithelial layer which is made up predominately of ciliated and secretory cells. Proportion of cell types vary within different regions of the oviduct. Ciliated cells predominate in the distal oviduct and decrease toward the uterus, whereas the inverse is true of secretory cells. Ciliary beat is toward the uterus. This shows the importance of the formulations ability to flow and fill when selecting the formulation for fallopian tube occlusion.

The length of the fallopian tube varies considerably among patients, though in the human female, a minimum length of 8cm and maximum length of 14cm are generally recognized as the upper and lower lengths, with 11 cm being average. The fallopian tube is divided into four sections:

1. The Intramural Its length varies from 0.8cm to 2cm, and has a lumen cross-section which can vary from 0.2mm (hair like) to 2mm. 2. The Isthmus Lumen cross section can vary from 2mm to 3mm at Ampulla junction to 0.2 to 2mm at the Intramural junction. The length of the Isthmus can vary from 2cm to 3cm. 3. The Ampulla This is the longest portion of the fallopian tube, usually two thirds of the total length. The length can vary from 5cm to 8cm. The lumen cross section in this region will vary from 1mm to 10mm. 4. The Infundibulum This section has a short trumpet shape with a maximum cross section of between 5mm to 20mm at its distal end. Its length can vary from 1cm to 1.5cm.

The fallopian tube is a well vascularized organ whose primary function is to transport Ovum and Spermatozoa in opposite directions and then transport the developing embryo into the uterus. The Infundibulum and Ampulla with their thin wall, large lumen, and complex densely ciliated mucosal folds. Ciliary activity is of major importance in Ovum transport, with contractual activity a subordinate effector. In contrast, transport through the Isthmus with narrow lumen and sparsely ciliated endosalpinx appears to result primarily from contractile activity.

The Ostium is the entrance from the Uterine Cavity to the fallopian tubes Intramural portion and is funnel shaped which aids access.

The configuration of the Intramural portion is important to the present invention as its catheter is placed into this portion of the fallopian tube to allow delivery of the occluding compound.

The path through the Intramural portion can be (A) Straight, (B) Convex, (C) Tortuous, (D) Angulated. The anatomy of the fallopian tube will significantly affect the performance of any sterilization device both during and after placement. Precise placement and plug formation can be significantly affected by tubal anatomy. The present invention addresses anatomical variations in the selection of values for the volume of cyanoacrylate occluding compound to be delivered, the flow rate and its viscosity and the manner of placement of the delivery component of the present invention.

SUMMARY OF THE INVENTION

The present invention provides a medical device for delivering an occluding compound comprising a cyanoacrylate, the device comprising a catheter having a distal end, a proximal end and a lumen extending there between and a mixing device for mixing the occluding compound with an additive.

The present invention also provides a medical device for delivering an occluding compound, where the cyanoacrylate is selected from methyl cyanoacrylate, ethyl cyanoacrylate, butyl cyanoacrylates, such as n-butyl cyanoacrylate, iso-butyl cyanoacrylate, or sec-butyl cyanoacrylate, octyl cyanoacrylates, and combinations thereof.

The present invention also provides a medical device for delivering an occluding compound where the additive comprises a contrast agent to enhance visualization of the occluding compound during delivery, which may be in the form of a solid and is preferably silver.

The medical device of the present invention has the advantage that a cyanoacrylate component of the occluding compound is not mixed with a silver component of the occluding compound until just before the occluding compound is delivered to a fallopian tube. This improves the shelf life of the medical device. Therefore the cyanoacrylate component and the silver component of the occluding compound are packaged separately.

It is important to add the silver just prior to use for the following reasons: 1) The silver will fall out of suspension and is difficult to redisperse;

2) If the silver and adhesive are mixed together and then exposed to sterilisation conditions there may be a) an increase in viscosity, due to initiation of polymerization and b) the shelf stability of the occluding compound is greatly reduced.

The present invention further provides an occluding compound for use with the medical device where the occluding compound comprises a cyanoacrylate which is polymerizable into a plug, where the plug causes inflammation of the fallopian tube and stenosis resulting in permanent occlusion of the fallopian tube. The plug may also cause functional destruction of the fallopian tube.

The use of a water insoluble contrast agent such as silver in the sterilization procedure has the added advantage of providing a facile means to locate the polymeric blockage in the fallopian tubes for a considerable period after the polymer has been placed there.

The invention is also directed to an occluding compound for use with the medical device, the occluding compound comprising a cyanoacrylate which may be chosen from methyl cyanoacrylate, ethyl cyanoacrylate, butyl cyanoacrylates, such as, n-butyl cyanoacrylates, iso-butyl cyanoacrylates, or sec -butyl cyanoacrylates, octyl cyanoacrylates and other cyanoacrylates known in the art and described in particular in U.S. Patent Nos. 5,530,037 (McDonnell), 5,684,042 (Greff) and 5,665,817 (Greff), the disclosures of each of which being hereby incorporated herein by reference.

The occluding compound is chosen for its ability to cure into a solid plug and to occlude the fallopian tube. Cyanoacrylates have been identified as a desirable occluding compound, which are used for dispensing into the fallopian tube in the liquid state.

Preferably, the occluding compound comprises a polymerizable cyanoacrylate ester which is a polymerizable monomer or reactive oligomer of a cyanoacrylate ester which, in monomeric form, is represented by the structure of formula (I):

(I)

where R is selected from: alkyl of 1 to 16 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkyl groups of from 5 to 8 carbon atoms, haloalkyl, aryl, aralkyl, allyl, alkoxyalkyl preferably 2-ethoxyethyl or 3-methoxybutyl, and a substituent of the formula:

where each R' is independently selected from: hydrogen and methyl, and R" is selected from: alkyl of from 1 to 6 carbon atoms, alkenyl of from 2 to 6 carbon atoms, alkynyl of from 2 to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, aralkyl selected from benzyl, methylbenzyl, phenylethyl, phenyl, and phenyl substituted with 1 to 3 substituents selected from hydroxy, chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms, and alkoxy of from 1 to 4 carbon atoms. More preferably, in the cyanoacrylate esters of formula I, R is alkyl of from 1 to 10 carbon atoms and still more preferably alkyl of from 4 to 8 carbon atoms.

Thus, in formula I, R is an alkyl group of from 1 to 10 carbon atoms including methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, iso-pentyl, n-hexyl, iso- hexyl, 2-ethylhexyl, n-heptyl, octyl, nonyl, and decyl. More preferably, R is butyl, pentyl or octyl and most preferably, R is n-butyl. Mixtures of such compounds can also be employed.

A preferred cyanoacrylate ester for use in the invention is therefore n-butyl 2- cyanoacrylate.

The polymerizable cyanoacrylate esters described herein rapidly polymerize in the presence of water moisture or tissue protein.

The composition of the occluding compound for use with the medical device of the invention comprises a specific polymerization inhibitor and the amount of this inhibitor effectively inhibits both premature and too rapid polymerization of the cyanoacrylate adhesive component of the composition. In a preferred embodiment, the composition further comprises a suitable amount of a thickening agent to provide for a compositional viscosity of the occluding compound.

Advantageously the cyanoacrylate of the occluding compound for use with the medical device of the invention is mixed or is mixable with plasticizers, dye or pigments and/or soluble or solid contrast agents and a free radical stabilizer.

