Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
  • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

• the invention is directed to a system for the controlled and sustained delivery of therapeutic agents to the human bladder.
• the drug doxorubicin is instilled directly into the bladder.
• a mycobacterium Bacillus Calmette-Guerin, is also administered intravesically for treatment of carcinoma located in the bladder.
• DMSO is instilled intravesically to provide symptomatic relief.
• the anticholinergic drug oxybutynin chloride has been reported to have been used.
• a sustained or controlled delivery device that is capable of delivery of the drug for an extended period of time, preferably one week or longer, with the device biodegrading or bioeroding over time to clear the bladder .
• the invention provides a bioerodible, sustained- release preparation for placement into the bladder through the urethra.
• the preparation may have a specific gravity less than or equal to that of the specific gravity range of human urine.
• the preparation comprises a pharmaceutically active ingredient and at least one bioerodible, pharmaceutically acceptable carrier, which is capable of sustaining delivery of the active ingredient within the bladder and is bioerodible and excretable without blockage of the urinary tract.
• Fig. 1 shows a preferred device according to the invention comprising a reservoir with a backing material
• Fig. 2 shows a preferred device according to the invention comprising a reservoir with an adhesive coating
• Fig. 3 shows an embodiment or device of the invention comprising a randomly oriented filament network
• Fig. 4 shows an expanded view of one end of a filament, showing a segmented structure
• Fig. 5 shows a preferred device according to the invention comprising a filament network having multiple segments which form a spherical cage.
• Fig. 6 shows the rate of release of oxybutynin from a gel-in-place system in simulated urine solutions at pH 5.7 , 6.2 and 6.7.
• Fig. 7 shows the rate of release of oxybutynin from two gels of different surface areas.
• Fig. 8 shows the rate of release of oxybutynin from two gels having concentration of 3% and 1% oxybutynin.
• Fig. 9 shows the rate of release of oxybutynin from gels having 3%, 6.25%, 12.5% and no oleic acid as a release rate modifier.
• a bioerodible carrier according to the present invention means a carrier which is readily dissolved, eroded, or is subject to degradation in the bladder.
• the carrier material according to the present invention does not substantially decompose, disperse, disintegrate or dissolve in the bladder until most of the drug has been released.
• portions of the device will decompose, disperse, disintegrate or dissolve in a controlled manner so as to provide a controlled release of the drug contained in the decomposing portions.
• Many carrier materials which are suitable for these embodiments are natural products, such as keratin, salol, triglycerides, fatty acids, lipids, latexes, as well as derivatives of natural products such as modified collagens, modified gelatins, regenerated proteins, celluloses, cellulose derivatives, salts of cellulose derivatives, alkaline or alkaline earth salts of cellulose acetate phthalate, ammonium salts of hydroxypropyl methyl cellulose phthalate, polysaccharides, synthetic polymers, such as, polyglycolic acid and derivatives of polyethylene glycol, polycaprolactone, polylactic acid, and copolymers thereof; materials such as starch, fatty alcohols, alginate polymers, albumin, calcium caseinate, calcium polypectate or gellan gum.
• the carrier for the active ingredient may made by any number of methods known in the art for forming materials which contain medicaments.
• a filament can be made with a centrifugal extrusion device or by coextrusion.
• the filament texture is preferably a porous, open cell foam. Filaments may also be made by interfacial polymerization processes, known in the art, for example, for the manufacture of nylon.
• the filament may be formed into random or regular coils, hoops, spheres, and the like.
• Production by extrusion also enables the changing of the amount of the drug contained in the filament along the length of the filament, thereby allowing control of the dosage delivered in the bladder.
• Extrusion also enables the containment of the drug in one portion of the filament and the use of one or more additional drugs or an alternate formulation of the same drug, in other portions of the filament for the same purpose.
• the filament may contain two or more incompatible drugs in spatially distinct portions of the filament.
• the drugs may also be encapsulated in the carrier.
• the time release of the drug may be controlled by diffusion from the carrier and/or erosion of the carrier, which simultaneously releases the drug.
• the bioerosion mechanism may be controlled by serially degrading segments of a filament. This may be accomplished, for example, by providing an outer layer of slowly bioerodible material with a core of rapidly bioerodible material containing the drug. Thus the exposed ends of the core will preferentially bioerode . At various points along the filament, weakened portions may be provided by which an outer layer may be detached once the core has been bioeroded, thereby causing the filament to be eroded in segments starting from the exposed ends .
• the carrier materials may be formed in the desired shape or formed into sheets and cut into the appropriate form.
