Source: http://www.google.com/patents/US6168777?dq=7,546,338
Timestamp: 2015-05-04 15:14:00
Document Index: 84892415

Matched Legal Cases: ['art. 1', 'art13', 'art.13', 'art.14', 'art.13', 'art 1']

Patent US6168777 - Methods for treating prostate tumors using radioactive compositions - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsDisclosed are methods for treating solid mass prostate tumors in a male mammal by use of a radiation composition....http://www.google.com/patents/US6168777?utm_source=gb-gplus-sharePatent US6168777 - Methods for treating prostate tumors using radioactive compositionsAdvanced Patent SearchPublication numberUS6168777 B1Publication typeGrantApplication numberUS 09/185,147Publication dateJan 2, 2001Filing dateNov 3, 1998Priority dateNov 3, 1997Fee statusPaidAlso published asCA2307190A1, CA2307191A1, DE69828436D1, DE69828436T2, DE69830072D1, DE69830072T2, EP1028757A1, EP1028757A4, EP1028757B1, EP1028758A1, EP1028758A4, EP1028758B1, US6015541, US6214315, US6562317, US20010009656, USRE39456, WO1999022774A1, WO1999022775A1Publication number09185147, 185147, US 6168777 B1, US 6168777B1, US-B1-6168777, US6168777 B1, US6168777B1InventorsRichard J. Greff, George WallaceOriginal AssigneeMicro Therapeutics, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (13), Non-Patent Citations (11), Referenced by (14), Classifications (24), Legal Events (4) External Links: USPTO, USPTO Assignment, EspacenetMethods for treating prostate tumors using radioactive compositions
US 6168777 B1Abstract
Disclosed are methods for treating solid mass prostate tumors in a male mammal by use of a radiation composition.
What is claimed is: 1. A method for causing necrosis to a portion of a solid mass prostate tumor in a male mammal which method comprises:
(a) selecting a fluidic compositions comprising: (i) a biocompatible, non-cross-linked, non-biodegradable polymer which polymer is insoluble in body fluid of a mammal; (ii) a biocompatible solvent which is an organic material liquid at least at body temperature of the mammal and which solubilizes said polymer with the proviso that when said solvent comprises water, the amount of water employed is sufficiently small that the dissolved polymer precipitates upon contact with the blood; and (iii) a water insoluble radioisotope with the proviso that when the radioisotope is either water soluble or water reactable, said isotope is used as a water insoluble salt (b) injecting a sufficient amount of said composition into the prostate of a male mammal under conditions wherein a solid non-migratory precipitate is formed wherein the radioisotope is employed in an amount effective to cause necrosis of at least a portion of said tumor. 2. The method according to claim 1 wherein said biocompatible solvent is selected from the group consisting of dimethylsulfoxide, ethanol and acetone.
4. The method according to claim 1 wherein said non-biodegradable biocompatible polymer is selected from the group consisting of cellulose acetates, ethylene vinyl alcohol copolymers, hydrogels, polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose, copolymers of urethane/carbonate, copolymers of styrene/maleic acid, and mixtures thereof.
5. The method according to claim 4 wherein said non-biodegradable biocompatible polymer is a copolymer of ethylene and vinyl alcohol.
6. The method according to claim 1 wherein said radioisotope is selected from the group consisting of 90yttrium, 192iridium, 198gold, 125iodine, 137cesium, 60cobalt, 55cobalt, 56cobalt, 57cobalt, 57magnesium, 55iron, 32phosphorus, 90strontium, 81rubidium, 206bismuth, 67gallium, 77bromine, 129cesium, 73selenium, 72selenium, 72arsenic, 103palladium, 203lead, 111indium, 52iron, 167thulium, 57nickel, 62 zinc, 61copper, 201thallium, and 123iodine.
7. The method according to claim 1 which further comprises a non-radioactive contrast agent.
8. The method according to claim 7 wherein said non-radioactive contrast agent is water soluble.
9. The method according to claim 8 wherein said water soluble non-radioactive contrast agent is selected from the group consisting of metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and meglumine.
10. The method according to claim 7 wherein said non-radioactive contrast agent is water insoluble.
11. The method according to claim 10 wherein said water insoluble contrast agent is tantalum, tantalum oxide, barium sulfate, tungsten, gold and platinum.
12. The method according to claim 1 wherein said fluidic composition comprises from about 0.1 to about 35 weight percent of a water insoluble radioisotope having from a radioactive content of from about 0.5 microcurie to about 200 millicurie.
