U.S. patent application number 11/094390 was filed with the patent office on 2005-09-08 for kit of parts for treating urinary incontinence in mammals.
This patent application is currently assigned to Micro Therapeutics, Inc.. Invention is credited to Greff, Richard J., Wallace, George.
Application Number | 20050196341 11/094390 |
Document ID | / |
Family ID | 23029212 |
Filed Date | 2005-09-08 |
United States Patent
Application |
20050196341 |
Kind Code |
A1 |
Wallace, George ; et
al. |
September 8, 2005 |
Kit of parts for treating urinary incontinence in mammals
Abstract
Disclosed are methods for treating urinary incontinence in a
mammal wherein a composition comprising a biocompatible polymer, a
biocompatible solvent, and a contrast agent is delivered to the
periurethral tissue of the mammal.
Inventors: |
Wallace, George; (Coto De
Caza, CA) ; Greff, Richard J.; (St. Pete Beach,
FL) |
Correspondence
Address: |
FOLEY & LARDNER LLP
1530 PAGE MILL ROAD
PALO ALTO
CA
94304
US
|
Assignee: |
Micro Therapeutics, Inc.
Irvine
CA
|
Family ID: |
23029212 |
Appl. No.: |
11/094390 |
Filed: |
March 29, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11094390 |
Mar 29, 2005 |
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10330533 |
Dec 30, 2002 |
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10330533 |
Dec 30, 2002 |
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09848303 |
May 4, 2001 |
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6555104 |
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09848303 |
May 4, 2001 |
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09269931 |
Sep 27, 1999 |
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6569417 |
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09269931 |
Sep 27, 1999 |
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PCT/US97/18313 |
Oct 10, 1997 |
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Current U.S.
Class: |
424/9.4 ;
424/78.31; 514/57 |
Current CPC
Class: |
A61K 49/0002 20130101;
A61K 31/765 20130101; A61K 49/048 20130101; A61K 31/717
20130101 |
Class at
Publication: |
424/009.4 ;
424/078.31; 514/057 |
International
Class: |
A61K 049/04; A61K
031/74; A61K 031/716 |
Claims
What is claimed is:
1. A method for treating urinary incontinence in a mammal, which
method comprises delivering a composition comprising a
bidcompatible polymer, a biocompatible solvent, and a contrast
agent to the periurethral tissue of the mammal wherein said
delivery is conducted under conditions such that a polymer
precipitate forms in situ in the periurethral tissue thereby
reducing urinary incontinence in the mammal.
2. The method according to claim 1 wherein said biocompatible
polymer is selected from the group consisting of cellulose acetate
polymers, ethylene vinyl alcohol copolymers and polyacrylates.
3. The method according to claim 2 wherein said biocompatible
polymer is a cellulose acetate polymer or an ethylene vinyl alcohol
copolymer.
4. The method according to claim 1 wherein said biocompatible
solvent is selected from the group consisting of dimethylsulfoxide,
ethanol, and acetone.
5. The method according to claim 4 wherein said biocompatible
solvent is dimethylsulfoxide.
6. The method according to claim 1 wherein said contrast agent is a
water insoluble contrast agent.
7. The method according to claim 6 wherein said water insoluble
contrast agent is selected from the group consisting of tantalum,
tantalum oxide, tungsten, and barium sulfate.
8. The method according to claim 1 wherein said contrast agent is a
water soluble contrast agent.
9. The method according to claim 8 wherein said water soluble
contrast agent is metrizamide.
10. The method according to claim 1 wherein said composition is
delivered into the periurethral tissue via a cystoscope.
11. A method for the delivery of a composition comprising a
biocompatible polymer, a biocomparible solvent, and a water
insoluble contrast agent to the periurethral 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 periurethral tissue delivering
a composition comprising a biocompatible polymer, a biocompatible
solvent, and a contrast agent to the periurethral 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 periurethral tissue thereby
further reducing urinary incontinence in the mammal.
12. The method according to claim 11 wherein visualization is
conducted by direct visualization, fluoroscopy or ultrasound.