Specifically, in a first embodiment of the composition of the occluding compound, it comprises (a) from about 85 to 90 weight percent of an alkyl cyanoacrylate of formula I above; (b) from about 50 to 500 parts per million of a polymerization inhibitor; (c) from about 10 percent to about 15 percent by weight of a biocompatible thickener; and (d) from about 5,000 to 20,000 parts per million of a free-radical stablizer

In a second embodiment of the composition of the occluding compound, it comprises (a) from about 85 to 90 weight percent of n-butyl cyanoacrylate; (b) from about 50 to 500 parts per million of boron trifluoride (BF₃) as a polymerization inhibitor; (c) from about 10 percent to about 15 percent by weight of polymethylmethacrylate (PMMA); and (d) from about 5,000 to 20,000 parts per million of butylated hydroxyanisole (BHA) as a free radical stablizer.

In this embodiment the n-butyl cyanoacrylate, in monomeric form, is represented by the formula:

Use of from 50 to 500 ppm of BF₃ as the polymerization inhibitor provides for an alkyl cyanoacrylate composition having a curing time which is neither too fast (i.e. less than about 10 seconds) nor too slow (greater than 60 seconds) so as to interfere with effective application.

The occluding compound is preferably stored in a container. Optionally the container is manufactured from glass, plastic, or a suitable metal or metal alloy, most preferably the container is manufactured from aluminium.

In a preferred embodiment, the alkyl cyanoacrylate occluding compound further comprises a sufficient amount of a thickening agent to provide for a viscosity of from about 10 to 5,000 mPas at 25°C. The thickening agent employed is any biocompatible material which increases the viscosity of the alkyl cyanoacrylate composition and includes, by way of example, a partial polymer of the alkyl cyanoacrylate, PMMA or other preformed polymers soluble in the alkyl cyanoacrylate of formula I, a suspending agent such as fumed silica, and the like with PMMA being preferred.

The cyanoacrylate may be mixed with dye and/or pigments to enhance its visualization and permit monitoring of the injection while it is taking place to ensure that the sterilization procedure is being carried out properly. Moreover, the use of a water insoluble contrast agent in the sterilization procedure has the added advantage of providing a facile means to locate the polymeric blockage in the fallopian tubes potentially years after the polymer has been placed there. Ideally this can be achieved by using a radiographic contrast agent by pelvic radiographic examination.

In a particularly preferred embodiment, the contrast agent is a water insoluble contrast agent which, upon polymerization of the monomer in situ, will form part of the polymer. The contrast agent retained in the polymeric composition can be employed to identify the location of the polymeric blockage in the fallopian tubes.

The occluding compound is polymerisable into a plug, where the plug causes inflammation of the fallopian tube and stenosis resulting in permanent occlusion of the fallopian tube. The occluding compound having been subjected to a sterilizing condition selected from the group consisting of gamma irradiation, E-beam, heat and ultrafiltration

In the case where the initiating device is packaged with the occluding compound in the form of a kit, the kit may be sterilized by exposure to ethylene oxide, well known in the art.

Preferably, the occluding compound has a viscosity range between lOmPas to 5,000mPas at 25°C.

In the preferred embodiment, the occluding compound is in the form of a liquid. TABLE 1

where CA in Table 1 is cyanoacrylate of formula I above.

The medical device of the present invention includes a mixing device which is used to mix the above cyanoacrylate formulation with silver.

The present invention further provides an occluding compound for use with the medical device wherein the occluding compound includes a thickening agent capable of inducing a fibrotic or inflammatory response.

The present invention further provides an occluding compound for use with the medical device where the thickening agent is PMMA.

Additives for cyanoacrylates are known for biomedical end uses and certain of these additives are described in particular in U.S. Patent Nos. 5,530,037 (McDonnell), 5,684,042 (Greff) and 5,665,817 (Greff), the disclosures of each of which being hereby incorporated herein by reference. Some of these additives for the occluding compound are discussed below in the section entitled "Detailed Description of the Invention".

The catheter of the medical device may have, on its distal end, a plug for sealing the opening of the fallopian tube prior to delivery of the occluding compound.

The catheter may have at its distal end a tapered or beveled distal tip or optionally an oblique beveled distal tip and preferably the distal tip of the catheter has a lubricious coating which is suitable for sterilisation by sterilising means selected from the group comprising gamma radiation, E-beam, heat and ultrafiltration. Most preferably the distal tip of the catheter has a coating of polyethylene (PE), which is suitable for sterilisation using gamma radiation. Thus the choice of coating material is contingent on the sterilisation technique employed.

The catheter may be provided at its distal end with a series of holes about its circumference or a sealed distal tip with a series of holes about its circumference.

The catheter can have a detachable distal tip that may be chosen from a biodegradable material, if desired.

Preferably, the catheter has a curved distal end preformed so as to aid location of the catheter in the fallopian tube and the internal lumen of the catheter tapers at various points along its length.

Advantageously, the catheter may have an internal mixing chamber connecting a plurality of lumens.

Optionally, the catheter incorporates a screw, which in the preferred option is an Archiamedian screw.

Advantageously one or more lumens may exit through the sidewall at the distal end of the catheter and one or more lumens may exit through the distal tip of the catheter.

Conveniently, the catheter may have on its distal end means for retaining an anesthetic material which is used to deliver localized anesthesia to the fallopian tube.

In the medical device of the present invention, preset markers or radio opaque markers may be provided along the catheter to indicate or dictate depth of insertion. Preferably, the catheter has along at least a portion of its length, an integral stiffening member which may taper from its proximal end to its distal end and have a thickened catheter cross-section with a tapered or bumped extrusion.

The stiffening member may be a braid running along the length of the catheter or part thereof or may be a spiral braid along the length of the catheter or part thereof and may comprise a stiffening wire extruded along the length of the catheter or part thereof which can be manually loaded into the catheter prior to insertion into the fallopian tube.

The stiffening wire may optionally have on its distal end an anesthetic material for delivering localised anesthesia to the fallopian tube prior to insertion of the catheter.

Optionally, temporary use of a manually loaded stiffening wire during insertion may decrease the preformed curved distal end of the catheter. Conversely temporary use of a manually loaded stiffening wire during withdrawal may accentuate the preformed curved distal end of the catheter.

Preferably, the catheter is transparent along all or a portion of its length has a radiopaque or fluoroscopic mark at its distal tip for accessing its positioning and location within the fallopian tube. Furthermore the catheter may have a hydrophilic coating along its length, or at its distal end to give it non-stick properties within the fallopian tube.

The catheter may have various sections of diminishing circumferences along its length from its proximal end towards its distal end and/or may have various sections of diminishing circumferences at its distal end only together with a tapered distal tip that acts as a locator allowing easier insertion of the catheter into the fallopian tube and a means of securing the distal tip of the catheter in the fallopian tube. Optionally the catheter has at its proximal end a collapsible longitudinal section.

Advantageously the catheter may comprise a primary catheter and a secondary catheter for concealing the primary catheter during insertion through the cervical canal and uterine cavity or the operating channel of a hysteroscopy sheath, whereby the second catheter protects the primary catheter. The secondary catheter may act as a plug to seal the entrance of the fallopian tube prior to insertion of the primary catheter into the fallopian tube.

The secondary catheter may act as a guide to the primary catheter so it can be located at the entrance of the fallopian tube.

The secondary catheter may have at its distal end, a raised circumferential surface for sealing the entrance to the fallopian tube. The raised circumferential surface may be in the form of a foam ring or molded stop.

Optionally, the secondary catheter may have an oversized conical distal end tapering down to its distal tip; a plug in the form of an expandable balloon or membrane at its distal end; a suction cup at its distal end; or a convex plate at its distal end to seal the fallopian tube during delivery of the occluding compound the convex plate being adapted to halt and mould any backflow of occluding compound from the fallopian tube with the distal tip of the secondary catheter being used to aid accurate location and depth of insertion of the primary catheter into the fallopian tube prior to and during delivery of an occluding compound.