This application is a continuation-in-part of U.S. patent application Ser. No. 08/962,819 filed Nov. 3, 1997 which application is incorporated herein by reference in its entirety.
This invention is directed to methods for treating prostate tumors by use of radioactive compositions. Specifically, these methods entail the in vivo delivery of radioactive compositions which are delivered as a fluid to one or more sites in the prostate of a male mammal including the solid mass tumor(s) located on or in the prostate. Subsequent solidification of this composition in the prostate results in delivery of a controlled amount of radiation to the prostate.
In one embodiment, the fluidic radioactive compositions employed in the methods of this invention comprise a biocompatible polymer, a biocompatible solvent and a radioactive agent which provides therapeutic doses of radiation. In another embodiment, the fluidic radioactive compositions employed in the methods of this invention comprise a biocompatible prepolymer, a radioactive agent and optionally a biocompatible solvent which provides therapeutic doses of radiation to the prostate.
8 Taki, et al., �Selection and Combination of Various Endovascular Techniques in the Treatment of Giant Aneurysms�, J Neurosurg., 77:37-24 (1992)
13 Nori, et al., Current Issues in Techniques of Prostate Brachytherapy, Seminars in Surgical Oncology, 13:444-453 (1997)
14 Anderson, et al., Spacing Nomograph for Interstitial Implants of 125-I Seeds, Med. Phys., 3:48-51 (1976)
Adenocarcinoma of the prostate is the most common malignancy diagnosed among men in the United States. Current therapeutic regimens for treating prostate tumors include external radiation therapy, brachytherapy, surgery, radical prostatectomy, and the like as well as combinations of two or more of the above.
Brachytherapy, or the internal deposition of radioactive particles into the prostate, has superior potency preservation rates as compared to external beam radiation therapy or surgery. Brachytherapy is characterized as temporary (i.e., radioactive seeds are delivered, e.g., by a catheter to the prostate for a short period of time and then removed) or permanent (i.e., radioactive seeds are delivered to the prostate and not removed). Permanent brachytherapy typically involves needle injection of radioactive seeds into the prostate.13 The radioactive seeds comprise a radioactive agent, e.g., 192iridium, typically dimensioned with a length of from 2-4 millimeters. Such seeds are typically injected via a 17 or 18 gage needle into the prostate via stereotactic imaging with the aid of ultrasound or fluoroscopic guidance and the protocol typically entails the delivery of up to 20 or more seeds. Stereotactic imaging allows the clinician to accurately deliver these seeds to the desired location in the prostate and the radiation emitted from these seeds effectively causes necrosis of at least a portion of the tumor over time.
One drawback with such permanent brachytherapy is that the total dose of radiation delivered into the prostate is governed by the size and number of the seeds delivered as well as the radioactive content of the seeds. Typically, the size and radioactive content of the seeds employed is dictated by the commercial availability of the seeds and, accordingly, the clinician typically has control only over the number of seeds delivered as a means to control the total dose of radiation. In certain cases where delivery of a high local dose of radiation to a particular portion of the prostate is desired by the clinician, multiple seed injections in this area will be required.
It is clear, however, that allowing the clinician better control of the radiation dose delivered to the prostate will simplify the protocol and provide greater flexibility in the treatment regimen selected by the clinician.
This invention is directed to methods for treating prostate tumors by use of radioactive compositions. These compositions are delivered to the prostate as a fluid composition which solidifies in vivo to form a solid, coherent radioactive mass. The methods of this invention permit the clinician to control the total amount of radiation delivered to the prostate during each injection merely by adjusting the quantity of fluid delivered and the concentration of radiation per given volume of fluid. In any event, sufficient amounts of radiation are delivered to the prostate to effect necrosis of at least part of the solid mass tumors located thereon or therein.
Accordingly, in one of its method aspects, this invention is directed to a method for causing necrosis to a portion of a solid mass prostate tumor which method comprises:
(a) selecting a fluidic composition comprising a biocompatible polymer, a biocompatible solvent and a water insoluble radioisotope; and
(b) injecting a sufficient amount of said composition into the prostate of a male mammal under conditions wherein a solid mass is formed
wherein the radioisotope is employed in an amount effective to cause necrosis of at least a portion of said tumor.
(c) from about 0. 1 to about 35 weight percent of a water insoluble radioisotope having a radioactive content of from about 0.50 microcurie to about 200 millicuries.
