U.S. patent application number 10/846313 was filed with the patent office on 2005-04-28 for gynecologic embolotherapy methods.
Invention is credited to Greff, Richard J..
Application Number | 20050090714 10/846313 |
Document ID | / |
Family ID | 21865999 |
Filed Date | 2005-04-28 |
United States Patent
Application |
20050090714 |
Kind Code |
A1 |
Greff, Richard J. |
April 28, 2005 |
Gynecologic embolotherapy methods
Abstract
This invention is directed to novel methods for gynecologic
embolotherapy. The methods directly access the blood vessels to be
embolized transcervically rather than arterially. The methods
provide precise directed delivery of embolizing compositions, and
are particularly suited for treating uterine fibroids. Kits
containing one or more devices for transcervical injection and an
embolizing composition are also provided. In a preferred
embodiment, fluid embolizing compositions are used. In a more
preferred embodiment, these fluid embolic compositions comprise a
biocompatible polymer, a biocompatible solvent and a biocompatible
water insoluble contrast agent. In a most preferred embodiment, the
contrast agent is characterized by having an average particle size
of about 10 .mu.m or less.
Inventors: |
Greff, Richard J.; (St. Pete
Beach, FL) |
Correspondence
Address: |
FOLEY & LARDNER LLP
1530 PAGE MILL ROAD
PALO ALTO
CA
94304
US
|
Family ID: |
21865999 |
Appl. No.: |
10/846313 |
Filed: |
May 13, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10846313 |
May 13, 2004 |
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09346306 |
Jul 2, 1999 |
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09346306 |
Jul 2, 1999 |
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09032636 |
Feb 27, 1998 |
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6059766 |
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Current U.S.
Class: |
600/135 ;
606/200 |
Current CPC
Class: |
A61B 17/1219 20130101;
A61B 17/42 20130101; A61M 31/005 20130101; A61B 17/12022 20130101;
A61L 24/001 20130101; A61B 17/12186 20130101; A61L 24/06 20130101;
A61L 24/02 20130101; A61B 17/00491 20130101; A61L 24/06 20130101;
A61L 31/18 20130101; A61B 2017/4216 20130101; A61B 17/12109
20130101; A61L 2430/36 20130101; C08L 29/04 20130101 |
Class at
Publication: |
600/135 ;
606/200 |
International
Class: |
A61B 001/307 |
Claims
1-14. (canceled)
15. A kit of parts particularly adapted for carrying out
gynecological embolization comprising: (a) a hysteroscope which
allows catheter insertion through the cervix and into the uterus
and visualization of the uterine wall; (b) one or more catheters
capable of being inserted through the cervix and into the uterus
and thereafter penetrating a blood vessel to be embolized; (c) at
least one of the one or more catheters capable of delivering an
embolic composition to the blood vessel to be embolized and is
compatible with the embolic composition; and (d) an embolic
composition comprising a chemically inert biocompatible polymer a
biocompatible contrast agent and a biocompatible solvent comprising
an organic material liquid.
16. (canceled)
17. The kit of claim 15 wherein the catheter capable of penetrating
the blood vessel to be embolized is needle tipped.
18. The kit of claim 15 wherein one catheter is capable of both
penetrating the blood vessel and delivering the embolic
composition.
19. (canceled)
20. The kit of claim 15 wherein the embolic composition is a fluid
embolizing composition comprising: (a) from about 2.5 to about 8.0
weight percent of a chemically inert biocompatible polymer; (b)
from about 10 to about 40 weight percent of a water insoluble,
biocompatible contrast agent having an average particle size of
about 10 .mu.m or less; and (c) from about 52 to about 87.5 weight
percent of a biocompatible solvent comprising an organic material
liquid: wherein the weight percent of the polymer, contrast agent
and biocompatible solvent is based on the total weight of the
complete composition.
21. The kit according to claim 20 wherein said biocompatible
solvent is selected from the group consisting of dimethylsulfoxide,
ethanol and acetone.
22. The kit according to claim 21 wherein said biocompatible
solvent is dimethylsulfoxide.
23. The kit according to claim 20 wherein said water insoluble
contrast agent is the group consisting of tantalum, tantalum oxide,
tungsten and barium sulfate.
24. The kit according to claim 23 wherein said contrast agent is
tantalum.