The secondary catheter may act as a means of removing surplus occluding compound from the primary catheter after delivery of the occluding compound into the fallopian tube.

The secondary and primary catheters may have corresponding indicators on their external surfaces allowing for controlled insertion and withdrawal through the alignment of the indicators by the operator. The secondary catheter may have a sealed distal tip which is perforated by the primary catheter after the secondary catheter has been located in the fallopian tube.

Preferably, the actuator is located at the proximal end of the catheter.

Advantageously, the inventive medical device is provided with an actuator having a handle to enable an operator to hold the actuator together with other instruments or devices. The handle may be provided with a universal applicator so as to adhere to the other instruments or devices and the actuator are rotatable about the handle. Optionally the universal applicator is a universal catheter adapter.

The actuator may be loaded with an occluding compound or loadable with a vessel containing an occluding compound and is operable to deliver a predetermined amount of occluding compound at a predetermined speed directly into the primary catheter.

Alternatively, the actuator is loaded or loadable with vessels containing an occluding compound and associated compounds such as an initiator for mixing with the occluding compound to initiate the polymerization of the occluding compound. Preferably the initiator is selected from the group consisting of dimethyl-p-toluidine, dimethylamino- phenyl-ethanol, and combinations thereof.

The actuator may also be preloaded or loadable with vessels containing the occluding compound and contrast agents for mixing with the occluding compound to give the mixed occluding compound radiopaque properties. Preferably the radiopaque or contrast agent is selected from tantalum, tantalum oxide, lipiodol, silver, gold, tungsten, platinum powders, metrizamide, iopamidol, iothalamate sodium, iodomide sodium, meglumine, or combinations thereof.

The actuator may be further preloaded or loadable with vessels containing the occluding compound and a biocompatible dye or pigment. Preferably, the actuator which may be composed of several separately functioning parts is provided with a chamber into which predetermined amounts of occluding compound and optional additives are separately deliverable for mixing prior to delivery through the actuator into the primary catheter or with a plurality of chambers into which predetermined amounts of occluding compound and associated compounds are separately deliverable from the vessels prior to mixing. The actuator may include or may be provided with a mixing device into which the predetermined amounts of occluding compound and associated compounds are deliverable and mixed prior to their delivery through the actuator into the primary catheter.

Preferably the actuator includes a stop/start button to control its actions. Advantageously, the actuator may also include a plunger that compresses upon entry of the compound thereby exposing a bleed hole through which air emboli is expelled into an overflow chamber which includes a porous plug at its exit port permitting passage of air but preventing passage of the occluding compound. Preferably the actuator includes a leadscrew to advance the plunger in the barrel, where the leadscrew is threaded into the centre axis of a torque output drum which is in turn rotated by a motor spring. The motor spring contains a storage drum and the torque output drum where the motor spring unwinds from the torque output drum to the storage drum upon activation of the stop/start button where the stop/start button engages with the torque output drum.

The cyanoacrylate is mixed with silver using a mixing device, which is not part of the actuator. Once the mixing of the cyanoacrylate and silver is complete, the actuator is connected either directly to the mixing device or alternatively, the actuator is connected to the mixing device by means of an adapter in the form of hollow tube. The mixed compound is then transferred from the mixing device to a chamber in the actuator.

Preferably the mixing device of the present invention comprises a chamber preloaded with the additive where the additive is expelled from the chamber by the cyanoacrylate component of the occluding compound and the additive returns through the chamber in combination with the cyanoacrylate component of the occluding compound. Preferably the mixing device further includes a mixing head including the chamber for storing the additive for mixing with the cyanoacrylate component of the occluding compound, the chamber preferably being in the form of a conduit. Optionally the mixing device also includes means for locking the mixing head of the mixing device in a forward position. Advantageously, the cyanoacrylate component of the occluding compound is stored in a container with a seal, the seal on the container is pierced as the mixing device is engaged with the container, prior to cyanoacrylate component being drawn into a mixing chamber in the mixing device and optionally where the mixing device is rotatably engaged with the container or where the container is pierced through with a thrusting motion.

In the preferred embodiment of the medical device, the mixing device or actuator includes a device for counting and visually indicating when the correct number of mixing cycles has been completed, the first mixing cycle being completed when the additive in the chamber has been urged out of the chamber by the cyanoacrylate component of the occluding compound passing therethrough.

The actuator may utilize a power source which may include springs, propellant gas, CO₂, manual pressure or any combination thereof as allows for a controlled mixing and delivery at a predetermined speed of the occluding compound.

Optionally the mixing device may be used to transfer the occluding compound directly to the catheter.

A further aspect of the invention is directed to a transcervical method for delivery of an occluding compound comprising inserting a catheter of the medical device through the operating channel of a hysteroscopic sheath through the vagina, cervical canal and uterine cavity under visualization to access the fallopian tube sealing the entrance to the fallopian tube, and delivering the occluding compound into the fallopian tube.

The step of insertion may be aided by a guidewire or by the stiffening member. The step of delivering the occluding compound may involve the withdrawal of the catheter back along a longitudinal section of the fallopian tube to a predetermined point within the fallopian tube; and involves the actuation of the actuator to deliver along a longitudinal section of the fallopian tube a precise and predetermined amount of occluding compound at a calculated and determined speed.

Delivery of the occluding compound results in an occlusion along a longitudinal section of the fallopian tube as the occluding compound cures to form a plug resulting in stenosis, fibrosis and deposition of collagen within the fallopian tube.

The cured occluding compound results in the formulation of a permanent occlusion along a longitudinal section of the fallopian tube.

A still further aspect of the invention provides a method of manufacturing a medical device for delivering an occluding compound within a fallopian tube, the manufacturing method comprising the steps of forming a catheter with a distal end, a proximal end and a lumen extending therebetween and providing a plug on the distal end of the catheter and optionally including the step of providing on the distal end of the catheter means for retaining anesthetic material, providing a mixing device for combining the cyanoacrylate with a radiopaque material and subsequently transferring the mixed compound from the mixing device to the actuator; including the step of providing at the proximal end of the catheter an actuator to deliver an occluding compound through the catheter, and optionally including the step of forming the external shape of the distal end of the catheter to assist placement within the fallopian tube, optionally including the step of coating the distal tip of the catheter with a coating of polyethylene, and optionally incorporating a fluorescent marker on the distal end of the catheter. The step of combining the cyanoacrylate with a radiopaque material consists of a number of repetitive cycles and is optionally aided by using a counter device for counting and visually indicating when the predetermined number of cycles has been completed.

The manufacturing method may also involve providing the medical device with any one or more of the features identified in this description.

The medical device of the invention may be used as a transcervical female sterilization device suitable for out patient clinic or consultancy room based use, requires limited training for the physician and maximizes comfort and convenience for the patient.

It should be understood that the medical device may have other medical procedure applications.

Occlusion is achieved by a mixed mode of action of the occluding compound which combines adhesion, mechanical blockage, tissue toxicity and fibrosis.

Placement, sterilization, and biocompatibility are important considerations for safety and efficacy of the medical device which is the subject of this invention. Mixing, plug formation, adherence and stenosis are important for plug retention, leading to successful sterilization.

In the invention, it is desirable to dispense a preset amount of an occluding compound, at a predetermined rate, into the fallopian tubes ensuring that the dispensed occluding compound does not flow into the peritoneal cavity.