In another aspect of this invention, the biocompatible polymer can be replaced with a biocompatible prepolymer and, when so used, the presence of the biocompatible solvent becomes optional. In this embodiment, this invention is directed to a method comprising:
(a) selecting a fluidic composition comprising a biocompatible prepolymer, a water insoluble radioisotope and optionally a biocompatible solvent; and
(c) from about 0.1 to about 35 weight percent of a water insoluble radioisotope having a radioactive content of from about 0.5 microcurie to about 200 millicurie.
In a preferred embodiment of either of the method aspects, the amount and radioactive content of the radioisotope is sufficient to provide for a cumulative ionizing radiation dosage at the site of implantation in a mammalian subject of from about 1000 to about 20,000 rads [10-200 Gray (Gy)].
It is, of course, understood that both the activity of the radioactive element and dose of radiation delivered to the prostate varies widely due to the requirements of different tumors, tissues, volume of tissue treated, amount of tumor present, etc. Evaluation of such factors to determine the appropriate activity of the radioactive isotope and the dose of radiation delivered are well within the skill of the art.
In a further preferred embodiment of either of the method aspects, the biocompatible solvent is dimethylsulfoxide (DMSO), ethanol or acetone.
This invention is directed to methods for treating prostrate tumors in male mammals by use of radioactive compositions which methods entail the in vivo delivery of radioactive compositions which are delivered as a fluid to one or more sites in the prostate. Subsequent solidification of this composition in the tissue results in delivery of a controlled amount of radiation into the prostate.
The term �solid mass tumor� refers to cancerous and non-cancerous conditions manifested by a solid mass growth as opposed to conditions lacking such a solid mass growth, e.g., leukemia. The term �solid mass prostate tumors� refer to solid mass tumors located on or in the prostate gland of male mammals.
Biodegradable polymers are disclosed in the art. 1,3 For example, Dunn, et al.1 discloses the following examples of biodegradable polymers: linear-chain polymers such as polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, and copolymers, terpolymers and combinations thereof. Other biodegradable polymers include, for example, gelatin, collagen, etc.3 Suitable non-biodegradable biocompatible polymers include, by way of example, cellulose acetates2,6-7 (including cellulose diacetate5), ethylene vinyl alcohol copolymers4,8, hydrogels (e.g., acrylics), polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate, nitrocellulose, copolymers of urethane/carbonate, copolymers of styrene/maleic acid, and mixtures thereof9.
Ethylene vinyl alcohol copolymers are either commercially available or can be prepared by art recognized procedures. Preferably, the ethylene vinyl alcohol copolymer composition is selected such that a solution of 5 weight percent of the ethylene vinyl alcohol copolymer, 20 weight percent of a tantalum contrast agent in DMSO has a viscosity equal to or less than 60 centipoise at 20� C. As is apparent to one skilled in the art, with all other facts being equal, 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 delivery can be readily achieved by merely adjusting the molecular weight of the copolymer composition.
The term �radioisotope� refers to naturally or non-naturally occurring water insoluble radioisotopes conventionally employed in nuclear medicine including, by way of example only, 90yttrium, 192iridium, 198gold, 125iodine, 137cesium, 60cobalt, 55cobalt, 56cobalt, 57cobalt, 52magnesium, 55iron, 32phosphorus, and 90strontium. Other radionuclides currently being produced for use in nuclear medicine include, for example, 81rubidium, 206bismuth, 67gallium, 77bromine, 129cesium, 73selenium, 72selenium, 72arsenic, 103palladium, 203lead, 111indium, 52iron, 167thulium, 57nickel, 62zinc, 61copper, 201thallium, and 123iodine. Each of these isotopes can be made by standard techniques well known in the art13. Additionally, radioisotopes which are water soluble or water reactable are typically used as water insoluble salts.
The term �absorbed dose� or �radiation dose� refers to the dose of radiation typically employed by the attending oncologist in treating solid mass tumors. The radiation dose is defined in terms of energy deposited per unit mass, given in the following units: 1 Gray (Gy)=1 Joule per kilogram. In the past, the standard unit of radiotherapy was 1 rad, and 1 Gy=100 rads.
Treatment dosages of radiation employed in a particular patient are, of course, dependent upon the judgment of the attending clinician and nuclear medicine professional depending upon factors such as the type and severity of the solid mass prostate tumor in the patient, the age, weight and general condition of the patient, the toxicity and/or side effects due to the radiation treatment and the like. Such factors are well known to the skilled artisan.
