[go: up one dir, main page]

WO1998017200A1 - Procede servant a traiter le reflux anormal d'urine vesicale vers les ureteres - Google Patents

Procede servant a traiter le reflux anormal d'urine vesicale vers les ureteres Download PDF

Info

Publication number
WO1998017200A1
WO1998017200A1 PCT/US1997/018120 US9718120W WO9817200A1 WO 1998017200 A1 WO1998017200 A1 WO 1998017200A1 US 9718120 W US9718120 W US 9718120W WO 9817200 A1 WO9817200 A1 WO 9817200A1
Authority
WO
WIPO (PCT)
Prior art keywords
polymer
biocompatible
composition
contrast agent
mammal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1997/018120
Other languages
English (en)
Inventor
George Wallace
Richard J. Greff
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Micro Therapeutics Inc
Original Assignee
Micro Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/734,016 external-priority patent/US5785642A/en
Priority claimed from US08/874,677 external-priority patent/US5958444A/en
Application filed by Micro Therapeutics Inc filed Critical Micro Therapeutics Inc
Priority to AU46725/97A priority Critical patent/AU4672597A/en
Publication of WO1998017200A1 publication Critical patent/WO1998017200A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/0004—Closure means for urethra or rectum, i.e. anti-incontinence devices or support slings against pelvic prolapse
    • A61F2/0031—Closure means for urethra or rectum, i.e. anti-incontinence devices or support slings against pelvic prolapse for constricting the lumen; Support slings for the urethra
    • A61F2/0036—Closure means for urethra or rectum, i.e. anti-incontinence devices or support slings against pelvic prolapse for constricting the lumen; Support slings for the urethra implantable
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • This invention is directed to methods for treating vesicoureteral reflux in mammals generally and humans in particular.
  • a composition comprising a biocompatible polymer, a biocompatible solvent, and a contrast agent is delivered to the subureteral region of a mammal.
  • the biocompatible polymer is selected to be soluble in the biocompatible solvent, but insoluble in fluids of the subureteral regicn.
  • the biocompatible solvent is miscible/ soluble in the fluids of this tissue and, upon contact with such fluids, the biocompatible solvent quickly diffuses away whereupon the biocompatible polymer precipitates to form an occlusion or implant in the subureteral region which compresses the ureter thereby increasing resistance to retrograde urine flow into the ureter from the bladder.
  • Vesicoureteral reflux is a condition wherein urine moves from the bladder into the ureters and sometimes the renal pelvis during voiding or with elevated pressure in the bladder. Vesicoureteral reflux is common in children with anatomic abnormalities of the urinary tract, however, it also occurs in children with anatomically normal but infected urinary tracts.
  • the junction of the terminal ureter with the urinary bladder provides a competent sphincter so that during micturition urine leaves the bladder only via the urethra. Reflux occurs when there is inadequate intravesical sub mucosal tunnel (valve mechanism) or defective attachment of the ureter to the bladder.
  • valve mechanism intravesical sub mucosal tunnel
  • an anatomically impaired vesicoureteral junction facilitates reflux of urine and bacteria into the ureters and results in upper tract infection and renal damage.
  • the initial treatment of vesicoureteral reflux usually consists of suppressive antibiotics in anticipation of spontaneous resolution.
  • reflux of minor degree may disappear with standard treatment for intercurrent urinary infection, i.e., antibiotics.
  • surgical correction is usually necessary for more severe degrees of reflux and minor reflux unresponsive to antibiotics.
  • open surgical repair has a well recognized morbidity, which consists of pain and immobilization of a lower abdominal incision, as well as the attendant risks of surgery in general, e.g. , anesthesia.
  • Endoscopic subureteral injection is a simple procedure in which a substance is injected into the subureteral region, usually on an outpatient basis.
  • the injected substance implants in the subureteral region and enhances its bulk.
  • the enhanced bulk of the subureteral region narrows the ureteral orifice 5 thereby inhibiting retrograde urine flow.
  • the ideal injected substance used as an implant material should be non-migratory, conserve its volume, be non-antigenic and be able to be delivered e ⁇ doscopically.
  • endoscopic subureteral injection of various substances has had varying results. For example, polytetrafluorethyiene (TeflonTM) was one of the first substances utilized.
  • TeflonTM induces a granulomatous reaction and is capable of migration to distant areas such as the pelvic lymph nodes, spleen, lungs and brain.
  • Another substance that has been utilized is glutaraldehyde cross-Linked bovine dermal collagen 4 - 5,9 .