A general description of some of the embodiments of the device include a mixing device for combining the cyanoacrylate with the radiopaque agent, a primary catheter, which may, in one embodiment, carry on its distal end a plug, the catheter having at its proximal end an ergonomically designed actuator to control the speed of delivery and the amount of a mixed occluding compound delivered. Brief Description of the Drawings

The invention will hereinafter be more particularly described with reference to the accompanying drawings, which, shown by way of example only, a number of embodiments of a medical device and occluding elements according to the invention.

Figure 1 is a cross sectional front view of the uterine cavity and a fallopian tube showing the placement of a catheter into the fallopian tube;

Figure 2 is a perspective view of a adhesive capsule for housing and facilitating extraction of cyanoacrylate from a container thereof;

Figures 3(a), (b) and (c) are different perspective views of the mixing device;

Figure 4 is a sectional view of the mixing device;

Figure 5 is a perspective view of the adhesive capsule engaged with the mixing device;

Figure 6 is a perspective view of the adhesive capsule engaged with the mixing device shown before the container of cyanoacrylate is punctured and with the adhesive capsule shown in section;

Figure 7 shows the same view as in Figure 6 except that Figure 7 shows the configuration after the container of cyanoacrylate has been punctured;

Figure 8 is a perspective view of the mixing device filled with cyanoacrylate and detached from the adhesive capsule;

Figures 9(a) and 9(b) are two perspective views of the mixing device shown ready to mix the cyanoacrylate with the silver powder which is stored in the mixing head within the barrel of the mixing device; Figures 10(a) and 10(b) are respective perspective views corresponding to those shown in Figures 9(a) and 9(b) with the mixing device being used for mixing the cyanoacrylate and the silver powder;

Figures 11(a) and (b) are perspective views corresponding to those shown in Figures 9(a) and (b) and 10(a) and (b) but showing the configuration with the mixing process completed and the cyanoacrylate and silver powder having being homogenously mixed;

Figure 12 is a perspective view of the delivery device (actuator);

Figure 13 is a side sectional view of Figure 12;

Figure 14 shows a top perspective inside view of an actuator showing the detail of the porous plug, extending from the overflow chamber hole;

Figure 15 is a partial section through front end of the actuator showing a vent hole in the actuator barrel and the overflow chamber;

Figures 16(a) and (b) are two perspective views of the mixing device coupled to an actuator to deliver a predetermined amount of cyanoacrylate to the actuator for subsequent delivery to a fallopian tube; and

Figure 17 is a perspective view of the actuator connected to an inner catheter;

Detailed Description of the Invention

Example 1

Formulation of occluding compound in accordance with the present invention.

The occluding compound is a mixture of two parts: Part A (cyanoacrylate based compound of the occluding compound)

Material % Wt

n-butyl cyanoacrylate 87.042

BHA 1.45

PMMA 11.5

BF₃ 0.008

These materials are put in a container, in this case an aluminium tube, and the container is then sterilised by gamma irradiation, if so desired.

This formulation results in a post-irradiation viscosity of between 1500 and 2500mPas when measured at 25°C. The amount of PMMA depends to some extent on the molecular weight of the PMMA, which in this case is between 300,000 and 500,000.

Part B (silver component of the occluding compound)

The silver component is silver particles of an average particle size of 4 - 8 microns, which are also sterilised by gamma radiation if desired.

When the two components are mixed using the mixing device included in the medical device of the present invention, there is an increase in viscosity of the resulting occluding compound. The extent of the increase is dependent upon the amount of silver added. Preferably silver is included at between 15 and 17% wt/volume of silver. If 15% of silver is added there is approximately a 12% increase in viscosity. If 17% of silver is added the viscosity increase is in the order of 13.5%. The desired final viscosity is between 1800 and 2800mPas. The formulation given here in Example 1 results in a viscosity nearer the 1800 mPas end of the range as this will help prolong the shelf life of the formulation under normal storage conditions. In this specification, the term "sterilizing" refers to a process for making a female human or an animal subject unable to produce offspring. In the context of this invention, sterilization is carried out by delivering an occluding compound into the fallopian tube of the female human or animal subject. The occluding compound then fills, plugs or causes closure of the fallopian tube so that eggs cease to pass therethrough.

The term "polymerizable cyanoacrylate esters" refers to polymerizable formulations comprising of cyanoacrylate monomers or polymerizable oligomers which, in their monomeric form, are preferably compounds represented by formula I as described hereinbelow.

The term "contrast agent" refers to a biocompatible (non-toxic) radiopaque material capable of being monitored during injection into a mammalian subject by, for example, radiography or after delivery by x-ray.

References to cyanoacrylate or CA in the following description of the medical device refer to the cyanoacrylate based component of the occluding compound of the formulation referred to above in Table 1.

Referring to the drawings there is shown in Fig 1, the female reproductive organs which includes a uterus 2 joined to a pair of fallopian tubes 3. The lower section of the uterus 2 includes the vaginal canal 4, cervix 5 and cervical canal 6. The uterus 2 is hollow and thick walled creating the uterine cavity 7. It varies in size, shape and wall thickness. The fallopian tubes 3 have openings into the upper end of the uterus 2 known as the ostium 8. The fallopian tubes 3 vary in size from female to female, varying between 8cm and 14cm long and extending from the upper end of the uterus 2 to the ovaries 9. The fallopian tube 3 is divided into four sections, namely the intramural 10, isthmus 11, ampulla 12 and infundibulum 19 sections.

The medical device of the present invention includes an inner catheter 16 which is shown passing through an outer catheter 17 and a hysteroscopic sheath 18. The inner catheter 16 is sufficiently long to pass through the vaginal cavity 4 and cervical canal 6 through the uterine cavity 7 and into the fallopian tubes 3.

The following is a list of the features indicated in the drawings and the associated reference numeral used to indicate those features:

100 - adhesive capsule

101 - gripping fingers 105 - container

110 - mating port

111 - container seal 112 - ribs

200 - mixing device

201 - plunger

202 - connector port

203 - transfer port

205 - mixing device barrel

206 - handle

207 - locking tab

208 - slot

209 - shoulder

210 - mixing device head

211 - powder chamber 215 - compression spring

220 - sealing cap

221 - indicator

222 - index counter

300 - actuator

301 - On/Off button

302 - actuator barrel

305 -actuator connector port

306 - vanes 307 - stop tab

308 - torque output drum

309 - storage drum

310 - overflow chamber

311 - vent hole 312 - lead screw 313 - plunger seal 314 - porous plug 315 - motor spring

400 - catheter connection 600 - transfer adapter

Referring to Figures 2 to 17 of the drawings, the medical device of the invention includes the following components: an adhesive capsule indicated generally by reference number 100; a mixing device indicated generally by reference numeral 200; a first actuator indicated generally by reference numeral 300 and a second actuator (300) which is constructionally and operationally the same as the first actuator (300).

Thus the medical device of the present invention includes two actuators, a first of which is shown in the drawings and indicated generally by reference numeral 300 and a second identical actuator. The first actuator is used for delivering the occluding compound to the first fallopian tube and the second actuator is used for delivering occluding compound to the second fallopian tube.

All references in this specification to an actuator are to be understood to apply in the same way to both the first actuator 300 and the second actuator. The adhesive capsule 100 includes gripping fingers 101 for holding an aluminium container 105 of cyanoacrylate. The adhesive capsule 100 also includes a mating port 110 adapted for detachably receiving the mixing device 200. The mating port 110 is adapted so as to engage the connector port 202 on the mixing device 200.