13. A kit of parts comprising: a first member which is an embolic
composition comprising a biocompatible polymer, a biocompatible
solvent and a contrast agent; and a second member which is a needle
selected from the group consisting of a puncture needle and spinal
needle.
14. The kit of parts according to claim 13 wherein said
biocompatible polymer is selected from the group consisting of
cellulose acetates, ethylene vinyl alcohol copolymers,
polyalkyl(C.sub.1-C.sub.6)acrylates, polyalkyl alkacrylates wherein
the alkyl and the alk groups contain no more than 6 carbon atoms;
and polyacrylonitrile.
15. The kit of parts according to claim 14 wherein said
biocompatible polymer is a cellulose acetate polymer or an ethylene
vinyl alcohol copolymer.
16. The kit of parts according to claim 14 wherein said
biocompatible solvent is selected from the group consisting of
dimethylsulfoxide, ethanol, and acetone.
17. The kit of parts according to claim 16 wherein said
biocompatible solvent is dimethylsulfoxide.
18. The kit of parts according to claim 13 wherein said contrast
agent is a water insoluble contrast agent.
19. The kit of parts according to claim 18 wherein said water
insoluble contrast agent is selected from the group consisting of
tantalum, tantalum oxide, tungsten, and barium sulfate.
20. A method for treating urinary incontinence in a mammal, which
method comprises delivering a composition comprising a
biocompatible polymer and a biocompatible solvent to the
periurethral tissue of the mammal wherein said delivery is
conducted under conditions such that a polymer precipitate forms in
situ in the periurethral tissue thereby reducing urinary
incontinence in the mammal.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention is directed to methods for treating urinary
incontinence in mammals generally and humans in particular. In
these methods, a composition comprising a biocompatible polymer, a
biocompatible solvent and a contrast agent is delivered to the
periurethral tissue of a mammal.
[0003] The biocompatible polymer is selected to be soluble in the
biocompatible solvent, but insoluble in the periurethral tissue.
The biocompatible solvent is miscible or 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 in the periurethral tissue which
compresses the urethra thereby preventing or reducing the
involuntary leakage of urine from the bladder.
REFERENCES
[0004] The following publications are cited in this application as
superscript numbers:
[0005] .sup.1Murless, "The Injection Treatment of Stress
Incontinence," J. Obstet. Gynaecol., 45: 67-73 (1938).
[0006] .sup.2Quackels, "Deux Incontinences Aprs Adnomecomie Guries
Par Injection de Paraffine Dans Le Prine," Acta Urol. Belg., 23:
259-262 (1955).
[0007] .sup.3Sachse, "Treatment of Urinary Incontinence with
Sclerosing Solutions: Indications, Results, Complications," Urol.
Int., 15: 225-244 (1963).
[0008] .sup.4Politano. et al., "Periurethral Teflon Injection for
Urinary Incontinence." J. Urol., 111: 180-183 (1974).
[0009] .sup.5Lim, et al., "Periurethral Teflon Injection: A Simple
Treatment for Urinary Incontinence," Br. J. Urol., 55: 208-210
(1983).
[0010] .sup.6Schulman, et al., "Endoscopic Injection of Teflon to
Treat Urinary Incontinence in Women," BMJ, 228: 192 (1984).
[0011] .sup.7Rodriguez, "Late Results of the Endourethral Injection
of Teflon in Stress Urinary Incontinence," J. Urol. (Paris), 62:
39-41 (1987).
[0012] .sup.8Vesey, et al., "Teflon Injection in Female Stress
Incontinence. Effect on Urethral Pressure Profile and Flow Rate,"
Br. J. Urol., 62: 39-41 (1988).
[0013] .sup.9Smart, "Poltef Paste for Urinary Incontinence," Aust.
N. Z. J. Surg., 61: 663-666 (1991).
[0014] .sup.10Malizia, et al., "Migration and Granulomatous
Reaction After Periurethral Injection of Polytef (Teflon)," JAMA,
251: 3227-3281 (1984).