  • the major problem with the use of collagen in the treatment of reflux is that the implant is biodegradable and, hence, volume size of the implant decreases with time. Tnis has made re-treatment necessary. Collagen is also quite viscous and therefore difficult to inject.
  • chondrocyte-alginate suspension Another injectable substance that has been used for the treatment of vesicoureteral reflux is a chondrocyte-alginate suspension.
  • 3,6 ' 3 Cho ⁇ drocytes cells capable of synthesizing cartilage, were harvested from animals, mixed with alginate to form a gel that was subsequently injected into the subureteral region of the animal. Although encouraging results have been seen, use of this suspension requires a biopsy in order to harvest the cho ⁇ drocytes with the patient having to return at a later date to undergo treatment with the autologous chondrocyte-alginate suspension.
  • injectable substances have been reported or proposed as implant materials for the treatment of bladder conditions, such as vesicoureteral reflux. These substances include polyvinyl alcohol foam, 17 glass particles, 18 and a detachable silicone balloon. 2
  • the present invention is directed to the discover/ that vesicoureteral reflux can be treated in mammals by injecting sufficient amounts of a composition comprising a biocompatible water insoluble polymer and a biocompatible solvent to the subureteral region under conditions such that a polymer precipitate forms in situ in the subureteral region. Tnis polymer precipitate forms an implant which compresses the ureter opening thereby increasing resistance to retrograde urine flow into the ureters during voiding and decreasing reflux in the mammal.
  • the polymeric compositions of this invention are non-biodegradable and, accordingly, do not substantially decrease in volume over time.
  • the injection process provides for a coherent implant mass, not particulates, which mass is non-migratory.
  • a contrast agent is employed in the composition to permit monitoring of the injection by conventional methods, e.g., fluoroscopy, to ensure proper placement.
  • this contrast agent becomes incorporated in the precipitate (implant) formed in situ thereby allowing post-injection monitoring of the implant by conventional methods to ensure correct retention of the implant months or even years after injection.
  • Conventional monitoring methods include, by way of example, fiuoroscopy, ultrasound, and in some cases visual detection.
  • This invention is directed to the discovery that unexpected and surprising results are achieved when mammals with vesicoureteral reflux are treated with a composition comprising a biocompatible water insoluble polymer and a biocompatible solvent.
  • deficiencies associated with the prior art procedures are reduced by the invention.
  • Such deficiencies include, for example, problems associated with migration of pa ⁇ iculates over time and the biodegradation of the injected mass (e.g., collagen type materials) employed to form an occlusion in the periurethral tissue of the mammal.
  • this invention is directed to a method for treating vesicoureteral reflux in a mammal, which method comprises delivering a composition comprising a water insoluble biocompatible polymer and a biocompatible solvent to the subureteral region of the mammal wherein said delivery is conducted under conditions such that a polymer precipitate forms in situ in the subureteral region thereby reducing the vesicoureteral reflux in the mammal.
  • the composition further comprises a contrast agent which then permits monitoring the accurate delivery of such compositions to the subureteral region.
  • the contrast agent is a water insoluble agent
  • post-delivery monitoring of the implant in the patient can be conducted for months, years after injection.
  • this invention is directed to a method for treating vesicoureteral reflux in a mammal, which method comprises delivering a composition comprising a water insoluble biocompatible polymer, a contrast agent and a biocompatible solvent to the subureteral region of the mammal wherein said delivery is conducted under conditions such that a polymer precipitate forms in situ in the subureteral region thereby reducing the vesicoureteral reflux in the mammal.
  • the contrast agent is a water insoluble contrast agent.
  • this invention is directed to a method for the delivery of a composition comprising a biocompatible polymer, a biocompatible solvent, and a water insoluble contrast agent to the subureteral tissue of the mammal which tissue already has deposited therein with an initial amount of this composition which method comprises visualizing the position of the deposited composition in the subureteral tissue delivering a composition comprising a biocompatible polymer, a biocompatible solvent, and a contrast agent to the subureteral tissue of the mammal containing said deposited composition wherein said delivery is conducted under conditions such that additional polymer precipitate forms in situ in the subureteral tissue thereby further reducing vesicoureteral reflux in the mammal.