The mixing device 200 includes a plunger 201 and a mixing device head 210. The mixing device 200 also includes a connector port 202 distal from the plunger 201. The connector port 202 engages with the adhesive capsule 100 mating port 110. The connector port 202 has a tapered spout for puncturing a seal 111 on the container (tube) 105 of cyanoacrylate . The mixing device 200 also includes a mixing device barrel 205.

The mixing device 200 includes handle 206 against which a user may press his fingers to assist gripping the mixing device 200. A locking tab 207 is also included in the mixing device 200 to prevent unintentional movement of the plunger 201. The mixing device 200 also includes a sealing cap 220, which may be secured on the connector port 202 of the mixing device 200. The mixing device head 210 includes a powder chamber 211 for containing silver.

A compression spring 215 in the mixing device 200 causes the mixing device head 210 to return to its start position after it has being pushed forward.

The actuator 300 includes an On/Off button 301, an actuator barrel 302, and a actuator connector port 305. The adapter 600 is used for coupling the actuator 300 to the mixer device 200.

The motor spring 315 is stored on the torque output drum 308 within the actuator 300. The pre-tensioned spring 315 unwinds from the torque output drum 308 onto the storage drum 309. A leadscrew 312 having a plunger seal 313 attached to a first end is engaged with the threaded center of the torque output drum 308 at the mid-section of the leadscrew. Where the mid-section is defined as being intermediate a first and second end of the leadscrew and where the first and second end of the leadscrew are positioned remote from each other. As the torque output drum 308 turns, the leadscrew 312 moves forward into the actuator barrel 302, the plunger seal 313 pushes the occluding compound out of the actuator barrel 302. The stop tab 307 controlled by the On/Off switch 301 engages with the vanes 306 on the torque output drum 308 and prevents the motor spring 315 from running.

The actuator 300 also includes an overflow chamber 310 and a porous plug 314.

The medical device of the present invention may also include a catheter connection 400 for selectively coupling to a catheter 16 to the actuator 300.

Procedure for Use of Medical Device:

The components of the medical device and procedure for use of medical device in accordance with the present invention will now be described.

ADHESIVE CAPSULE

The medical device of the present invention includes a container 105 of cyanoacrylate occluding compound of the formulation described above. The container 105 is held rigidly within the adhesive capsule 100. The first step in the procedure is to transfer the cyanoacrylate occluding compound from the adhesive capsule 100 to the mixing device 200. The connector port 202 of the mixing device 200 is inserted into the mating port 110. The mixing device 200 is rotated clockwise to mechanically engage both devices. As the clockwise rotation continues, a transfer port 203 engages with a piercing collar (not shown) and is advanced against the container seal 111 until it punctures through the container seal 111 thereby opening a fluid path between the container 105 and the barrel 205 of the mixing device 200. The locking tab 207 is removed from the mixing device 200 and the plunger 201 is pulled back to draw 6ml of cyanoacrylate occluding compound into the mixing device barrel 205. In order to expel any air bubbles captive within the cyanoacrylate occluding compound, 4ml of cyanoacrylate occluding compound is dispensed back into the adhesive capsule 100 and as the assembly is held vertical during this process, air bubbles will advance into the container 105. The adhesive capsule 100 is then disconnected and discarded. A sealing cap 220 is placed on the connector port 202 of the mixing device 200. MIXING DEVICE

The mixing device 200 is used to combine and mix the cyanoacrylate occluding compound with the silver powder. The silver powder is stored in the mixing device head 210 within the barrel 205 of the mixing device. Once the cyanoacrylate occluding compound is within the barrel 205 and sealing cap 220 is attached the process of mixing can begin. The mixing device head 210 is engaged by rotating the plunger 201 into the mixing position. Once the plunger 201 is aligned with the slot 208, the plunger is then pushed forward to the end of the slot 208. Pushing on the plunger 201 advances the mixer head to the distal end of the mixing device barrel 205. When advanced, the mixing head 210 is pushed into the cyanoacrylate occluding compound causing the cyanoacrylate occluding compound to push the silver powder out of its powder chamber 211 in the mixing head 210 thus forming a conduit so that the cyanoacrylate occluding compound can pass from one side of the mixing head 210 to the other side thereof. Once the mixing head 210 reaches the distal end of the barrel 205, the plunger 201 is released and the compression spring 215 acts to return the plunger 201 and mixing device head 210 to its start position. As the mixing device head 210 is pushed forward it rotates through 90 degrees. As the mixing device head 210 returns through the cyanoacrylate occluding compound and silver, the mixture must pass through the powder chamber 211 in the mixing head 210 causing it to mix further. The forward and back movement of the plunger 201 and head 210 occurs 20 times. The reciprocating motion, in combination with the rotary motion causes the occluding compound to be mixed effectively. An index counter 221 within the mixing device body signals the 20^th cycle by releasing a green indicator. This is the signal to the user to stop mixing. The next step in the process involves the transfer of the cyanoacrylate occluding compound from the mixing device 200 to each of the actuators 300.

ACTUATOR

Two identical actuators 300 are included in the medical device of the present invention, i.e. one actuator 300 for delivery of occluding compound to each fallopian tube. The sealing cap 220 is removed from the connector port 202 of the mixing device 200 and the transfer adapter 600 is connected to the transfer port 203. The actuator connector port 305 on the actuator 300 is connected to the other end of the adapter 600. Alternatively, the connector port 202 of the mixing device 200 may be connected directly to the actuator connector port 305 of the actuator 300. The mixing device plunger 201 is rotated to the dispense position and half of the contents (1ml) within the mixing device barrel 205 are injected through the transfer adapter 600 and into the barrel 302 of the actuator 300. The plunger seal 313 will compress to expose a vent hole 311 in the barrel 302 (Figure 15) through which the air and some adhesive will exit into an overflow chamber 310. As air enters the overflow chamber 310 it is allowed to exit through a porous plug 314 at the rear (Figure 14). The porous plug will allow air to pass through it but will not allow the occluding compound to pass. The fluid will stop entering the actuator barrel 302 once it and the overflow chamber 310 is full of occluding compound. The actuator 300 is disconnected from the mixing device 200 and the actuator is attached to the catheter connection 400.

CATHETER

The first step in the procedure involves placement of the hysteroscopy sheath 18 and hysteroscope transvaginally. Once in position, a camera is attached to the hysteroscope and the clinician has a clear view of the uterine cavity. Once the fallopian tubes ostia are visualized by the clinician, the outer catheter 17 is placed into the operating channel of the hysteroscopy sheath with the aid of a stiffening wire (not shown). The stiffening wire is then removed from the outer catheter 18. The inner catheter 16 with an actuator 300 connected and with a guidewire (not shown) pre-loaded is positioned within the outer catheter 17. The distal inner catheter tip is then guided into the fallopian tube to a depth of between 5 and 10mm. This is performed with the aid of the outer catheter 17 and a guidewire. Correct depth of insertion is indicated by a ring marker on the catheter 16. The guidewire is removed from the inner catheter 16 and a perfusion test is performed to confirm catheter placement in the fallopian tube using 1ml of methylene blue dye injected into the fallopian tube via the side port of the catheter connection 400.

The clinician will confirm visually that the distal tip of the catheter is in position in the fallopian tube before pushing down and forward on the actuator On/Off button 301 causing the motor spring to actuate and advance the plunger 201 into the barrel 302. The occluding compound will advance through the catheter 16 and into the fallopian tube. Should the clinician wish to stop the delivery, the actuator button 301 is pushed back to the "Off' position where it engages with the vanes 306 of the torque output drum and stops the motor spring.