[0015] .sup.11Stricker, et al., "Injectable Collagen for Type 3
Female Stress Incontinence: The First 50 Australian Patients," Med.
J. Aust., 158: 89-91 (1993).
[0016] .sup.12Moore, et al., "Periurethral Implantation of
Glutaraldehyde Cross-Linked Collagen (Contigen.RTM.) in Women with
Type I or III Stress Incontinence: Quantitative Outcome Measures,"
Br. J. Urol., 75: 359-363 (1995).
[0017] .sup.13Capozza, et al., "Endoscopic Treatment of
Vesico-Ureteric Reflux and Urinary Incontinence: Technical Problems
in the Pediatric Patient," Br. J. Urol., 75: 538-542.(1995).
[0018] .sup.14Atala, et al., "Injectable Alginate Seeded with
Chondrocytes as a Potential Treatment for Vesicoureteral Reflux,"
J. Urol., 150: 745-747 (1993).
[0019] .sup.15Meriguerian, et al., "Submucosal Injection of
Polyvinyl Alcohol Foam in Rabbit Bladder," J. Urol., 144: 531-533
(1990).
[0020] .sup.16Walker, et al., "Injectable Bioglass as a Potential
Substitute for Injectable Polytetrafluoroethylene," J. Urol., 148:
645 (1992).
[0021] .sup.17Atala, et al., "Endoscopic Treatment of
Vesicoureteral Reflux with a Self-Detachable Balloon System," J.
Urol., 148: 724-728 (1992).
[0022] .sup.18Kinugasa, et al., "Direct Thrombosis of Aneurysms
with Cellulose Acetate Polymer", J. Neurosurg., 77:501-507
(1992).
[0023] .sup.19Kinugasa, et al., "Early Treatment of Subarachnoid
Hemorrhage After Preventing Rerupture of an Aneurysm", J.
Neurosurg., 83:34-41 (1995).
[0024] .sup.20Kinugasa, et al., "Prophylactic Thrombosis to Prevent
New Bleeding and to Delay Aneurysm Surgery". Neurosurg., 36:661
(1995).
[0025] .sup.21Greff, et al., U.S. patent application Ser. No.
08/508,248 for "Cellulose Diacetate Compositions for Use in
Embolizing Blood Vessels", filed Jul. 27, 1995.
[0026] .sup.22Greff, et al., U.S. patent application Ser. No.
08/507,863 for "Novel Compositions for Use in Embolizing Blood
Vessels", filed Jul. 27, 1995.
[0027] .sup.23Taki, et al., "Selection and Combination of Various
Endovascular Techniques in the Treatment of Giant Aneurysms", J.
Neurosurg., 77:37-42 (1992).
[0028] .sup.24Park. et al., "New Polymers for Therapeutic
Embolization", Poster #47, Meeting of Radiological Society of North
America (1993)
[0029] .sup.25Winters. et al., "Periurethral Injection of Collagen
in the Treatment of Intrinsic Sphincteric Deficiency in the Female
Patient", Urologic Clinics of North America, 22(3):473-478
(1995)
[0030] All of the above references are herein incorporated by
reference in their entirety to the same extent as if each
individual reference was specifically and individually indicated to
be incorporated herein by reference in its entirety.
[0031] 2. State of the Art
[0032] Urinary incontinence is an extremely common problem
especially in women. In particular, many women suffer from
incontinence including stress incontinence. In this condition, the
pelvic-floor muscles which support the base of the bladder and
close off the top of the urethra are weakened by, for example,
childbirth or obesity. As a result, when pressure is exerted on
these muscles by coughing, lifting, etc., urine is involuntarily
discharged from the bladder through the urethra.
[0033] The initial treatment for stress incontinence typically
consists of exercises to strengthen the pelvic-floor muscles. If
these exercises are ineffective, open surgical repair of the
bladder neck is often attempted. However, such surgical repair
procedures are not successful for all patients. Moreover, there are
always certain risks associated with open surgical procedures, such
as trauma, infection, risks of anesthesia, etc.