While there is no consensus on the ideal radiotherapy prescription for a particular tumor type, a number of prescriptions are currently used based either on the principle of administering the dose of radiation either over a relatively long treatment time in relatively small fractions or over a short treatment time in relatively large fractions. For example, 64 Gy in 32 fractions over 6.5 weeks or 52 Gy in 15 fractions over 3 weeks. Appropriate prescription is based on an assessment of the individual tumor.
In view of the above, the compositions described herein preferably comprise from about 0.1 to about 35 weight percent of a water insoluble radioisotope having from a radioactive content of from about 0.5 microcurie to about 200 millicurie. In another preferred embodiment, the amount and radioactive content of the radioisotope is sufficient to provide for a cumulative ionizing radiation dosage at the site of implantation in a mammalian subject of from about 1000 to 20,000 rads [10 to 200 Gray (Gy)].
The compositions described above can be employed in the treatment of solid mass prostate tumors. Prior to treatment, preplanning of the therapeutic protocol is necessary to evaluate the prostate volume, determine the total radiation activity needed to encompass the prostate gland and deliver the appropriate minimum peripheral dose, and to determine the pattern of placement of the radioactive composition in the prostate. Each of these preplanning steps is well known and documented in the art.13 For example, determination of the prostate volume can be conducted using transrectal ultrasound, computed tomography, and the like. Likewise, determination of total radioactivity and positioning of the seeds can be achieved from software programs described in the art.14 Upon completion of the preplanning protocol, injection of the radioactive composition may be performed intraoperatively or percutaneously under conditions well known in the art.13 In either case, a sufficient amount of this composition is introduced into one or more sites in the prostate using, for example, needle delivery under fluoroscopy so that precipitation of the polymer or polymerization of the prepolyrner in the prostate can be visualized.
When the polymeric composition is introduced in vivo, the biocompatible solvent diffuses rapidly into the body fluid and a solid, non-migratory precipitate or solid mass forms which precipitate is the water insoluble polymer and radioisotope encapsulated therein as well as any non-radioactive water insoluble contrast agent. Without being limited to any theory, it is believed that initially, a soft gel to spongy solid precipitate or solid mass forms upon contact with the body fluid.
In either case, a solid non-migratory radioactive mass forms in the prostate which ablates at least a portion of the tumor(s) located therein.
The compositions described herein are useful in ablating solid mass prostate tumors. When employed, the level of radiation employed in the composition is sufficient to ablate at least a portion of such solid mass prostate tumors. Accordingly, these compositions find use in human male and other male mammalian subjects requiring treatment. It is contemplated that the compositions used in the methods of this invention can also be employed as a carrier for a chemotherapeutic agent wherein this agent is delivered in vivo for subsequent release to the solid mass prostate tumor. Such chemotherapeutic agents are well known in the art and, include by way of example only, fluorouracil, methotrexate, cisplatin and the like. A pharmaceutical agent such as an anti-inflammatory agent, an antibiotic, and the like can be employed either in combination with the chemotherapeutic agent or as an alternative thereto.
gray (units for dose of radiation;
The purpose of this example is to demonstrate the preparation of polymer compositions useful in this invention. These compositions were prepared using �cold� isotopes in order to illustrate the compatibility of the compositions and suitability for delivery in vivo. It is understood that �hot� compositions could be similarly prepared.
After dissolution of the polymer at 50� C., 3 cc of this composition was then added to 0.03 g iridium powder (Aldrich Chemical Company, Milwaukee, Wis., USA, Catalog No. 20968-6, 99.9% purity, screened to <25 μm) to provide for a suspension comprising 0.4% by weight iridium. The resulting composition was then shaken for 4 minutes to disperse the insoluble materials. Immediately, 0.8 cc of the suspension was withdrawn via a 1 cc syringe through a 21 gauge needle. Three 0.1 cc aliquots were then injected into an excess of normal saline maintained at about 37� C. to generate the precipitate. The saline was then stirred for about 10 minutes whereupon the precipitate was examined for inner/outer consistency. In each case, a solid coherent precipitate formed in the saline.
The purpose of this example is to demonstrate the preparation of a prepolymer composition useful in this invention. This compositions was prepared using �cold� isotopes in order to illustrate the compatibility of the 20 composition and suitability for delivery in vivo. It is understood that �hot� compositions could be similarly prepared.
Specifically, a cyanoacrylate prepolymer composition was prepared by adding 500 mg of iridium non-radioactive powder (Aldrich Chemical Company, Milwaukee, Wis., USA, Catalog No. 20968-6, 99.9% purity, screened to <25 μm) to 2 g n-butyl cyanoacrylate containing 100 ppm SO2 as a stabilizer to yield a composition comprising 20% by weight of iridium. The ingredients mixed well, yielding a black/gray suspension. The iridium settled within several seconds after mixing, so constant, gentle agitation was required. In this regard, a higher viscosity cyanoacrylate composition could be used to prolong the suspension time of the iridium or, alternatively, a smaller particle size of the iridium can be used.