Once complete, the inner catheter 16 is withdrawn back through the outer catheter and discarded along with the first actuator 300. A second inner catheter 16 with pre-loaded guidewire is connected to a second actuator 300 and is advanced into position through the outer catheter 17 for delivery of occluding compound to the second fallopian tube. When delivery is complete, the sheath 18 is removed from the patient and any excess occluding compound is removed from the distal tip of both catheters before they are withdrawn through the operating channel of the sheath 18. This is to ensure that no adhesive residues are left within the channel.

Precise delivery and plug formation and adherence are dependent on a number of variables which the present invention addresses including the anatomy and physiology of fallopian tubes, the occluding compound and the plug shape.

Occluding Compound Additives

Additives for the occluding compound can include the following:

Plasticizer

The term "biocompatible plasticizer" refers to any material which is soluble or dispersible in the cyanoacrylate ester of formula I and which increases the flexibility of the resulting polymer plug and which is compatible with the human and animal body. Suitable plasticizers are well known in the art and include those disclosed in U.S. Patent Nos. 2,784,127 and 4,444,933, the disclosures of both of which are incorporated herein by reference. Specific plasticizers include, by way of example only, acetyl tri-n-butyl citrate, n-butylryl tri-n-hexyl citrate, benzoate esters of di-and polyhydroxy branched aliphatic compounds, tri(p-cresyl) phosphate, and the like. The particular plasticizer employed is not critical provided that it does not result in irritation of the human or animal body. Thickening Agent

The composition of the occluding compound of the present invention can optionally contain a sufficient amount of a thickening agent to provide for a viscosity of from about 10 to 5,000 cps at 25°C. The thickening agent employed is any biocompatible material which increases the viscosity of the alkyl cyanoacrylate composition and includes, by way of example, a partial polymer of the alkyl cyanoacrylate, PMMA or other preformed polymers soluble in the alkyl cyanoacrylate, a suspending agent such as formed silica and the like with PMMA being preferred. Thickening agents are deemed to be suitable if they are both soluble in the alkyl cyanoacrylate composition and are biocompatible.

The particular thickening agent employed to enhance the viscosity of the composition may be chosen by a person skilled in the art. Preferred thickening agents include PMMA, partially polymerized cyanoacrylate adhesives as disclosed in U.S. Patent Nos. 3,654,239 and 4,038,345, each of which are incorporated herein by reference. The thickening agent may also have an additional function as a fibrotic agent.

Contrast Agent

The contrast agent used in conjunction with the composition of the occluding compound, can be either water soluble or water insoluble. Examples of water soluble contrast agents include metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and meglumine. Examples of solid water insoluble contrast agents include tantalum, lipiodol, tantalum oxide, and barium sulfate, each of which is commercially available in the proper form for in vivo use including a particle size of about 10 μm or less. Other water insoluble contrast agents include silver, gold, tungsten, and platinum powders.

Preferably, the contrast agent is water insoluble (i.e., has a water solubility of less than 0.01 mg/ml at 20°C) and most preferably the contrast agent is silver.

Dyes

When the occluding compound is liquid (as in the case of a cyanoacrylate), the use of a biocompatible dye or pigment to enhance visualization of the occluding compound during delivery is advantageous. Alternatively, the contrast agent used, for example, silver, may impart colour to the occluding compound.

Polymerization Inhibitors

Cyanoacrylate adhesives are stabilised against anionic and free-radical polymerisation in order to ensure shelf life stability. U.S. Patent No. 5,530,037 (McDonnell) discloses a method of making a sterilized cyanoacrylate composition. The composition comprises a combination of an anionic stabilizer and a free-radical stabilizer in amounts effective to stabilize the composition during irradiation and to stabilize the sterilized composition during irradiation and storage prior to cure, where the free-radical stabilizer is a phenolic antioxidant.

Preparation of the Occluding Compound

Silver Contrast Agent

Compositions of the occluding compound can be prepared by adding sufficient amounts of the silver contrast agent to the cyanoacrylate to achieve an effective concentration. Preferably, the cyanoacrylate occluding compound should comprise from about 10 to about 40 weight percent of the silver contrast agent and most preferably about 15 weight percent. . When the contrast agent is not soluble, agitation may be employed to effect homogeneity of the resulting suspension. The silver particles can be up to 50 microns in particle size. In order to enhance formation of the suspension, the particle size of the silver contrast agent is preferably maintained at about 10 μm or less and more preferably at from about 4 to about 8 μm which provides an average particle size of approximately 6 μm.

The methods of this invention facilitate female sterilization because the presence of the contrast agent and dyes in the composition permits monitoring of the delivery of the biocompatible polymer while it is taking place and after it is delivered. In this way, one can ensure that the biocompatible polymer is being delivered to the fallopian tubes as well as determine whether the size of the polymer precipitate thus-formed will be sufficient to block the passage of eggs. Plug formation and Plug Shape

Proper plug formation and adherence are features for success of occlusion and sterilization. Successful plug formation requirements are dependent on volume, flow rate and viscosity. Adherence depends on the identity and concentration of the occluding compound.

The delivered occluding compound occludes the fallopian tube lumen and remains in place. The fallopian tube lumen is stretched by the occluding plug to anchor the plug and to seal off the fallopian tube. The plug delivered by the present invention is flexible; thus the present invention takes into account that tubal diameter changes with hormonal phases, and thus the plug distends outwards towards the epithelial lining for complete occlusion.

It will of course be understood that the invention is not limited to the specific details herein described, which are given by way of example only and that various alterations and modifications may be made without departing from the scope of the invention as defined in the appended claims and the invention described may have other medical procedure applications.

Claims

CLAIMS:

1. A medical device for delivering an occluding compound comprising a cyanoacrylate, the device comprising a catheter having a distal end, a proximal end and a lumen extending there between, and, a mixing device for mixing the occluding compound with an additive.

2. A medical device as claimed in claim 1 wherein the cyanoacrylate is selected from the group consisting of methyl cyanoacrylate, ethyl cyanoacrylate, butyl cyanoacrylates, n-butyl cyanoacrylates, iso-butyl cyanoacrylates, sec-butyl cyanoacrylates, octyl cyanoacrylate, and combinations thereof.

3. A medical device as claimed in Claim 1 or Claim 2 wherein the additive comprises a radiopaque or contrast agent to enhance visualization of the occluding compound during delivery and thereafter.

4. A medical device as claimed in Claim 3 wherein the radiopaque or contrast agent is in the form of a solid, and is preferably silver.

5. An occluding compound for use with the medical device as claimed in claim 1 wherein the occluding compound comprises a cyanoacrylate which is polymerisable into a plug, wherein the plug causes inflammation of the fallopian tube and stenosis resulting in permanent occlusion and optionally causes functional destruction of the fallopian tube.

6. An occluding compound as claimed in Claim 5, wherein the occluding compound comprises a polymerizable cyanoacrylate ester which is a polymerizable monomer or reactive oligomer of a cyanoacrylate ester which, in monomeric form, is represented by the structure O II CH₂=C— C OR C≡N

(I) wherein R is selected from the group consisting of: alkyl of 1 to 16 carbon atoms, alkenyl of 2 to 10 carbon atoms, cycloalkyl groups of from 5 to 8 carbon atoms, haloalkyl, aryl, aralkyl, allyl, alkoxyalkyl preferably 2-ethoxyethyl or 3-methoxybutyl, and a substituent of the formula: R' O I II — C— C— OR" I R' wherein each R' is independently selected from the group consisting of: hydrogen and methyl, and

R" is selected from the group consisting of: alkyl of from 1 to 6 carbon atoms, alkenyl of from 2 to 6 carbon atoms, alkynyl of from 2 to 6 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, aralkyl selected from the group consisting of benzyl, methylbenzyl and phenylethyl, phenyl, and phenyl substituted with 1 to 3 substituents selected from the group consisting of hydroxy, chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms, and alkoxy of from 1 to 4 carbon atoms.