[0034] As an alternative to surgical repair, urinary incontinence
has been treated by injecting various substances into the tissue
surrounding the urethra, i.e., the periurethral tissue, to add bulk
to this tissue. The aim of this treatment is to compress the
urethra at the level of the bladder neck thus impeding the
involuntary flow of urine from the bladder. Many substances have
been tried for this purpose with varying results.
[0035] For example, Murless has reported the use of sodium
morrhuate for the treatment of stress incontinence..sup.1. However,
this material was not successful in preventing incontinence and
pulmonary infarction was observed as a complication. Similarly,
paraffin.sup.2 and other sclerosing solutions.sup.3 have been tried
with poor results.
[0036] More recently, polytetrafluoroethylene particles
(TEFLON.TM., POLYTEF.TM.) have been used as an injectable material
for the correction of urinary incontinence with a success rate of
from 30% to 86% in some studies..sup.4-9 However, these particles
have subsequently been demonstrated to generate foreign body
granulomas and to migrate to distant organs, such as the lungs,
liver, spleen and brain..sup.10 Accordingly, the use of
polytetrafluoroethylene particles is currently disfavored.
[0037] Another injectable material that has been used recently for
the treatment of urinary incontinence is glutaraldehyde
cross-linked bovine dermal collagen..sup.11-13 However, a major
problem associated with the use of collagen materials is the
tendency of the implant to decrease in volume over time thereby
necessitating retreatment..sup.14 In addition, collagen has been
associated with adverse immune responses and allergic reactions to
bovine dermal collagen have been described..sup.12
[0038] Various other 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,.sup.15 glass particles,.sup.16 a
chondrocyte-alginate suspension.sup.14 and a detachable silicone
balloon..sup.17
[0039] In addition to the various problems associated with many of
the substances used to treat urinary incontinence, the methods
currently employed for delivering injectable materials to the
periurethral tissue have certain disadvantages. In particular, the
amount of material necessary to compress the urethra must typically
be estimated by observing the compression of the urethra wall using
a cystoscope or endoscope. If an insufficient amount of material is
injected in the first procedure, top-up injections administered in
subsequent procedures may be necessary..sup.11 Accordingly, it
would be advantageous to be able to more accurately monitor the
size of the occlusion formed by the injected material to ensure
that it is sufficient to block the involuntary leakage of urine
from the bladder. Additionally, if follow-up injections are
necessary, it would be advantageous to be able to locate accurately
the site of the material previously injected.
[0040] In view of the above, it is evident that there is an ongoing
need in the art for new methods of treating urinary incontinence in
mammals. Preferably, such methods would allow an occlusion-forming
substance to be delivered accurately to the periurethral tissue.
The substance employed would preferably conserve its volume in
vivo, be non-migratory and be substantially non-immunogenic.
[0041] This invention is directed to the discovery that urinary
incontinence can be treated in mammals by delivering sufficient
amounts of a composition comprising a biocompatible polymer a
biocompatible solvent, and a contrast agent to the periurethral
tissue under conditions such that a polymer precipitate forms in
situ in the periurethral tissue. This polymer precipitate
compresses the urethral opening thereby affording increased outlet
resistance and reducing urinary incontinence in the mammal. The
polymeric compositions of this invention are non-biodegradable and,
accordingly, do not substantially decrease in volume over time.
Moreover, the injection process provides for a coherent mass, not
particulates, which mass is nonmigratory. Moreover, the contrast
agent permits monitoring of the injection by conventional methods
while it is taking place to ensure that it is being carried out
properly. The contrast agent also allows monitoring post-injection
by conventional methods to ensure correct placement of the mass
months or even years after injection. Conventional monitoring
methods include, by way of example, fluoroscopy, ultrasound, and in
some cases visual detection.