  • the biocompatibie polymer is preferably an ethylene vinyl alcohol copolymer or a cellulose re 3te polymer.
  • the biocompatible polymer is selected to be substantially non-immunogenic.
  • the biocompatible solvent is preferably dimethylsulfoxide and, more preferably, anhydrous dimethylsulfoxide.
  • This invention is directed to methods for treating vesicoureteral reflux in mammals, which methods comprise delivering a composition comprising a water insoluble biocompatibie polymer and a biocompatible solvent to the subureteral region of the mammal.
  • vesicoureteral reflux refers to the retrograde movement of urine through the ureter from the bladder during voiding or with elevated pressure in the bladder.
  • Methods for diagnosing vesicoureteral reflux are well known to those skilled in the relevant art. Such methods included, for example, intravenous pyelography, voiding cystourethrography and the like.
  • subureteral region and “subureteral tissue” refer to the tissue surrounding the junction of the ureter with the bladder.
  • the ureter is an orifice attached at its base to the bladder and permits discharge of urine into the bladder from the kidneys.
  • the polymeric compositions of the present invention are delivered to the subureteral region at or near the base of the ureter in the submucosal plane.
  • water insoluble biocompatible polymer refers to polymers which, in the amounts employed, are not appreciably soluble in water (solubility of less than 0.1 mg/mL in water at 20°C), non-toxic, non-peptidyl, non-migratory, chemically inert, and substantially non-immunogenic when used internally in the mammal and which are substantially insoluble in the -subureteral region.
  • the biocompatible polymers do not substantially decrease in volume over time and, since the polymer forms a solid inert mass, it does not migrate to distant organs within the body.
  • Suitable biocompatible polymers include, by way of example, cellulose acetates 1 ⁇ 12 (including cellulose diacetate 13 ), ethylene vinyl alcohol copolymers 14,15 , polyalky - ) acrylates, polyalkyl alkacryiates wherein the alkyl and the alk groups contain no more than 6 carbon atoms, polyacrylonitrile and the like. Additional biocompatible polymers are disclosed in U.S. Patent Application Serial No. 08/655,822 entitled “Novel Compositions for Use in Embolizing Blood Vessels" which application is incorporated herein by reference in its entirety. Further examples of biocompatible polymers are provided by Park, et al. 16 Preferably, the biocompatible polymer is also non-inflammatory when employed in vivo.
  • biocompatible polymer employed is not critical and is selected relative to the viscosity of the resulting polymer solution, the solubility of the biocompatible polymer in the biocompatible solvent, and the like. Such factors are well within the skill of the artisan.
  • the biocompatible polymers do not appreciably absorb water upon contact with the fluid of the subureteral region and typically will have an equilibrium water content of less than about 25% water and preferably less than about 15% water.
  • biocompatible polymers include cellulose diacetate and ethylene vinyl alcohol copolymer.
  • Cellulose diacetate polymers are either commercially available or can be prepared by art-recognized procedures.
  • the number average molecular weight, as determined by g ⁇ l permeation ⁇ chromatography, of the cellulose diacetate composition is from about 25,000 to about 100,000; more preferably from about 50,000 to about 75,000; and still more preferably from about 58,000 to 64,000.
  • the weight average molecular weight of the cellulose diacetate composition, as determined by gel permeation chromatography is preferably from about 50,000 to 200,000 and more preferably from about 100,000 to about 180,000.
  • cellulose diacetate polymers having a lower molecular weight will impart a lower viscosity to the composition as compared to higher molecular weight polymers. Accordingly, adjustment of the viscosity of the composition can be readily achieved by mere adjustment of the molecular weight of the polymer composition.
  • Ethylene vinyl alcohol copolymers comprise residues of both ethylene and vinyl alcohol monomers. Small amounts (e.g., less than 5 mole percent) of additional monomers can be included in the polymer structure or grafted thereon provided such additional monomers do not alter the occlusion-forming properties of the composition.
  • additional monomers include, by way of example only, maleic anhydride, styrene, propylene, acrylic acid, vinyl acetate, and the like.
  • Ethylene vinyl alcohol copolymers are either commercially available or can be prepared by art-recognized procedures.