7. An occluding compound as claimed in Claim 1 in which the cyanoacrylate is mixed or mixable with plasticizers, dye or pigments and/or soluble or solid contrast agents, and a free radical stabilizer.

8. An occluding compound as claimed in Claim 6, wherein the occluding compound comprises,

(a) from about 85 to 90 weight percent of an alkyl cyanoacrylate of formula I; (b) from about 50 to 500 parts per million of a polymerization inhibitor; (c) from about 10 percent to about 15 percent by weight of a biocompatible thickener; and (d) from about 5,000 to 20,000 parts per million of a free-radical stabilizer.

9. An occluding compound as claimed in Claim 6, wherein the occluding compound comprises,

(a) from about 85 to 90 weight percent of n-butyl cyanoacrylate; (b) from about 50 to 500 parts per million of boron trifluoride (BF₃) as a polymerization inhibitor; (c) from about 10 percent to about 15 percent by weight of polymethylmethacrylate (PMMA); and (d) from about 5,000 to 20,000 parts per million of butylated hydroxyanisole as the free radical stablizer.

10. An occluding compound as claimed in Claim 1 in which the cyanoacrylate component of the occluding compound is stored in a container optionally manufactured from glass, plastic and preferably manufactured from aluminium.

11. An occluding compound as claimed in any one of Claims 5 to 10, wherein the occluding compound is sterilized by sterilizing means selected from the group consisting of gamma irradiation, E-beam, heat, and ultrafiltration.

12. An occluding compound as claimed in any one of Claims 5 to 11 having a viscosity range between lOmPas to 5,000mPas at 25°C.

13. An occluding compound as claimed in any one of Claims 5 to 12 including a thickening agent capable of inducing a fibrotic or inflammatory response.

14. An occluding compound as claimed in Claim 13 where the thickening agent is polymethylmethacrylate (PMMA).

15. A medical device for delivering an occluding compound as claimed in Claims 1 to 3 further comprising an actuator for delivering the occluding compound through the catheter.

16. A medical device as claimed in any one of Claims 1 to 3 and 15, wherein the catheter has, on its distal end, a plug for sealing the opening of the fallopian tube prior to delivery of the occluding compound.

17. A medical device as claimed Claim 16 wherein the actuator is provided at the proximal end of the catheter, to deliver an occluding compound therethrough, wherein the actuator is operable to deliver a predetermined amount of occluding compound at a predetermined speed directly through the catheter into a fallopian tube; optionally wherein the actuator is optionally provided with a handle universally adaptable to enable an operator to hold the actuator together with other instruments or devices; optionally, the actuator has a universal catheter adapter fixed or rotatably mountable upon accessory instruments and devices; and optionally, the actuator including a separate or integral mixing device for mixing the occluding compound with optional additives.

18. A medical device as claimed in Claim 17, wherein the actuator includes a plunger that compresses upon entry of the compound thereby exposing a bleed hole through which air emboli is expelled into an overflow chamber which includes a porous plug at its exit port permitting passage of air but preventing passage of the occluding compound.

19. A medical device as claimed in Claim 17, wherein the mixing device contains an initiator and is preferably selected from the group consisting of dimethyl-p- toluidine, dimethylamino-phenyl-ethanol, and combinations thereof.

20. A medical device as claimed in Claim 17, wherein the mixing device contains a radiopaque or contrast agent, which is preferably selected from the group consisting of tantalum, tantalum oxide, lipiodol, barium sulphate, silver, gold, tungsten, platinum powders, metrizamide, iopamidol, iothalamate sodium, iodomide sodium, meglumine, or combinations thereof.

21. A medical device as claimed in Claims 17, wherein the occluding compound or the mixing device contains a biocompatible dye or pigment.

22. A medical device as claimed in Claims 17 to 21 wherein the mixing device is loadable with the occluding compound or loadable with a vessel containing the occluding compound and optionally is provided with at least one chamber into which predetermined amounts of occluding compound and optional additives are separately deliverable from vessels for mixing prior to delivery into the actuator.

23. A medical device as claimed in Claim 22 wherein the mixing device comprises a a chamber preloaded with the additive and wherein the additive is expelled from the chamber by the cyanoacrylate component of the occluding compound and returns through the chamber in combination with the cyanoacrylate component occluding compound .

24. A medical device as claimed in any one of Claims 17 to 23 wherein the mixing device includes a mixing head including the chamber for storing the additive for mixing with the cyanoacrylate component of the occluding compound, the chamber preferably being in the form of a conduit.

25. A medical device as claimed in Claim 24 wherein the mixing device includes means for locking the mixing head of the mixing device in a forward position.

26. A medical device as claimed in any one of Claims 17 to 25 wherein the mixing device includes a device for counting and visually indicating when the correct number of mixing cycles has been completed, the first mixing cycle being completed when the additive in the chamber has been urged out of the chamber by the cyanoacrylate component of the occluding compound passing therethrough.

27. A medical device as claimed in any one of Claims 17 to 26 wherein the cyanoacrylate component of the occluding compound is stored in a container with a seal and the seal on the container is pierced as the mixing device is engaged with the container, prior to cyanoacrylate component being drawn into a mixing chamber in the mixing device and optionally wherein the mixing device is rotatably engaged with the container or wherein the container is pierced through with a thrusting motion.

28. A medical device as claimed in any one of Claims 18 to 27 wherein the actuator includes a leadscrew to advance the plunger in the barrel.

29. A medical device as claimed in Claim 28 wherein the leadscrew is threaded into the centre axis of a torque output drum which is in turn is rotated by a motor spring wherein the motor spring contains a storage drum and the torque output drum; the motor spring unwinding from the torque output drum to the storage drum upon activation of the device.

30. A medical device as claimed in any one of Claim 15 to 29 wherein the actuator includes a stop/start button which engages with the torque output drum.

31. A medical device as claimed in Claim 1, wherein the catheter has at its proximal end a collapsible longitudinal section.

32. A medical device as claimed in Claim 1, wherein the catheter has at its proximal end a serrated longitudinal section which acts as a ratchet to secure the catheter within the operating channel of a hysteroscopic sheath.

33. A medical device as claimed in Claim 1, wherein the catheter has at its distal end a tapered or beveled distal tip, which is preferably an oblique beveled distal tip, which distal tip acts as a locator allowing easier insertion of the catheter into the fallopian tubes.

34. A medical device as claimed in Claim 1, wherein the distal tip of the catheter has a lubricious coating which is suitable for sterilisation by sterilising means selected from the group consisting of gamma irradiation, E-beam, heat and ultrafiltration.

35. A medical device as claimed in Claim 1, wherein the distal tip of the catheter has a lubricious coating comprising polyethylene (PE) which is suitable for gamma irradiation.

36. A medical device as claimed in any one of Claims 33, 34 and 35, wherein the catheter has a detachable distal tip.

37. A medical device as claimed in Claim 1, wherein the catheter has on its distal end means for retaining an anesthetic material which is used to deliver localized anesthesia to the fallopian tube.

38. A medical device as claimed in Claim 1, wherein the catheter has a curved distal end preformed so as to aid location of the catheter in the fallopian tube.

39. A medical device as claimed in Claim 1, wherein the internal lumen of the catheter tapers at various points along its length.

40. A medical device as claimed in Claim 1, wherein the catheter has a plurality of lumens.

41. A medical device as claimed in Claim 1, wherein the catheter incorporates a screw, preferably an Archiamedian screw within a lumen.