SUMMARY OF THE INVENTION
[0042] This invention is directed to the discovery that unexpected
and surprising results are achieved when mammals with urinary
incontinence are treated with a composition comprising a
biocompatible polymer, a biocompatible solvent, and a contrast
agent. In particular, deficiencies associated with the prior art
procedures are reduced by the invention. Such deficiencies include,
for example, problems associated with migration of particulates
over time, the biodegradation of the injected mass (e.g., collagen
type materials) employed to form an occlusion in the periurethral
tissue of the mammal, problems associated with the accurate
delivery of such substances, and problems associated with
post-delivery monitoring of the deposited materials.
[0043] Accordingly, in one of its method aspects, this invention is
directed to a method for treating urinary incontinence in a
manunal, which method comprises delivering a composition comprising
a biocompatible polymer, a biocompatible solvent, and a contrast
agent to the periurethral tissue of the mammal
[0044] wherein said delivery is conducted under conditions such
that a polymer precipitate forms in situ in the periurethral tissue
thereby reducing the urinary incontinence in the mammal.
[0045] In another aspect of this invention, the use of a contrast
agent is not required and the method is conducted by delivering a
composition comprising a biocompatible polymer and a biocompatible
solvent to the periurethral tissue of the mammal
[0046] wherein said delivery is conducted under conditions such
that a polymer precipitate forms in situ in the periurethral tissue
thereby reducing the urinary incontinence in the mammal.
[0047] However, the use of a contrast agent in the composition is
preferred.
[0048] The methods of this invention are preferably practiced using
a kit of parts comprising:
[0049] a first member which is a polymeric composition comprising a
biocompatible polymer, a biocompatible solvent and a contrast
agent; and
[0050] a second member which is a needle selected from the group
selected of a puncture needle and spinal needle.
[0051] In the embolic compositions employed herein, the
biocompatible polymer is preferably an ethylene vinyl alcohol
copolymer or a cellulose acetate polymer. In a particularly
preferred embodiment, the biocompatible polymer is selected to be
substantially non-immunogenic.
[0052] The biocompatible solvent is preferably dimethylsulfoxide
and, more preferably, anhydrous dimethylsulfoxide.
DETAILED DESCRIPTION OF THE INVENTION
[0053] This invention is directed to methods for treating urinary
incontinence in mammals, which methods comprise delivering a
composition comprising a biocompatible polymer, a biocompatible
solvent, and a contrast agent to the periurethral tissue of the
mammal.
[0054] Prior to discussing this invention in further detail, the
following terms will first be defined:
[0055] The term "urinary incontinence" refers to the involuntary
leakage of urine through the urethra from the bladder. Methods for
diagnosing urinary incontinence are well known to those skilled in
the relevant art. Such methods included, for example, video
urodynamics and pad tests as described by Moore, et al..sup.12
[0056] The term "periurethral tissue" refers to the tissue
surrounding the urethra. As is understood in the art, the urethra
is an orifice attached at its base to the bladder and permits
discharge of urine from the bladder. Preferably, the polymeric
compositions of the present invention are delivered to the
periurethral tissue at or near the base of the urethra.
[0057] The term "biocompatible polymer" refers to polymers which,
in the amounts employed are 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 periurethral tissue. 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.sup.18-20 (including cellulose
diacetate.sup.21), ethylene vinyl alcohol copolymers.sup.22,23,
polyalkyl(C.sub.1-C.sub.6)acrylates, polyalkyl alkacrylates 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 Ser. 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..sup.24 Preferably, the biocompatible polymer is
also non-inflammatory when employed in vivo.
[0058] 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 artisan.
[0059] Preferably, the biocompatible polymers do not appreciably
absorb water upon contact with the fluid of the periurethral tissue
and typically will have an equilibrium water content of less than
about 25% water and preferably less than about 15% water.
[0060] Particularly 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.
[0061] 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. Such additional monomers include, by way of example
only, maleic anhydride, styrene, propylene, acrylic acid, vinyl
acetate, and the like.
[0062] 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 or
needle delivery can be readily achieved by mere adjustment of the
molecular weight of the copolymer composition.
[0063] 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 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). 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. 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. These compositions provide for
requisite precipitation rates suitable for treating urinary
incontinence in mammals.
[0064] 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.
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.