  • the ethylene vinyl alcohol copolymer composition is selected such that a solution of 6 weight percent of the ethylene vinyl alcohol copolymer, 35 weight percent of a tantalum contrast agent in DMSO has a viscosity equal to or less than 60 centipoise at 20 °C.
  • copolymers having a lower molecular weight will impart a lower viscosity to the composition as compared to higher molecular weight copolymers. Accordingly, adjustment of the viscosity of the composition as necessary for catheter or needle delivery can be readily achieved by mere adjustment of the molecular weight of the copolymer composition.
  • the ratio of ethylene to vinyl alcohol in the copolymer affects the overall hydrophobicity/hydrophiliciry of the composition which, in turn, affects the relative solubility of the composition in the biocompatible solvent as well as the rate of precipitation of the copolymer in an aqueous solution (e.g. , plasma).
  • the copolymers employed herein comprise a mole percent of ethylene of from about 25 to about 60 and a mole percent of vinyl alcohol of from about 40 to about 75. More preferably, these copolymers comprise from about 40 to about 60 mole percent of vinyl alcohol and from about 60 to 40 mole percent of ethylene.
  • contrast agent refers to a biocompatible (non-toxic) radiopaque material capable of being monitored during injection into a mammalian subject by, for example, radiography.
  • the contrast agent can be either water soluble or water insoluble.
  • water soluble contrast agents include metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and megiumine.
  • water insoluble contrast agents include tantalum, tantalum oxide, and barium sulfate, each of which is commercially available in 7200
  • water insoluble contrast agents include gold, tungsten, and platinum powders.
  • the contrast agent is water insoluble (i.e., has a water solubility of less than 0.01 mg ml at 20 °C).
  • biocompatibie solvent refers to an organic material liquid at least at body temperature of the mammal in which the biocompatible polymer is soluble and, in the amounts used, is substantially non-toxic.
  • suitable biocompatible solvents include, by way of example, dimethylsulfoxide, analogues/homologues of dimethylsulfoxide, ethanol, acetone, and the like.
  • Aqueous mixtures with the biocompatible solvent can also be employed provided that the amount of water employed is sufficiently small that the dissolved polymer precipitates upon contact with the subureteral region.
  • the biocompatible solvent is dimethylsulfoxide. More preferably, the biocompatible solvent is anhydrous dimethylsulfoxide.
  • the polymer employed in the methods of this invention are prepared by conventional methods whereby each of the components is added and the resulting composition mixed together until the overall composition is substantially homogeneous.
  • polymer compositions can be prepared by adding sufficient amounts of the biocompatible polymer to the biocompatible solvent to achieve the effective concentration for the polymer composition.
  • the polymer composition will comprise from about 2.5 to about 8.0 weight percent of the biocompatible polymer based on the total weight of the polymer composition, including contrast agent and biocompatibie solvent, and more preferably from about 4 to about 5.2 weight percent.
  • gentie heating and stirring can be used to effect dissolution of the biocompatible polymer into the biocompatibie solvent, e.g., 12 hours at 50 °C.
  • the polymer composition will comprise from about 10 to about 40 weight percent of the contrast agent and more preferably from about 20 to about 40 weight percent and even more preferably about 35 weight percent each based on the total weight of the polymer composition including the biocompatible polymer and the biocompatible solvent.
  • stirring is employed to effect homogeneity of the resulting suspension.
  • the particle size of the contrast agent is preferably maintained at about 10 ⁇ m or less and more preferably at from about 1 to about 5 ⁇ m (e.g., an average size of about 2 ⁇ ).
  • the particle sizs of a water insoluble contrast agent is prepared, for example, by fractionation.
  • a water insoluble contrast agent such as tantalum having a particle size of less than about 20 microns is added to an organic liquid such as ethanol (absolute) preferably in a clean environment. Agitation of the resulting suspension followed by settling for approximately 40 seconds permits the larger particles to settle faster. Removal of the upper portion of the organic liquid followed by separation of the liquid from the particles results in a reduction of the particle size which is confirmed under a microscope. The process is optionally repeated until a desired particle size is reached.
  • the particular order of addition of components to the biocompatible solvent is not critical and stirring of the resulting suspension is conducted as ⁇ ecessary to achieve homogeneity of the composition.