• the carrier material will be typically one of two types.
• One type bioerodes rather uniformly over time, so that the bioerosion of the carrier is also the primary mechanism for releasing the drug into the bladder.
• the second type is a material which essentially remains intact during a substantial portion of the release period of the drug.
• the mechanism of release of the drug is by diffusion or other mechanism which does not require the carrier to be concurrently bioeroded. However, in such cases, shortly after the drug has been depleted from the carrier, erosion should proceed in order to avoid the necessity of removing the device from the bladder.
• the sustained delivery of the drug into the bladder will be for an extended period, longer than about three days and preferably, at least about one week.
• the drug be delivered over a period up to about one month.
• the carrier materials, containing or impregnated with the drug may have a specific gravity less than or equal to that of urine, which is normally about 1.005 gm/ml to 1.033 gm/ml at 25°C. This allows the device to be neutrally buoyant or float in the urine of the bladder to minimize the occurrence of blockage of the urethra.
• a preferred embodiment of the delivery system is a flowable gel or set-in-place system that can be introduced into the bladder via a cannula.
• set-in- place it is meant that the gel sets when introduced into the bladder.
• the drug is dispersed or placed in a carrier (microsphere, liposome, emulsion, etc.) which in turn is dispersed in a gel-forming system, such as gellan gum, a polysaccharide derived fermentation of Pseudomonas elodea, available as Gelrite ® from Kelco. Solutions of this material gel when contacted with an ionic environment, which, in this case, is the urine in the bladder.
• the preferred gel is an ionic gel-in-place type, such as gellan gum.
• the retention mechanism is the buoyancy of the device, so its specific gravity must be less than or equal to that of human urine.
• the ionic strength of the urine causes, for example, a solution of gellan gum to gel. Since oils have a density less than 1 gm/ml, a lipid emulsion component of the gel has a density less than 1.0 gm/ml.
• the combination of the gel, having a density approximately equal to the surrounding medium, and a lipid, having a density less than 1.0 gm/ml affords a device with a net density less than the surrounding medium.
• the gellan gum will slowly solubilize into the urine and be excreted, as will the lipid droplets.
• the gelling system will preferably contain, in addition to the phase changing component (gellan, gum, alginate, CMC, polyacrylic acid, carboxymethyl chitosan, and the like), a rheology modifier.
• This modifier will be a water-soluble high molecular weight polymer such as polyethylene oxide, PVP, dextran, dextrose, PEO/PVP copolymers, hyaluronic acid, hydroxyethyl cellulose, polyacrylamide, PVA, chitosan, gelatin or other high molecular weight water-soluble polymers.
• the molecular weight of the rheology modifier is preferably in the range of about 10 5 -10 7 daltons .
• the drug formulation is typically introduced into the lipid phase by mixing a salt form of the drug in water in the oil phase and increasing the pH. Deprotonation of the drug causes selective partition into the lipid phase, then the remainder of the components (the gelling component) are added. Alternatively, an un-ionized form of the drug is dissolved in the lipid phase, the release modifier is added, then the mixture is emulsified. The remaining components are then added.
• the second preferred embodiment of a delivery system is a device physically capable of being retained in the bladder without blocking the urinary tract .
• These devices are retained in the bladder by their shape such as a filament.
• These systems must be formed from a bioerodible polymer that will reliably release drug over the predefined period of time and completely erode during that period. It is not necessary that this type of device have a density less than human urine.
• At least one surface of the device may be coated with a mucoadhesive in order that the device adhere to the wall of the bladder.
• Mucoadhesive coated microspheres are preferred.
• mucoadhesives may be selected from a number of known synthetic, naturally-occurring or modified naturally-occurring substances which exhibit of tackiness.
• the adhesive must be biocompatible, that is, nontoxic and/or inert, within the bladder. The adhesive will also be compatible with the material forming the carrier, as well as the drug.
• Substances appropriate for use as mucoadhesives include, but are not limited to, carboxymethyl and hydroxypropyl methyl cellulose, and other cellulose derivatives; tragacanth, caraya, locust bean and other synthetic and naturally gums such as algin, chitosan, starches, pectins, and naturally- occurring resins, polyvinyl pyrrolidone, polyvinyl alcohol, and polyacrylic acid.
• a device consisting of a drug reservoir 10 having a backing 12 bearing a mucoadhesive 11 on the back surface.
• Fig. 2 shows a device according to the invention comprising a reservoir 13 to which is directly applied the mucoadhesive coating 14 so that the device may be attached to the wall of the bladder.