Examples of water insoluble contrast agents include tantalum,
tantalum oxide, and barium sulfate, each of which is commercially
available in the proper form for in vivo use including a particle
size of about 10 .mu.m or less. Other water insoluble contrast
agents include gold, tungsten, and platinum powders.
[0065] Preferably, the contrast agent is water insoluble (i.e., has
a water solubility of less than 0.01 mg/ml at 20.degree. C.).
[0066] 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 periurethral
tissue. Preferably, the biocompatible solvent is
dimethylsulfoxide.
[0067] Compositions
[0068] 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.
[0069] 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 based on the total weight of the polymer
composition, including contrast agent and biocompatible solvent,
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.
[0070] Sufficient amounts of the contrast agent are then added to
the solution to achieve the effective concentration for the
complete polymer composition. Preferably, 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. 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 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 particle size of a water insoluble contrast agent
is prepared, for example, by fractionation. In-such an embodiment,
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 o~f the particle size which is confirmed under a
microscope. The process is optionally repeated until a desired
particle size is reached.
[0071] 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 may be heat sterilized and then stored
preferably in sealed bottles (e.g., amber vials) or vials until
needed.
[0072] Methods
[0073] The compositions described above are then employed in
methods for treating urinary incontinence in mammals. In these
methods, the composition is introduced to the periurethral tissue
via conventional catheter or needle technology using, for example,
cystoscopic techniques. Specifically, the injection may be
performed through a puncture needle or spinal needle placed
directly through the cystoscope or periurethrally with a spinal
needle placed percutaneously at the introitus and positioned in the
tissue adjacent to the urethra as described by Winters, et
al..sup.25 Alternatively, the periurethral tissue can be expose
surgically and the composition injected directly into the
tissue.
[0074] Upon discharge of the composition from the catheter or the
needle into the periurethral tissue, the biocompatible solvent
dissipates into the fluid of the periurethral tissue resulting in
the precipitation of the biocompatible polymer which precipitate
forms a coherent mass. The formed precipitate in the periurethral
tissue swells this tissue restricting the urethral orifice thus
impeding the involuntary flow of urine from the bladder.
[0075] The particular amount of polymer composition employed is
dictated by the level of pre-existing support of the periurethral
tissue, 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 support of the periurethral
tissue will require injection of more polymer composition in order
to bulk up this tissue and constrict the urethra as compared to
individuals with stronger pre-existing support.
[0076] The methods of this invention are particularly advantageous
because the presence of the contrast agent in the composition
permits, if desired, monitoring of the delivery of the
biocompatible polymer while it is taking place either by
fluoroscopy, ultrasound, or-visually. In this-way, one can ensure
that the biocompatible polymer is being delivered to the optimal
location in the periurethral tissue as well as determine whether
the size of the polymer precipitate thus-formed will be sufficient
to block the involuntary leakage of urine from the bladder.
[0077] Moreover, 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.
[0078] When delivery of the polymeric composition to the
periurethral tissue is conducted via a cystoscope used in
combination with a small diameter medical catheter (which typically
employs a needle as described by Capozza, et al..sup.13), 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).
In this regard, it is preferred to use 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.
[0079] When introduced into the periurethral tissue, the
biocompatible solvent rapidly diffuses into the fluids of this
tissue leaving a solid precipitate. The precipitate is a coherent
mass comprising a combination of the biocompatible polymer and the
contrast agent. Without being limited to any theory, it is believed
that this-precipitate bulks up the periurethral tissue thereby
increasing outlet resistance to urinary flow from the bladder. This
enhanced outlet resistance reduces the urinary incontinence in the
treated mammal.
[0080] Another advantage of this invention is that the precipitate
forms a coherent mass which is substantially retained at the site
of injection thereby obviating prior art concerns with migration of
injected particulates into the periurethral tissue. Moreover, the
polymeric compositions of this invention are non-biodegradable and,
accordingly, do not substantially decrease in volume over time.
[0081] Still another advantage of this invention is that the
polymer employed can be selected to be non-immunogenic thereby
obviating concerns raised by use of collagen-type materials which
can produce an immune response in vivo.