  • ⁇ iixmg/stirri ⁇ g of the composition is conducted under an anhydrous atmosphere at ambient pressure.
  • the resulting composition may be heat sterilized and then stored preferably in sealed bottles (e.g., amber vials) or vials until needed.
  • compositions described above are then employed in methods for treating vesicoureteral reflux in mammals.
  • the composition is introduced to the subureteral region via conventional catheter or needle technology using, for example, cystoscopic techniques employing, e.g., cystoscopes and ureteralscopes.
  • cystoscopic techniques employing, e.g., cystoscopes and ureteralscopes.
  • the injection may be performed through a puncture needle or cannuia placed directly through the cystoscope or subureterally to the tissue adjacent to the ureter.
  • the subureteral region can be exposed surgically and the composition injected directly into the tissue.
  • the viscosity of the formulation is preferably 30 to 100 centipoise at
  • the biocompatible solvent Upon discharge of the composition from the catheter or the needle into the subureteral region, the biocompatible solvent dissipates into the fluid or surrounding tissue of the subureteral region resulting in the precipitation of the water insoluble biocompatible polymer which precipitate forms a coherent mass.
  • the coherent mass includes both the contrast agent and the water insoluble biocompatibie polymer which form an integral coherent precipitate which does not separate into individual components.
  • the formed precipitate in the subureteral region sweQs (bulks) this tissue restricting the ureter orifice thus impeding the retrograde flow of urine from the bladder into the ureter.
  • the particular amount of polymer composition employed is dictated by the level of pre-existing support of the subureteral region, the concentration of polymer in the composition, the rate of precipitation (solids formation) of the polymer, etc.. Such factors are well within the skill of the artisan. For " example, individuals with weak pre-existing suppo ⁇ of the subureteral region will require injection of more polymer composition in order to bulk up this tissue and constrict the ureter as compared to individuals with stronger preexisting support.
  • the methods of this invention are particularly advantageous when a contrast agent is incorporated into the composition because this contrast agent permits, if desired, monitoring of the delivery of the biocompatible polymer while it is taking place either by fluoroscopv, ultrasound, or visually. In this way, one can ensure that the biocompatible polymer is being delivered to the optimal location in the subureteral region.
  • the contrast agent when the contrast agent is water insoluble, the contrast agent will be incorporated into the resulting precipitate (implant) which permits monitoring the size of the polymer precipitate thus-formed to ensure that it will be sufficient to block the retrograde flow of urine from the bladder into the ureter and which further permits post-injection monitoring of the implant.
  • the treatment process can be modified by altering the rate of precipitation of the polymer which can be controlled merely by changing the overall hydrophobicity/hydrophilicity of the polymer. As is understood in the art, faster precipitation rates are achieved by a more hydrophobic polymer composition.
  • the catheter employed is not critical provided that polymeric catheter components are compatible with the polymeric composition (i.e., the catheter components will not readily degrade in the polymer composition and none of the components of the polymer compositions will readily degrade in the presence of the catheter components).
  • polyethylene in the catheter components because of its inertness in the presence of the polymeric composition described herein.
  • Other materials compatible with the composition can be readily determined by the skilled artisan and include, for example, other polyolefins, fluoropolymers (e.g. , polytetrafluoroethylene, perfluoroalkoxy resin, fluorinated ethylene propylene polymers), silicone, etc.
  • the biocompatible solvent When introduced into the subureteral region, the biocompatible solvent rapidly diffuses into the fluids of this tissue leaving a solid precipitate.
  • the precipitate is a coherent mass comprising the water insoluble biocompatible polymer and, when employed, the water insoluble contrast agent. Without being limited to any theory, it is believed that this precipitate bulks up the subureteral region thereby increasing outlet resistance to urinary flow from the bladder. This enhanced outlet resistance reduces the vesicoureteral reflux in the treated mammal.
  • Another advantage of this invention is that the precipitate forms a coherent mass which is substantially retained at the site of injection thereby obviaring prior art concerns with migration of injected particulates into the subureteral region.