• Fig. 3 shows a randomly oriented filament network 17 containing the drug.
• This filament may be saturated with the drug, and may have a coating to control diffusion rate.
• the filament may also be segmented.
• Fig. 4 a view of an end of a segmented filament is shown.
• the drug is shown to be contained within an axial drug reservoir 18 in the filament.
• the network comprises segments 19 with erodible linking sections between the segments which allow the segments to detach as the drug reservoir is depleted within that segment .
• Fig. 5 shows another network of filaments forming a spherical cage 20.
• the devices containing the drug are insertable into the bladder through the urethra by a catheter.
• the devices are preferably made of flexible or gel-like material so that they may be coiled or compressed to fit through a catheter of sufficient size.
• the devices Upon being released from the catheter, the devices will have a sufficient shape memory to uncoil or expand into the shapes shown, for example, in the accompanying figures.
• the devices per se will not be drawn into the urethra to cause blockage, but will be retained within the bladder for an extended period of time.
• the mucoadhesive surface will eventually contact the bladder wall, thus achieving the desired implantation.
• Drugs for urge incontinence include dicyclomine, desmopressin, oxybutynin, estrogen, terodiline, propantheline, doxepin, imipramine and flavoxate.
• Other drugs include phenylpropanolamine, terazosin, praxosin, pseudoephedrine and bethanechol .
• Oxybutynin and impranine are the two most widely used for urge incontinence and are preferred.
• doxorubicin is preferred.
• Bacillus Calmette-Guerin a mycobacterium, may be utilized for treatment of carcinoma in situ of the bladder.
• DMSO or an anesthetic agent may be utilized for treatment of interstitial cystitis.
• any drug may be utilized for the treatment of any condition related to the bladder or urethral tract, including urge incontinence, cancer, infections, inflammation, and the like.
• the dosages utilized will depend upon the protocol required for the treatment of the particular condition and the patient. Particularly by use of filaments, variation in dosages is readily available since it is merely a case of using a longer or shorter length.
• the drug will be combined with a carrier and, optionally, a release modifier which alters the release of the drug into bladder.
• Typical carriers include corn oil, soybean oil, canola oil, safflower oil, polypropylene glycol and other natural oils.
• Typical release rate modifiers include oleic, stearic, palmitic and other saturated or unsaturated fatty acids; cholic acid, diacylphosphoric acid and other hydrophobic anionic compounds; phospholipids, diesters of citric acid, benzoic acid, substituted benzoic acids, substituted phenols, ion exchange polymers, EudragitTM, methacrylate-methacrylic acid copolymers, TweensTM, SpansTM, lecithin, alkyl nitrates, ethyl or methyl cellulose.
• a gel-in-place drug delivery system will include two components: the gelling components containing the phase change material and, optionally, a rheology modifier; and the drug release component containing the drug, carrier and, optionally, a release rate modifier.
• the drug release rate may also be regulated by the carrier per se when there is a chemical affinity of the drug to the carrier.
• a release rate modifier may be incorporated into the carrier, forming complexes or conjugates of carrier and modifier, and the like.
• the drug release component may also comprise a drug unmodified by release modifiers.
• a component for example, may comprise the drug dispersed in a solid lipophilic system such as anionic wax, self-emulsifying wax, cholesterol, fatty acid esters, beeswax or tallow.
• a reservoir device such as that shown in Figures 1 or 2 may be utilized where the reservoir can contain a much larger dose of drug compared to, for example, the filament configuration.
• a gel is used to provide sustained delivery of the drug it can be readily sterilized during preparation, then aseptically loaded into a sterile delivery device. Gels may be formulated as low viscosity dispersions with the drug or drug carrier which, when in contact with urine in the bladder, then gel or precipitate to form a solid filament or mass, thereby forming a delivery vehicle which can be retained in the bladder.
• the device must have a configuration, not limited to those disclosed, such that it does not block the flow of urine from the bladder or cause excessive mechanical irritation to the bladder wall.
• a configuration not limited to those disclosed, such that it does not block the flow of urine from the bladder or cause excessive mechanical irritation to the bladder wall.
• a solution of oxybutynin chloride (titer: 50 mg/ml) (1 ml) and 2% collagen (50 grams) is homogeneously mixed with stirring while preventing occurrence of foam.
• the mixture is lyophilized and pulverized at a low temperature using liquid nitrogen.
• the pulverized product is formed under compression to give a needle- shaped preparation.