25. The kit according to claim 20 wherein said biocompatible
polymer is 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.
26. The kit according to claim 25 wherein said biocompatible
polymer is an ethylene and vinyl alcohol copolymer.
27. The kit according to claim 26 wherein said contrast agent is a
particulate and has an average particle size of from 1 to 10
microns.
Description
BACKGROUND OF THE INVENTION
[0001] Field of the Invention
[0002] This invention is directed to novel methods for gynecologic
embolotherapy. The methods of this invention specifically access
the blood vessels to be embolized transcervically rather than
arterially. The methods provide precise directed delivery of
embolizing compositions, and are particularly suited for treating
uterine fibroids.
[0003] Kits containing one or more devices for transcervical
injection and an embolizing composition are also provided. In a
preferred embodiment, fluid embolizing compositions are used. In a
more preferred embodiment, these fluid embolic compositions
comprise a biocompatible polymer, a biocompatible solvent and a
biocompatible water insoluble contrast agent. In a most preferred
embodiment, the contrast agent is characterized by having an
average particle size of about 10 .mu.m or less.
REFERENCES
[0004] The following publications are cited in this application as
superscript numbers:
[0005] .sup.1 Mandai, et al., "Direct Thrombosis of Aneurysms with
Cellulose Acetate Polymer", J. Neurosurg., 77:497-500 (1992)
[0006] .sup.2 Kinugasa, et al., "Direct Thrombosis of Aneurysms
with Cellulose Acetate Polymer", J. Neurosurg., 77:501-507
(1992)
[0007] .sup.3 Casarett and Doull's Toxicology, Amdur et al.,
Editors, Pergamon Press, New York, pp. 661-664 (1975)
[0008] .sup.4 Greff, et al. U.S. Pat. No. 5,667,767 for "Novel
Compositions for Use in Embolizing Blood Vessels", issued Sep. 16,
1997
[0009] .sup.5 Greff, et al., U.S. Pat. No. 5,580,568 for "Cellulose
Diacetate Compositions for Use in Embolizing Blood Vessels", issued
Dec. 3, 1996
[0010] .sup.6 Kinugasa, et al., "Early Treatment of Subarachnoid
Hemorrhage After Preventing Rerupture of an Aneurysm", J.
Neurosurg., 83:34-41 (1995)
[0011] .sup.7 Kinugasa, et al., "Prophylactic Thrombosis to Prevent
New Bleeding and to Delay Aneurysm Surgery", Neurosurg., 36:661
(1995)
[0012] .sup.8 Taki, et al., "Selection and Combination of Various
Endovascular Techniques in the Treatment of Giant Aneurysms", J.
Neurosurg., 77:37-42 (1992)
[0013] .sup.9 Evans, et al., U.S. patent application Ser. No.
08/802,252 for "Novel Compositions for Use in Embolizing Blood
Vessels", filed Feb. 19, 1997.
[0014] .sup.10 Castaneda-Zuniga, et al., Interventional Radiology,
in Vascular Embolotherapy, Part 1, 1:9-32, Williams & Wilkins,
Publishers (1992)
[0015] .sup.11 Rabinowitz, et al., U.S. Pat. No. 3,527,224, for
"Method of Surgically Bonding Tissue Together", issued Sep. 8,
1970
[0016] .sup.12 Hawkins, et al., U.S. Pat. No. 3,591,676, for
"Surgical Adhesive Compositions", issued Jul. 6, 1971
[0017] .sup.13 Evans, et al., U.S. patent application Ser. No.
08/655,987, for "Methods for the Reversible Sterilization of Male
Mammals, filed May 31, 1996
[0018] .sup.14 Evans, et al., U.S. patent application Ser. No.
08/656,394, for "Methods for the Reversible Sterilization of Female
Mammals, filed May 31, 1996
[0019] .sup.15 Evans, et al., U.S. Pat. No. 5,695,480, for "Novel
Embolizing Compositions, issued Dec. 9, 1997
[0020] .sup.16 Goodwin, et al., "Preliminary Experience with
Uterine Artery Embolization for Uterine Fibroids," J. Vasc.
Interven. Radiol. 8:517-526 (1997)
[0021] .sup.17 Vedantham, et al. "Uterine artery embolization: An
underused method of controlling pelvic hemorrhage," Am. J. Obstet.