  • the polymeric compositions of this invention are non-biodegradable and, accordingly, do not substantially decrease in volume over time.
  • Still another advantage of this invention is that the polymer employed can be selected to be non-immunoge ⁇ ic thereby obviating concerns raised by use of collagen-type materials which can produce an immune response in vivo.
  • Yet another advantage of a preferred aspect of this invention is the formation of a polymeric mass in the subureteral region which mass contains a water insoluble contrast agent that permits the physician to monitor the implant over time to assure proper retention of the mass in the tissue. Additionally, if a subsequent injection is necessary to further reduce vesicoureteral reflux in the mammal, placement of the additional polymeric material is facilitated when the material previously implanted can be visualized by, for example, fluoroscopy, ultrasound, and the like. A subsequent injection can occur at any time after the initial injection including, for example, months or years later.
  • the methods described herein are useful in treating mammals with vesicoureteral reflux. Accordingly, these methods find use in human and other mammalian subjects requiring such treatment.
  • Examples 1-2 illustrate the preparation of polymer compositions useful in the methods described herein which polymer compositions comprise EVOH and cellulose acetate.
  • Example 3 demonstrates how the methods of this invention would be employed in vivo.
  • EXAMPLE 1 An EVOH polymer composition was prepared by combining 8 grams of EVOH (44 mole percent ethylene), 30 grams of ta ⁇ taium having an average particle size of less than 10 ⁇ m (narrow size distribution), and 100 mL of anhydrous DMSO. Heating at about 50 "C for about 12 hours was used to aid dissolution. The composition was mixed until homogeneous.
  • Ta ⁇ taium having an average particle size of less than 10 ⁇ m was prepared by fractio ⁇ ation wherein ta ⁇ taium, having an average particle size of less than about 20 ⁇ m, was added to ethanol (absolute) in a clean environment. Agitation of the resulting suspension was followed by settling for approximately 40 seconds to permit the larger particles to settle faster. Removal of the upper portion of the ethanol followed by separation of the liquid from the particles results in a reduction of the particle size which, is confirmed under a microscope (Nikon AlphaphotTM). The process was repeated, as necessary, until an average 3 ⁇ m particle size was reached.
  • a cellulose diacetate polymer composition is prepared by combining 8 grams of cellulose acetate (39.7 weight percent acetyl content), 30 grams of tantalum having an average particle size of less than about 10 ⁇ m (narrow size distribution), and 100 mL of DMSO. The composition is mixed until homogeneous. Tantalum having an average particle size of about 3 ⁇ m (narrow size distribution) is prepared by fractionation as described in Example 1.
  • EXAMPLE 3 The following example illustrates how the methods of this invention could be practiced in vivo on a mammal.
  • a mini-pig is selected for illustration because of similarities between porcine and human bladders and kidneys, and its small body size.
  • the animal is anesthetized with ketamine (25 mg kg) and acepromazine (1 mg/kg) given intramuscuiarly. Additional anesthesia is with ketamine (25 mg/kg) and xylazine (10 mg kg) given intramuscularly.
  • Cystograms and an r P are done preoperativeiy. With the animal in the supine position, a 15.5 Fr cystoscope is introduced into the bladder. A 22 gage needle is passed through the scope and is inserted into the suburetheral region of the left refluxing ureter. Approximately 1 to 2 mL of the composition from Example 1 above is slowly injected by hand through the needle, while lifting the ureteral orifice, under endoscopic visualization. It is advisable to wait several seconds after injection is complete before needle removal to prevent spillage of any of the composition. The ureter orifice may take on a crescent appearance after the injection. The right refluxing ureter is left untreated as a control. A cystogram, sonography (and P/P) are performed after two to three months to confirm lack of reflux in the treated ureter. Exact tissue placement of the composition is determined and monitored by conventional fluoroscopv.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne des procédés servant à traiter le reflux anormal d'urine vésicale vers les uretères chez un mammifère et consistant à administrer au tissu sub-urétéral de ce mammifère une composition contenant un polymère biocompatible soluble dans l'eau et un solvant biocompatible.
PCT/US1997/018120 1996-10-18 1997-10-08 Procede servant a traiter le reflux anormal d'urine vesicale vers les ureteres Ceased WO1998017200A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46725/97A AU4672597A (en) 1996-10-18 1997-10-08 Method for treating urinary reflux