The purpose of this example is to illustrate how to deliver the composition of either Example 1 or 2 to the prostate of a male mammal. This example employs a dog with a solid mass tumor.
Specifically, a male dog (25 kg) having a tumor in the prostate gland is selected for use in this example. At this time, 0.10 mL of a 0.4% iridium composition described in Example 1 above (except that the iridium has a radioactive content of 150 μCi) is shaken to ensure homogeniety and then loaded into a 1 cc syringe fitted with a 26 gage needle. The tip of the syringe is positioned in the prostate gland of the dog with the aid of ultrasound or fluoroscopy to ensure proper positioning and approximately 0.05 mL of this composition is injected therein. Upon introduction into the prostate, a solid coherent precipitate forms which comprises the polymer, the contrast agent and the iridium which solidifies in the prostate.
After injection, the needle is repositioned into a second site within the prostate, again with the aid of either ultrasound or fluoroscopy, and the remaining 0.05 mL of the radioactive composition is delivered thereto.
Over 30 days, the amount of radiation delivered internally to the prostate of the dog is about 25 Gray.
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Neurosurg., 77:37-42 (1992).Referenced byCiting PatentFiling datePublication dateApplicantTitleUS6527693Jan 30, 2001Mar 4, 2003Implant Sciences CorporationMethods and implants for providing radiation to a patientUS6575888Jan 24, 2001Jun 10, 2003Biosurface Engineering Technologies, Inc.Bioabsorbable brachytherapy deviceUS6613432Dec 21, 2000Sep 2, 2003Biosurface Engineering Technologies, Inc.Plasma-deposited coatings, devices and methodsUS6689043 *Nov 5, 1999Feb 10, 2004Amersham PlcProducts and methods for brachytherapyUS6712782 *May 9, 2001Mar 30, 2004Varian Medical Systems Technologies, Inc.Brachytherapy apparatus and methodsUS7226622Sep 14, 2004Jun 5, 2007Boston Scientific Scimed, Inc.Chemoablation of tissue using biodegradable, solid salt dosage formsUS7906125Sep 18, 2003Mar 15, 2011Boston Scientific Scimed, Inc.Solid or semi-solid therapeutic formulationsUS8057827Jun 4, 2007Nov 15, 2011Boston Scientific Scimed, Inc.Chemoablation of tissue using biodegradable, solid salt dosage formsUS8263109May 9, 2005Sep 11, 2012Boston Scientific Scimed, Inc.Injectable bulking compositionsUS8389023Sep 23, 2011Mar 5, 2013Boston Scientific Scimed, Inc.Chemoablation of tissue using biodegradable, solid salt dosage formsUS8753620Aug 16, 2012Jun 17, 2014Boston Scientific Scimed, Inc.Injectable bulking compositionsEP2629780A2 *Oct 20, 2011Aug 28, 2013206 ORTHO, Inc.Implantable polymer for bone and vascular lesionsWO2004084920A2 *Mar 29, 2004Oct 7, 2004Santosolve AsAnti-inflammatory treatment based on strontium compoundsWO2004084920A3 *Mar 29, 2004Dec 29, 2004Santosolve AsAnti-inflammatory treatment based on strontium compounds* Cited by examinerClassifications U.S. Classification424/1.25, 600/3, 424/1.61, 424/1.29, 424/1.37, 424/1.33, 600/4, 424/1.65International ClassificationA61K49/04, A61K47/30, A61K51/12, A61K47/38, A61P35/00, A61K47/36, A61K47/34, A61K51/00, A61K47/32, A61N5/10, A61K51/06Cooperative ClassificationA61K2121/00, A61K51/1217, A61K51/06European ClassificationA61K51/06, A61K51/12ELegal EventsDateCodeEventDescriptionJul 2, 2012FPAYFee paymentYear of fee payment: 12Jul 2, 2008FPAYFee paymentYear of fee payment: 8Jun 29, 2004FPAYFee paymentYear of fee payment: 4Jan 20, 1999ASAssignmentOwner name: MICRO THERAPEUTICS, INC., CALIFORNIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GREFF, RICHARD J.;WALLACE, GEORGE;REEL/FRAME:009706/0087;SIGNING DATES FROM 19981224 TO 19990108RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services