Gynecol. 176(4):938-948 (1997)
[0022] .sup.18 Tranbahuy, et al., "Direct Intratumoral Embolization
of Juvenile Angiofibroma," Am. J. Otolaryng. 15(6):429-435
(1994)
[0023] .sup.19 Casasco, et al., "Devascularization of Craniofacial
Tumors by Percutaneous Tumor Puncture," Am. J. Neuroradiol.
15:1233-1239 (1994)
[0024] The disclosures of each of the above publications, patents
and patent application are herein incorporated by reference in
their entirety to the same extent as if the language of each
individual publication, patent and patent application were
specifically and individually included herein.
BACKGROUND OF THE INVENTION
[0025] Gynecologic embolotherapy may be conducted for a variety of
purposes including the treatment of postpartum and postcaesarean
bleeding, the treatment of postsurgical vaginal bleeding, the
prevention and/or treatment of hemorrhage from ectopic pregnancy,
prophylactically prior to myomectomy and in obstetrical patients at
high risk for bleeding, such as those patients with placenta
previa, placenta accreta, uterine fibroids and twin fetal death.
Gynecological embolotherapy, however, has only been used for
non-malignant conditions and the literature reports the use of
polyvinyl alcohol (PVA) particles of sizes varying from 150 to 700
.mu.m as the embolizing agents..sup.16
[0026] Complications arising from endovascular embolization using
PVA particles include complications of angiography, pelvic
infection, pelvic pain and ischemia..sup.16 Notwithstanding the use
of PVA particles as the embolizing agent, uterine fibroid shrinkage
was noted in patients with fibroids following gynecological
embolization of these patients for acute bleeding, leading to the
establishment of several clinical programs which use uterine artery
embolization for the treatment of uterine fibroids. Clinical
success of uterine artery embolization (defined as improvement in
bleeding, pain and mass effect such that no further operative
therapy is required) is good. Fibroid size is reduced, on average,
by about 50% in patients undergoing uterine artery
embolization..sup.16,17
[0027] In view of the above, better gynecological embolization
methods for treatment and/or prevention of gynecological and/or
obstetrical bleeding disorders which provide precise directed
embolization are needed. In particular, techniques which are
minimally invasive and which could be performed in a gynecologist's
office or an outpatient setting would be ideal.
[0028] This invention is directed to the use of embolization
methods which directly access the blood vessels to be embolized
transcervically rather than arterially. These methods, of course,
are less invasive and, accordingly, better tolerated as compared to
intravascular embolization techniques.
[0029] Heretofore, embolization methods preferably included the use
of a water insoluble, radiopaque contrast agent in the embolizing
compositions in order that the physician can visualize delivery of
the composition typically by microcatheter to the vascular site via
conventional techniques such as fluoroscopy. 1-8 Additionally, the
use of water insoluble contrast agents is beneficial during
posttreatment procedures to visualize the embolized mass during,
for example, surgery or to monitor the disease condition and/or for
retreatment purposes. Visualization is particularly necessary when
using catheter delivery techniques in order to ensure both that the
composition is being delivered to the intended vascular site and
that the requisite amount of composition is delivered. Preferably,
the water insoluble contrast agent has an average particle size of
about 10 .mu.m or less..sup.15
[0030] In addition to the above, intratumoral embolization of
vertebral bone tumors, craniofacial tumors and juvenile
angiofibroma prior to surgical removal of tumor is known..sup.18,19
Such embolization methods avoid the non-selective embolization of
primary or secondary branch arteries and may be used even after
ligation of feeding pedicles.
SUMMARY OF THE INVENTION
[0031] As noted above, this invention is directed to the use of
embolization methods which directly access the blood vessels to be
embolized transcervically rather than arterially. The methods
provide precise directed delivery of embolizing compositions using
minimally invasive procedures, and are particularly suited for
treating uterine fibroids. Kits containing one or more devices for
transcervical injection and an embolizing composition are also
provided.
[0032] In a preferred embodiment, fluid embolizing compositions are
used. In one preferred embodiment, these fluid embolic compositions
comprise a biocompatible polymer, a biocompatible solvent and a
contrast agent. In another preferred embodiment, these fluid
embolic compositions comprise a biocompatible prepolymer and a
contrast agent. In a most preferred embodiment, the contrast agent
is characterized by having an average particle size of about 10
.mu.m or less.