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/734,016 US5785642A (en) 1996-10-18 1996-10-18 Methods for treating urinary incontinence in mammals
US08/734,016 1996-10-18
US08/874,677 US5958444A (en) 1997-06-13 1997-06-13 Method for treating urinary reflux
US08/874,677 1997-06-13

Publications (1)

Publication Number Publication Date
WO1998017200A1 true WO1998017200A1 (fr) 1998-04-30

Family

ID=27112662

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/018120 Ceased WO1998017200A1 (fr) 1996-10-18 1997-10-08 Procede servant a traiter le reflux anormal d'urine vesicale vers les ureteres

Country Status (2)

Country Link
AU (1) AU4672597A (fr)
WO (1) WO1998017200A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6234955B1 (en) 1998-12-11 2001-05-22 Enteric Medical Technologies, Inc. Method for vascular occulusive therapy in gastrointestinal system
US6251064B1 (en) 1998-12-11 2001-06-26 Enteric Medical Technologies, Inc. Method for creating valve-like mechanism in natural body passageway
US6358197B1 (en) 1999-08-13 2002-03-19 Enteric Medical Technologies, Inc. Apparatus for forming implants in gastrointestinal tract and kit for use therewith
US6540789B1 (en) 2000-06-15 2003-04-01 Scimed Life Systems, Inc. Method for treating morbid obesity
US6595910B2 (en) 1998-12-11 2003-07-22 Scimed Life Systems, Inc. Method for treating fecal incontinence
US6652883B2 (en) 2000-03-13 2003-11-25 Biocure, Inc. Tissue bulking and coating compositions
US6676971B2 (en) 2000-03-13 2004-01-13 Biocure, Inc. Embolic compositions
AU2004201529B2 (en) * 1998-12-11 2008-01-10 Boston Scientific Limited Method for treating gastrointestinal tract
US8177707B2 (en) 1998-12-11 2012-05-15 Boston Scientific Scimed, Inc. Method for treating tissue with an implant
US9232805B2 (en) 2010-06-29 2016-01-12 Biocure, Inc. In-situ forming hydrogel wound dressings containing antimicrobial agents

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5007940A (en) * 1989-06-09 1991-04-16 American Medical Systems, Inc. Injectable polymeric bodies
US5336263A (en) * 1992-04-06 1994-08-09 Robert A. Ersek Treatment of urological and gastric fluid reflux disorders by injection of mmicro particles
US5580568A (en) * 1995-07-27 1996-12-03 Micro Therapeutics, Inc. Cellulose diacetate compositions for use in embolizing blood vessels

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5007940A (en) * 1989-06-09 1991-04-16 American Medical Systems, Inc. Injectable polymeric bodies
US5336263A (en) * 1992-04-06 1994-08-09 Robert A. Ersek Treatment of urological and gastric fluid reflux disorders by injection of mmicro particles
US5580568A (en) * 1995-07-27 1996-12-03 Micro Therapeutics, Inc. Cellulose diacetate compositions for use in embolizing blood vessels

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. NEUROSURG., Volume 77, October 1992, KAZUSHI K. et al., "Direct Thrombosis of Aneurysms with Cellulose Acetate Polymer, Part II: Preliminary Clinical Experience", pages 501-507. *