• EXAMPLE 2 Materials of Example 1 are prepared with the addition of glycerol in order to impart flexibility to the device. The mixture is extruded into a filament and then dried. The filament may be randomly wound and inserted through a catheter for insertion into the bladder . EXAMPLE 3
• EXAMPLE 4 Preparation of Drug Containing Emulsion
• a 100 ml plastic beaker 1.25 grams of oleic acid is combined with 3.75 grams of purified corn oil.
• 0.25 grams of Tween 80 is added and mixed well.
• a rotor stator type high shear mixer (Virtis, Cyclone)
• 42.25 ml of water is slowly added to the blend. The mixing is continued throughout the addition process and for an additional minute once the addition of the water is complete.
• the resulting emulsion is mixed with a magnetic stir bar.
• DL-polylactic acid (5 grams) is dissolved in dichloromethane (95 grams) with gentle mixing. Oxybutynin chloride (2.5 grams) is then added to the polymer solution and dissolved. The drug/polymer solution is spray-dried in a spray drier (Yamato) to yield hollow drug loaded polylactic acid microspheres .
• the filtered solution of gellan gum/polyacrylic acid solution (example 3) is added into a 200 ml beaker.
• microspheres (5 grams from example 5) are dispersed into 50 ml deionized water containing 0.25% Pluronic ® F-127.
• the filtered solution of 1% gellan gum solution (example 1) is placed into a 200 ml beaker and warmed to approximately 40 °C.
• the mixing head of the overhead mixer is placed into the beaker to begin agitation.
• the drug containing microsphere solution is slowly added to the gum solution. Mixing is continued for an additional 3 minutes after addition is complete.
• the solution is cooled to room temperature. Aliquots of 1 ml of the microsphere/gum dispersion are placed into 5 ml lyophilization vials, lyophilized and stored under vacuum.
• the solution of gellan gum solution (a) is added into a 200 ml beaker.
• the solution is warmed to approximately 40 °C.
• the mixing head of the overhead mixer is placed into the beaker to begin agitation.
• the drug containing emulsion (b) is added slowly to the gum solution. Mixing is continued for an additional 3 minutes after addition is complete.
• the solution is cooled to room temperature.
• the pH is adjusted to 6.5 with IN HC1 or NaOH as necessary.
• a sample of 0.25 grams of the desired delivery system (a 3% oxybutynin system is used unless otherwise indicated) is introduced into 250 mL of an artificial urine (composed of 500 mM solution of sodium chloride containing 50 mM phosphate buffer) via an 18 gage cannula.
• the pH of the elution buffer is 6.2 unless otherwise listed. Aliquots of the elution buffer are collected at the indicated times during a 24 hour period and analyzed by high performance liquid chromatography .
• the system was introduced into the buffer using a 18 gage cannula (0.8 mm diameter) as described above and into a second buffer system using a 3 mm diameter cannula. Drug release from each system was determined and plotted as a fraction of the total drug introduced into the system. The drug release was observed to be slower from the system delivered from the 3 mm cannula. See FIG. 7.
• Release study 3 Effect of Varying Drug Content Release studies were conducted on the two systems described above (A and B) . In this case, rather than sampling the buffer over a 24 hour period, the buffer was sampled every 24 hours and immediately was exchanged with fresh buffer to model the release over several days. A greater amount of drug was released from the 3% oxybutynin system than was released from the 1% oxybutynin system. The amount released from the 3% system was observed to be more consistent over the nine buffer exchanges than the amount released from the 1% system which released fractionally more drug early in the study. See FIG. 8. Release Study 4: Effect of Modifier Concentration
• Formulations containing 0, 3, 6.25 and 12.5% wt/wt oleic acid were prepared as described above, except that the appropriate amount of oleic acid was used. Release studies were conducted on each formulation and the amount of drug release was determined and plotted in FIG. 9 as the concentration in the buffer versus time. It was observed that less drug is released from the system as the modifier concentration is increased.

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• 1998
  • 1998-04-02 EP EP98914404A patent/EP0971641A4/en not_active Withdrawn
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  • 1998-04-02 WO PCT/US1998/006445 patent/WO1998043555A1/en not_active Ceased
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  • 1998-04-02 CA CA002285591A patent/CA2285591A1/en not_active Abandoned
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  • 1998-04-02 KR KR1019997009105A patent/KR20010006027A/ko not_active Withdrawn
• 1999
  • 1999-10-04 NO NO994837A patent/NO994837L/no not_active Application Discontinuation
• 2000
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