[0033] Accordingly, in one aspect the invention provides a method
for gynecological embolization comprising:
[0034] inserting a catheter capable of penetrating a blood vessel
through the cervix into the uterus using an instrument which allows
visualization of the uterine wall;
[0035] inserting the catheter through the cervix and into a blood
vessel to be embolized;
[0036] and delivering an embolic material through the catheter into
the vessel under conditions wherein said blood vessel is
embolized.
[0037] A hysteroscope may preferably be used to insert the
catheter, which preferably is needle tipped. The vessel may
preferably be a blood vessel of a uterine fibroid. The embolic
material may be a sclerosing agent, such as ethanol or hot fluids;
a particulate, such as polyvinyl alcohol (PVA); or, preferably, a
fluid embolizing substance.
[0038] Methods further comprising the step of delivering a
detectable agent, such as a contrast agent, through the catheter
after it has been inserted into the vessel and detecting the agent
to confirm that the catheter has the proper placement prior to
delivery of embolic material to the vessel are also provided.
[0039] In another aspect, the invention provides a kit of parts
comprising:
[0040] a device which allows catheter insertion and visualization
of the uterine wall;
[0041] a catheter capable of penetrating a blood vessel to be
embolized;
[0042] a catheter capable of delivering an embolic material;
and
[0043] an embolic material.
[0044] A hysteroscope may preferably be the catheter
insertion/visualization device. The catheter may preferably be
needle tipped, and a single catheter may be used both for vessel
penetration and embolizing composition delivery. The embolic
material may be a sclerosing agent, such as ethanol; a particulate,
such as PVA; or, preferably, a fluid embolizing substance. Kits
further comprising a detectable agent, such as a contrast agent,
are also provided.
DETAILED DESCRIPTION OF THE INVENTION
[0045] This invention is directed to novel gynecological
embolization methods which directly access the vessels to be
embolized transcervically rather than arterially. The methods
provide precise directed delivery of embolizing compositions using
minimally invasive procedures, and are particularly suited for
treating uterine fibroids.
[0046] However, prior to discussing this invention in further
detail, the following terms will first be defined:
[0047] The term "embolizing" refers to a process wherein a material
is injected into a blood vessel which fills or plugs the vessel
and/or encourages clot formation so that blood flow in the vessel
ceases. Embolization of the blood vessel is, therefore, important
in preventing/controlling bleeding due to lesions. In addition,
embolization can be used to ablate diseased tissue (e.g., tumors,
etc.) by cutting off its blood supply. Embolization may also be
used to prevent blood loss during or immediately following surgery.
Embolization of tumors may be performed preoperatively to shrink
tumor size and to aid in visualization of the tumor as well as to
prevent blood loss related to surgical procedures.
[0048] "Gynecological embolization" refers to embolization used to
control acute and chronic genital bleeding in a wide variety of
obstetric and gynecological disorders, including uterine
fibroids.
[0049] The term "biocompatible polymer" refers to polymers which,
in the amounts employed, are non-toxic, chemically inert, and
substantially non-immunogenic when used internally in the patient
and which are substantially insoluble in blood. Suitable
biocompatible polymers include, by way of example, cellulose
acetates.sup.2,6-7 (including cellulose diacetate.sup.5), ethylene
vinyl alcohol copolymers.sup.4,8, hydrogels (e.g., acrylics),
polyacrylonitrile, polyvinylacetate, cellulose acetate butyrate,
nitrocellulose, copolymers of urethane/carbonate, copolymers of
styrene/maleic acid, and mixtures thereof..sup.9 Preferably, the
biocompatible polymer is also non-inflammatory when employed in
situ.
[0050] The particular 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 art.
[0051] Preferred 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. In a preferred embodiment, the number
average molecular weight, as determined by gel 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. As is apparent to one skilled in
the art, with all other factors being equal, 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.
[0052] 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 embolizing properties of the composition.
Such additional monomers include, by way of example only, maleic
anhydride, styrene, propylene, acrylic acid, vinyl acetate and the
like.
[0053] 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 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.degree. C. As is apparent to one skilled in the art, with all
other factors 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 mere adjustment of the molecular weight
of the copolymer composition.
[0054] As is also apparent, the ratio of ethylene to vinyl alcohol
in the copolymer affects the overall hydrophobicity/hydrophilicity
of the composition which, in turn, affects the relative water
solubility/insolubility of the composition as well as the rate of
precipitation of the copolymer in an aqueous solution (e.g.,
blood). In a particularly preferred embodiment, 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. These compositions provide for requisite precipitation
rates suitable for use in embolizing blood vessels in gynecological
embolization procedures.
[0055] The term "contrast agent" refers to a biocompatible
(non-toxic) radiopaque material capable of being monitored during
injection into a mammalian subject by, for example, radiography or
fluoroscopy. The contrast agent can be either water soluble or
water insoluble. Examples of water soluble contrast agents include
metrizamide, iopamidol, iothalamate sodium, iodomide sodium, and
meglumine.
[0056] The term "water insoluble contrast agent" refers to a water
insoluble (i.e., has a water solubility of less than 0.01 mg/ml at
20.degree. C.), radiopaque material capable of being monitored
during injection into a mammalian subject by, for example,
radiography. Examples of water insoluble contrast agents include
tantalum, tantalum oxide and barium sulfate, which are commercially
available in the proper form for in vivo use. Methods for preparing
such water insoluble biocompatible contrast agents having an
average particle size of about 10 .mu.m or less are described
below. Other water insoluble contrast agents include gold, tungsten
and platinum.
[0057] The term "biocompatible 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 blood.
Preferably, the biocompatible solvent is dimethylsulfoxide
(DMSO).
[0058] The term "encapsulation" as used relative to the contrast
agent being encapsulated in the polymer precipitate is not meant to
infer any physical entrapment of the contrast agent within the
precipitate much as a capsule encapsulates a medicament. Rather,
this term is used to mean that an integral coherent precipitate
forms which does not separate into individual components.
[0059] The term "biocompatible prepolymer" refers to materials
which polymerize in situ to form a polymer and which, in the
amounts employed, are non-toxic, chemically inert, and
substantially non-immunogenic when used internally in the patient
and which are substantially insoluble in blood. Suitable
biocompatible prepolymers include, by way of example,
cyanoacrylates.sup.10,11,12, hydroxyethyl methacrylate, silicon
prepolymers, and the like. The prepolymer can either be a monomer
or a reactive oligomer.sup.12. Preferably, the biocompatible
prepolymer is also non-inflammatory when employed in situ.
[0060] Compositions
[0061] Any conventional embolizing material may be used in the
methods of the present invention. The requirements are that such
materials may be delivered through the catheter to the vasculature
to be embolized and that they are biocompatible. Because in many
cases smaller catheters will be used for delivery of embolizing
materials to smaller vessels, smaller particle sizes of particulate
embolizing materials are preferred. However, such small particles
can be visualized under fluoroscopy and, accoridngly, migrate
during injection can cause unwanted ischemia and necrosis..sup.17
Small particles such as PVA can compact and migrate resulting in
incomplete embolization.
[0062] Therefore embolizing compositions which contain small
particles but which provide for a solid coherent in vivo, such as
those described below, are preferably used. Selection of a suitable
embolizing material is known to those of skill in the art.
[0063] The embolization composition can comprise either a
biocompatible polymer or prepolymer. For example, the polymer
compositions preferably 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.
[0064] For example, 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. Preferably, the polymer composition will
comprise from about 2.5 to about 8.0 weight percent of the
biocompatible polymer composition based on the total weight of the
polymer composition and more preferably from about 4 to about 5.2
weight percent. If necessary, gentle heating and stirring can be
used to effect dissolution of the biocompatible polymer into the
biocompatible solvent, e.g., 12 hours at 50.degree. C.
[0065] Sufficient amounts of the contrast agent are then added to
the biocompatible solvent to achieve the effective concentration
for the complete composition. Preferably, the 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 30 weight percent. When the contrast
agent is not soluble in the biocompatible solvent, stirring is
employed to effect homogeneity of the resulting suspension. In
order to enhance formation of the suspension, the particle size of
the insoluble contrast agent is preferably maintained at about 10
.mu.m or less and more preferably at from about 1 to about 5 .mu.m
(e.g., an average size of about 2 .mu.m). In one preferred
embodiment, the appropriate particle size of the contrast agent is
prepared, for example, by fractionation. In such an embodiment, a
water insoluble contrast agent such as tantalum having an average
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 an optical microscope. The process is optionally repeated
until a desired average particle size is reached.
[0066] The particular order of addition of components to the
biocompatible solvent is not critical and stirring of the resulting
suspension is conducted as necessary to achieve homogeneity of the
composition. Preferably, mixing/stirring of the composition is
conducted under an anhydrous atmosphere at ambient pressure. The
resulting composition is heat sterilized and then stored preferably
in sealed amber bottles or vials until needed.
[0067] Each of the polymers recited herein is commercially
available but can also be prepared by methods well known in the
art. For example, polymers are typically prepared by conventional
techniques such as radical, thermal, UV, .gamma. irradiation, or
electron beam induced polymerization employing, as necessary, a
polymerization catalyst or polymerization initiator to provide for
the polymer composition. The specific manner of polymerization is
not critical and the polymerization techniques employed do not form
a part of this invention.
[0068] In order to maintain solubility in the biocompatible
solvent, the polymers described herein are preferably not
cross-linked.
[0069] When the embolization composition comprises a prepolymer,
such prepolymer compositions can be prepared by adding sufficient
amounts of the contrast agent to the solution (e.g., liquid
prepolymer) to achieve the effective concentration for the complete
prepolymer composition. Preferably, the prepolymer 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 30 weight percent. When the contrast
agent is not soluble in the biocompatible prepolymer composition,
stirring is employed to effect homogeneity of the resulting
suspension. In order to enhance formation of the suspension, the
particle size of the contrast agent is preferably maintained at
about 10 .mu.m or less and more preferably at from about 1 to about
5 .mu.m (e.g., an average size of about 2 .mu.m).
[0070] When the prepolymer is liquid, the use of a biocompatible
solvent is not absolutely necessary but may be preferred to provide
for an appropriate viscosity, etc. in the embolic composition.
Preferably, when employed, the biocompatible solvent will comprise
from about 30 to about 90 weight percent of the biocompatible
prepolymer composition based on the total weight of the prepolymer
composition and more preferably from about 60 to about 80 weight
percent. When a biocompatible solvent is employed, the prepolymeric
composition typically comprises from about 10 to about 50 weight
percent of the prepolymer based on the total weight of the
composition.
[0071] In a particularly preferred embodiment, the prepolymer is a
cyanoacrylate ester which is preferably employed in the absence of
a biocompatible solvent. When so employed, the cyanoacrylate
composition is selected to have a viscosity of from about 5 to
about 20 centipoise at 20.degree. C.
[0072] The particular order of addition of components is not
critical and stirring of the resulting suspension is conducted as
necessary to achieve homogeneity of the composition. Preferably,
mixing/stirring of the composition is conducted under an anhydrous
atmosphere at ambient pressure. The resulting composition is
sterilized and then stored preferably in sealed amber bottles or
vials until needed.
[0073] When the contrast agent employed in the polymer or
prepolymer composition is less than about 100 .mu.m in average
particle size, the composition is sometimes referred to herein as a
"fluid composition".
[0074] Methods
[0075] Suitable embolizing compositions such as those described
above can be employed in the claimed methods for gynecological
embolization of blood vessels. In the claimed methods, a catheter
capable of penetrating a vessel to be embolized, such as a needle
tipped (20 G) catheter (3-5 French), is inserted through the cervix
into the uterus using a device, such as a hysteroscope, which
allows visualization of the uterine wall. Generally, the patient is
prepared in the usual manner for a hysteroscopic procedure, and
warm saline is infused to inflate the uterus and help visualize the
uterine wall using the hysteroscope, then the catheter is inserted
through the scope. The vessel to be embolized is located and the
catheter inserted through the uterine wall and placed in the
vessel, e.g., the position of a uterine fibroid is determined and
the needle tip of the catheter placed in a blood vessel feeding or
within the fibroid mass.
[0076] In a preferred method, a detectable contrast agent is
injected by syringe through the catheter and, using, e.g.,
fluoroscopy, the needle tip positioned into the desired
vasculature. When the tip of the catheter is positioned as desired,
an embolic material is injected to precisely embolize the desired
vessel(s). Repeated placement of the catheter, contrast injection
and embolization may be needed to completely embolize the
vasculature of, e.g., a uterine fibroid or tumor tissue.
[0077] In such methods, a sufficient amount of embolizing
composition is introduced into the selected blood vessel via a
catheter delivery means, preferably under fluoroscopy, so that the
blood vessel is embolized. The particular amount of embolizing
composition employed is dictated by the total volume of the
vasculature to be embolized, the concentration of
polymer/prepolymer in the composition, the rate of precipitation
(solids formation) of the polymer, etc. Such factors are well
within the skill of the art.
[0078] One particularly preferred method for catheter delivering
the embolizing compositions of this invention to the selected
vascular site is via a small diameter medical catheter. The
particular catheter employed is not critical provided that
polymeric catheter components are compatible with the embolizing
composition (i.e., the catheter components will not readily degrade
in the embolizing composition). In this regard, it is preferred to
use polyethylene in the catheter components because of its
inertness in the presence of the embolizing composition described
herein. Other materials compatible with the embolizing compositions
can be readily determined by the skilled artisan and include, for
example, other polyolefins, fluoropolymers (e.g., Teflon.TM.),
silicone, etc.
[0079] When a polymer composition is introduced into the vascular
site, the biocompatible solvent diffuses rapidly into the blood and
a solid precipitate forms which precipitate is the water insoluble
polymer with the contrast agent encapsulated therein. Without being
limited to any theory, it is believed that initially, a soft gel to
spongy solid precipitate forms upon contact with the blood. This
precipitate then restricts blood flow, entrapping red cells thereby
causing clot embolization of the blood vessel.
[0080] When a prepolymer composition is introduced into the
vascular site, the prepolymer rapidly polymerizes and a solid
biocompatible polymer forms in the blood vessel which polymer
embolizes the blood vessel. Without being limited to any theory, it
is believed that initially, a soft gel to spongy solid precipitate
forms upon contact with the blood. This precipitate then restricts
blood flow, entrapping red cells thereby causing clot embolization
of the blood vessel.
[0081] Utility
[0082] The methods described herein are useful in gynecological
embolization to prevent/control bleeding related to gynecological
and/or obstetrical conditions. Accordingly, these compositions find
use in human and other mammalian subjects requiring such
embolization of blood vessels. Additionally, the methods can be
used in the reversible sterilization of mammalian patients as
described in concurrently filed applications by Evans, et
al..sup.13,14.
[0083] The following examples are set forth to illustrate the
claimed invention and are not to be construed as a limitation
thereof.
EXAMPLES
[0084] Unless otherwise stated, all temperatures are in degrees
Celsius. Also, in these examples and elsewhere, the following
abbreviations have the following meanings:
1 cc = cubic centimeter cm = centimeter DMSO = dimethylsulfoxide
EVOH = ethylene vinyl alcohol copolymer g = gram ID = internal
diameter in. = inch min. = minute mL = milliliter mm = millimeter
OD = outer diameter sec. = seconds .mu.m = micron
Example 1
[0085] In a gynecologist's office, a patient suffering from
excessive vaginal bleeding due to uterine fibroids is prepared in
the usual manner for a hysteroscopic procedure. Warm saline is
infused to inflate the uterus and help visualize the uterine wall
using the hysteroscope, then a needle tipped (20 G) catheter (5
French in size) is inserted through the scope so that it is
inserted through the cervix and into the uterus of the patient.
[0086] The position of a uterine fibroid is determined and the
needle tip of the catheter placed in a blood vessel within the
fibroid mass. An aqueous based iodinated contrast agent is injected
by syringe through the catheter and then the needle tip is
positioned into the desired vasculature. Using fluoroscopy, a flow
of contrast agent is used to determine proper placement of the
catheter.
[0087] When the tip of the catheter is positioned as desired, a
liquid embolic material under fluoroscopic digital roadmapping is
injected to precisely embolize the desired vessel(s) in the
fibroid. Repeated placement of the catheter, contrast injection and
embolization is performed until the vasculature of the uterine
fibroid is completely embolized.
[0088] From the foregoing description, various modifications and
changes in the composition and method will occur to those skilled
in the art. All such modifications coming within the scope of the
appended claims are intended to be included therein.
* * * * *