42. A medical device as claimed in Claim 40, wherein one or more lumens exit through the sidewall of the catheter at its distal end and one or more lumen exit through the distal tip.

43. A medical device as claimed in Claim 40, wherein the catheter has an internal mixing chamber connecting the plurality of lumens.

44. A medical device as claimed in any one of Claims 1 to 4 and 15 to 43, wherein the catheter has along its length preset markers to indicate or dictate depth of insertion, preferably along at least a portion of its length an integral stiffening member and wherein preferably the stiffening member tapers from its proximal end to its distal end.

45. A medical device as claimed in Claim 44, wherein the stiffening member consists of a thickened catheter cross-section with a tapered or bumped extrusion; or a braid running along the length of the catheter or part thereof wherein the braid is optionally a spiral braid; or a stiffening wire extruded along the length of the catheter or part thereof, optionally the stiffening wire being manually loaded into the catheter prior to insertion into the fallopian tube, and wherein optionally the stiffening wire has on its distal end an anesthetic material which is used to deliver localized anesthesia to the fallopian tube prior to insertion of the catheter and wherein insertion or withdrawal of the manually loaded stiffening wire decreases or accentuates the preformed curved distal end.

46. A medical device as claimed in any one of Claims 1 to 4 and 15 to 45, wherein the catheter is transparent along at least a portion of its length.

47. A medical device as claimed in any one of Claims 1 to 4 and 15 to 47, wherein the catheter has a radiopaque or fluoroscopic mark at its distal tip for accessing its positioning and location within the fallopian tube.

48. A medical device as claimed in any one of the preceding claims, wherein the catheter has a hydrophilic coating along its length, or at its distal end to enhance its lubricity within the fallopian tube.

49. A medical device as claimed in any one of the preceding claims, wherein the catheter has various sections of diminishing circumferences along at least a portion of its length from its proximal end towards its distal end and preferably the catheter has a section of diminished circumference at its distal end only.

50. A medical device as claimed in Claim 1, wherein it comprises a primary catheter and a secondary catheter for concealing the primary catheter during insertion through the cervical canal and uterine cavity or operating channel of a hysteroscopy sheath, whereby the second catheter protects the primary catheter, and optionally where the secondary catheter has a sealed distal tip which is perforated by the primary catheter after the secondary catheter has been located at the entrance of the fallopian tube.

51. A medical device as claimed in Claim 50, wherein the secondary catheter functions as the plug for sealing the entrance of the fallopian tube prior to insertion of the primary catheter into the fallopian tube.

52. A medical device as claimed in any one of Claims 50 or 51, wherein the plug on the secondary catheter preferably comprises a foam ring or molded stop.

53. A medical device as claimed in Claim 51, wherein the secondary catheter has an oversized conical distal end tapering down to its distal tip, or has a plug in the form of an expandable balloon or membrane at its distal end or a suction cup at its distal end or a convex plate at its distal end to seal the fallopian tube during delivery of the occluding compound, which convex plate is adapted to halt and mould any backflow of occluding compound from the fallopian tube, wherein the distal tip of the secondary catheter is used to aid accurate location and depth of insertion of the primary catheter into the fallopian tube prior to and during delivery of an occluding compound.

54. A medical device as claimed in any one of Claims 50 to 53 wherein the primary and secondary catheters have corresponding indicators on their external surfaces allowing for controlled insertion and withdrawal through the alignment of the indicators by the operator.

55. A medical device as claimed in any one of Claims 50 to 54 wherein the secondary catheters distal tip acts to remove surplus occluding compound from the primary catheter on the primary catheters removal from the fallopian tube.

56. A method for transcervical delivery of an occluding compound comprising inserting a hysteroscope through the vagina, cervical canal and uterine cavity to access the interior of the uterine cavity, inserting a catheter of the medical device as claimed in any one of Claims 1 and 15 to 57 through a hysteroscopic sheath and under direct visualization into the entrance of a fallopian tube and where insertion may be aided by a guidewire or the stiffening member.

57. A method as claimed in Claim 56, wherein the occluding compound is in the form of a liquid.

58. A method of using mixing device which involves adding cyanoacrylate to a mixing barrel; advancing the mixing head which causes cyanoacrylate component of the occluding compound to push radiopaque agent from a chamber; retracting and rotating the mixing head which causes cyanoacrylate component and the radiopaque agent component to pass through the chamber; and preferably this step is repeated a predetermined number of cycles.

59. A method as claimed in Claim 58 wherein the mixing device includes a counter device for counting and visually indicating when the predetermined number of cycles has been completed.

60. A method as claimed in Claim 56, including the following steps:

(a) attaching cyanoacrylate container to mixing device, drawing cyanocrylate from container into mixing device chamber, combining cyanoacrylate with radiopaque agent and expelling compound from mixing device into an actuator chamber, (b) actuating an actuator to deliver via a catheter into a longitudinal section of the fallopian tube a precise and predetermined amount of occluding compound at a calculated and determined speed, whereby the delivery of the occluding compound results in an occlusion along a longitudinal section of the fallopian tube as the occluding compound cures to form a plug within the fallopian tube, and (c) withdrawing the catheter back out of the fallopian tube.

61. A method for transcervical delivery of an occluding compound comprising the following steps:

(a) actuating an actuator to mix and then deliver via a catheter into a longitudinal section of the fallopian tube a precise and predetermined amount of occluding compound at a calculated and determined speed, whereby the delivery of the occluding compound results in an occlusion along a longitudinal section of the fallopian tube as the occluding compound cures to form a plug within the fallopian tube; and (b) withdrawing the catheter back out of the fallopian tube as the occluding compound is delivered.

62. A method as claimed in any one of Claims 60 or 61, wherein the use of cured occluding compound results in a solid occluding plug along a longitudinal section of the fallopian tube resulting initial mechanical blockage followed by stenosis, fibrosis and collagen deposition within the fallopian tube resulting in permanent occlusion along a longitudinal section of the fallopian tube being achieved.

63. A method of manufacturing a medical device for mixing and delivering an occluding compound within a fallopian tube, the manufacturing method comprising the steps of forming a catheter with a distal end, a proximal end and a lumen extending therebetween and optionally providing a plug on the distal end of the catheter; optionally including the step of providing on the distal end of the catheter means for retaining anesthetic material whereby the tip of the catheter can store anaesthetic material which is deposited on contact with tissue, including the step of providing at the proximal end of the catheter an actuator to mix and deliver an occluding compound through the catheter, and optionally including the step of forming the external shape of the distal end of the catheter to assist with location within the fallopian tube, and optionally including the step of coating the distal tip of the catheter with a coating of polyethylene and incorporating a fluorescent marker on the distal end of the catheter. including the step of manufacturing an occluding compound incorporating a radio opaque agent.

64. A method of manufacturing a medical device for mixing and delivering an occluding compound within a fallopian tube, the manufacturing method comprising the steps of forming a catheter with a distal end, a proximal end and a lumen extending therebetween and optionally providing a plug on the distal end of the catheter; optionally including the step of providing on the distal end of the catheter means for retaining anesthetic material, including the step of providing a mixing device containing a radiopaque component which is combined and mixed with the cyanoacrylate then transferring the occluding compound to the actuator, including the step of providing at the proximal end of the catheter an actuator to deliver an occluding compound through the catheter, and optionally including the step of forming the external shape of the distal end of the catheter to assist with location within the fallopian tube, and optionally including the step of coating the distal tip of the catheter with a coating of polyethylene and incorporating a fluorescent marker on the distal end of the catheter.