[0082] Yet another advantage of this invention is the formation of
a polymeric mass in the periurethral tissue 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 urinary incontinence 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.
[0083] In view of the above, the methods of this invention are
preferably practiced using a kit of parts which kit contains a
first member which is a polymeric composition comprising a
biocompatible polymer, a biocompatible solvent and a contrast
agent, and a second member which is a needle selected from the
group consisting from a puncture needle and spinal needle.
[0084] Utility
[0085] The methods described herein are useful in treating mammals
with urinary incontinence. Accordingly, these methods find use in
human and other mammalian subjects requiring such treatment.
[0086] Additionally, it is contemplated that the compositions of
this invention can be used to treat vesicoureteral reflux in a
mammal. In this condition, urine from the bladder refluxes into a
ureter often causing infection. It is contemplated the such reflux
can be treated by delivering a composition comprising a
biocompatible polymer, a biocompatible solvent, and a contrast
agent to the subureteral tissue of the mammal. This delivery would
be conducted under conditions such that a polymer precipitate forms
in situ in the subureteral tissue thereby reducing vesicoureteral
reflux in the mammal. The formation of a polymer precipitate in the
subureteral tissue is expected to compress the ureter thereby
reducing the reflux of urine into the ureter. Methods for
delivering the composition to treat vesicoureteral reflux are
described by Capozza, et al..sup.13
[0087] The following examples are set forth to illustrate the
claimed invention and are not to be construed as a limitation
thereof.
EXAMPLES
[0088] 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 DMSO = dimethylsulfoxide EVOH = ethylene
vinyl alcohol copolymer mL = milliliter mm = millimeter .mu.m =
micron
[0089] In the following examples, 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 the biocompatibility, non-migratory
and bulking properties of an EVOH polymer in vivo.
Example 1
[0090] An EVOH polymer composition was prepared by combining 8
grams of EVOH (44 mole percent ethylene), 30 grams of tantalum
having an average particle size of about 3 .mu.m (narrow size
distribution), and 100 mL of anhydrous DMSO. Heating at about
50.degree. C. for about 12 hours was used to aid dissolution. The
composition was mixed until homogeneous.
[0091] Tantalum having an average particle size of about 3 .mu.m
(narrow size distribution) was prepared by fractionation wherein
tantalum, having an average particle size of less than about 20
.mu.m, was added to ethanol (absolute) in a clean environment.
Agitation of the resulting suspension was followed by settling for
approximately 40 sec. 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
Alphaphot.TM.). The process was repeated, as necessary, until an
average 3 .mu.m particle size was reached.
Example 2
[0092] 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
about 3 .mu.m (narrow size distribution), and 100 mL of DMSO. The
composition is mixed until homogeneous. Tantalum having an average
particle size of about 3 .mu.m (narrow size distribution) is
prepared by fractionation as described in Example 1.
Example 3
[0093] The purpose of this example is to demonstrate the
biocompatibility of an EVOH polymer with the bladder tissue of a
mammal and to illustrate the non-migratory properties of such a
polymer. Additionally, this example illustrates the ability of such
a polymer to serve as a bulking agent in bladder tissue.
[0094] Female New Zealand white rabbits were utilized for this
investigation. Using a 26 gauge needle, several 0.5 cc injections
of an EVOH polymer composition, prepared in a manner essentially
the same as that described in Example 1, were made submucosally in
the bladder of each rabbit while the animals were under general
anesthesia. Prior to sacrifice, x-rays were obtained to search for
migration of the injected material. Two rabbits were sacrificed at
one week post-injection and the bladders excised and examined
histologically via 5 micron sectioning/staining of fresh-frozen and
paraffin embedded tissue samples of the injection sites and
surrounding areas. The injection sites showed black pigmentation
(tantalum) with some inflammation and cellular infiltration, i.e.,
a typical foreign body reaction. Tissues surrounding the injection
site were normal. The implant had not migrated and appeared as one
coherent mass.
[0095] 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.
* * * * *