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7249601B2 (en) 1998-12-11 2007-07-31 Scimed Life Systems, Inc. Method for vascular occlusive therapy
US7316645B2 (en) 1998-12-11 2008-01-08 Scimed Life Systems, Inc. Method for treating gastroesophageal reflux disease
US6248058B1 (en) 1998-12-11 2001-06-19 Enteric Medical Technologies, Inc. Method for treating tracheo-esophageal fistulas
US6251064B1 (en) 1998-12-11 2001-06-26 Enteric Medical Technologies, Inc. Method for creating valve-like mechanism in natural body passageway
US6251063B1 (en) 1998-12-11 2001-06-26 Enteric Medical Technologies, Inc. Method for treating wall forming gastrointestinal tract
AU2004201529B2 (en) * 1998-12-11 2008-01-10 Boston Scientific Limited Method for treating gastrointestinal tract
US6530878B2 (en) 1998-12-11 2003-03-11 Scimed Life Systems, Inc. Method for vascular occlusive therapy
US6533717B2 (en) 1998-12-11 2003-03-18 Scimed Life Systems, Inc. Method for treating fecal incontinence
US8882654B2 (en) 1998-12-11 2014-11-11 Boston Scientific Scimed, Inc. Method for treating fecal incontinence
US6575896B2 (en) 1998-12-11 2003-06-10 Scimed Life Systems, Inc. Method for treating tissue and apparatus for use therewith
US6595910B2 (en) 1998-12-11 2003-07-22 Scimed Life Systems, Inc. Method for treating fecal incontinence
US6595909B2 (en) 1998-12-11 2003-07-22 Scimed Life Systems, Inc. Method for treating tissue with an implant
US8177707B2 (en) 1998-12-11 2012-05-15 Boston Scientific Scimed, Inc. Method for treating tissue with an implant
US7771347B2 (en) 1998-12-11 2010-08-10 Boston Scientific Scimed, Inc. Method for treating tissue with an implant
US7704203B2 (en) 1998-12-11 2010-04-27 Boston Scientific Scimed, Inc. Kit for treating gastrointestinal tract
US7318801B2 (en) 1998-12-11 2008-01-15 Scimed Life Systems, Inc. Method for treating fecal incontinence
US6234955B1 (en) 1998-12-11 2001-05-22 Enteric Medical Technologies, Inc. Method for vascular occulusive therapy in gastrointestinal system
US7056277B2 (en) 1998-12-11 2006-06-06 Scimed Life Systems, Inc. Method for treating tissue with an implant
US6238335B1 (en) 1998-12-11 2001-05-29 Enteric Medical Technologies, Inc. Method for treating gastroesophageal reflux disease and apparatus for use therewith
US6358197B1 (en) 1999-08-13 2002-03-19 Enteric Medical Technologies, Inc. Apparatus for forming implants in gastrointestinal tract and kit for use therewith
US7846085B2 (en) 1999-08-13 2010-12-07 Boston Scientific Scimed, Inc. Kit for forming implants in wall of gastrointestinal tract
US6695764B2 (en) 1999-08-13 2004-02-24 Scimed Life Systems, Inc. Apparatus for treating wall of body cavity
US8221735B2 (en) 2000-03-13 2012-07-17 Biocure, Inc. Embolic compositions
USRE48302E1 (en) 2000-03-13 2020-11-10 Biocure, Inc. Embolic compositions
USRE47873E1 (en) 2000-03-13 2020-02-25 Biocompatibles Uk Limited Embolic compositions
US6676971B2 (en) 2000-03-13 2004-01-13 Biocure, Inc. Embolic compositions
USRE47121E1 (en) 2000-03-13 2018-11-13 Biocure, Inc. Embolic compositions
US6652883B2 (en) 2000-03-13 2003-11-25 Biocure, Inc. Tissue bulking and coating compositions
US7691152B2 (en) 2000-06-15 2010-04-06 Boston Scientific Scimed, Inc. Method for treating morbid obesity
US6802868B2 (en) 2000-06-15 2004-10-12 Scimed Life Systems, Inc. Method for treating morbid obesity
US8591598B2 (en) 2000-06-15 2013-11-26 Boston Scientific Scimed, Inc. Method for treating morbid obesity
US6540789B1 (en) 2000-06-15 2003-04-01 Scimed Life Systems, Inc. Method for treating morbid obesity
US8968177B2 (en) 2000-06-15 2015-03-03 Boston Scientific Scimed, Inc. Method for treating morbid obesity
US7044979B2 (en) 2000-06-15 2006-05-16 Scimed Life Systems, Inc. Method for treating morbid obesity
US7364591B2 (en) 2000-06-15 2008-04-29 Scimed Life Systems, Inc. Method for treating morbid obesity
US8048170B2 (en) 2000-06-15 2011-11-01 Boston Scientific Scimed, Inc. Method for treating morbid obesity
US9232805B2 (en) 2010-06-29 2016-01-12 Biocure, Inc. In-situ forming hydrogel wound dressings containing antimicrobial agents

Also Published As

Publication number Publication date
AU4672597A (en) 1998-05-15

Similar Documents

Publication Publication Date Title
US5958444A (en) Method for treating urinary reflux
US5755658A (en) Methods for treating urinary incontinence in mammals
US6756031B2 (en) Compositions for use in embolizing blood vessels
US6555104B2 (en) Methods for treating urinary incontinence in mammals
US5989580A (en) Methods for sterilizing female mammals
WO2000071170A9 (fr) Nouvelles compositions d'embolisation de grande viscosite
JP2002539856A (ja) 腹部大動脈動脈瘤の血管内修復の際の内部漏出の治療方法
CA2254848C (fr) Procedes de sterilisation de mammiferes males
WO1998017200A1 (fr) Procede servant a traiter le reflux anormal d'urine vesicale vers les ureteres
JP2004147916A (ja) 血管塞栓材料
EP0904089B1 (fr) Sterilisation de mammiferes femelles
CA2254958C (fr) Procede de sterilisation de mammiferes femelles

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
CFP Corrected version of a pamphlet front page

Free format text: ADD INID NUMBER (63) "RELATED BY CONTINUATION (CON) OR CONTINUATION-IN-PART (CIP) TO EARLIER APPLICATION" WHICH WAS INADVERTENTLY OMITTED FROM THE FRONT PAGE

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA