U.S. patent application number 12/909737 was filed with the patent office on 2011-02-10 for embolization.
This patent application is currently assigned to Boston Scientific Scimed, Inc., a Minnesota corporation. Invention is credited to Thomas V. Casey, II, Greg Kapoglis, Janel Lanphere, Ernest J. St. Pierre.
Application Number | 20110033553 12/909737 |
Document ID | / |
Family ID | 40352702 |
Filed Date | 2011-02-10 |
United States Patent
Application |
20110033553 |
Kind Code |
A1 |
Lanphere; Janel ; et
al. |
February 10, 2011 |
Embolization
Abstract
A composition includes a plurality of particles. At least some
of the plurality of particles include cross-linked polyvinyl
alcohol and have a diameter of about 500 microns or less. The
particles have a first average pore size in an interior region, and
a second average pore size at a surface region. The first average
pore size being greater than the second average pore size. The
composition also includes a carrier fluid. The plurality of
particles being in the carrier fluid.
Inventors: |
Lanphere; Janel; (Newton,
MA) ; Pierre; Ernest J. St.; (South Attleboro,
MA) ; Kapoglis; Greg; (Salem, MA) ; Casey, II;
Thomas V.; (Grafton, MA) |
Correspondence
Address: |
FISH & RICHARDSON P.C. (BO)
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Assignee: |
Boston Scientific Scimed, Inc., a
Minnesota corporation
|
Family ID: |
40352702 |
Appl. No.: |
12/909737 |
Filed: |
October 21, 2010 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12236051 |
Sep 23, 2008 |
7842377 |
|
|
12909737 |
|
|
|
|
10637130 |
Aug 8, 2003 |
7449236 |
|
|
12236051 |
|
|
|
|
10215594 |
Aug 9, 2002 |
7588780 |
|
|
10637130 |
|
|
|
|
10615276 |
Jul 8, 2003 |
|
|
|
12236051 |
|
|
|
|
Current U.S.
Class: |
424/501 ;
428/402; 514/772.4 |
Current CPC
Class: |
Y10T 428/249961
20150401; A61L 2430/36 20130101; Y10T 428/249953 20150401; A61K
49/0452 20130101; Y10T 428/2982 20150115; A61K 9/1652 20130101;
A61P 7/00 20180101; Y10T 428/24942 20150115; A61K 9/1635 20130101;
Y10S 514/964 20130101; A61L 24/0036 20130101; Y10S 514/951
20130101 |
Class at
Publication: |
424/501 ;
428/402; 514/772.4 |
International
Class: |
B32B 1/04 20060101
B32B001/04; A61K 9/14 20060101 A61K009/14; A61K 47/30 20060101
A61K047/30; A61P 7/00 20060101 A61P007/00 |
Claims
1.-31. (canceled)
32. A particle having a diameter of about 500 microns or less,
wherein the particle comprises a cross-linked polymer, the particle
has a first density of pores in an interior region and a second
density of pores at a surface region, and the first density is
different from the second density.
33. The particle of claim 32, wherein the polymer comprises
polyvinyl alcohol.
34. The polymeric particle of claim 32, wherein the first density
is greater than the second density.
35. The polymeric particle of claim 32, wherein the particle has a
first average pore size in the interior region and a second average
pore size at the surface region, the first average pore size being
different from the second average pore size.
36. The polymeric particle of claim 35, wherein the first average
pore size is greater than the second average pore size.
37. The polymeric particle of claim 32, wherein the particle has a
diameter of about 10 microns or more.
38. The polymeric particle of claim 32, wherein the particle has a
diameter of about 100 microns or more.
39. The polymeric particle of claim 37, wherein the particle has a
diameter of about 300 microns or less.
40. The polymeric particle of claim 32, wherein the particle has a
diameter of about 300 microns or more.
41. The polymeric particle of claim 32, wherein the polymer
comprises at least one polymer selected from the group consisting
of polyvinyl alcohols, polyacrylic acids, polymethacrylic acids,
poly vinyl sulfonates, carboxymethyl celluloses, hydroxyethyl
celluloses, substituted celluloses, polyacrylamides, polyethylene
glycols, polyamides, polyureas, polyurethanes, polyesters,
polyethers, polystyrenes, polysaccharides, polylactic acids,
polyethylenes, polymethylmethacrylates, polycaprolactones,
polyglycolic acids, and poly(lactic-co-glycolic) acids.
42. The polymeric particle of claim 32, wherein the particle is at
least partially coated with a substantially bioabsorbable
material.
43. The polymeric particle of claim 32, wherein the particle has a
density of from about 1.1 grams per cubic centimeter to about 1.4
grams per cubic centimeter.
44. The polymeric particle of claim 32, wherein the particle has a
sphericity of about 0.9 or more.
45. The polymeric particle of claim 32, wherein, after compression
to about 50 percent, the particle has a sphericity of about 0.9 or
more.
46. The polymeric particle of claim 32, wherein the particle
comprises about 2.5 weight percent or less polysaccharide.
47. The polymeric particle of claim 46, wherein the polysaccharide
comprises alginate.
48. The polymeric particle of claim 47, wherein the alginate has a
guluronic acid content of about 60 percent or greater.
49. The polymeric particle of claim 32, wherein the particle is
substantially insoluble in DMSO.
50. The polymeric particle of claim 32, wherein the particle is
substantially free of animal-derived compounds.
51. A composition, comprising: a plurality of particles comprising
a cross-linked polymer, at least some of the plurality of particles
having a diameter of about 500 microns or less, wherein at least
some of the particles having a diameter of about 500 microns or
less have a first density of pores in an interior region and a
second density of pores at a surface region, the first density
being different from the second density; and a carrier fluid, the
plurality of particles being in the carrier fluid.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of and claims
priority under 35 U.S.C. .sctn.120 to U.S. patent application Ser.
No. 10/215,594, filed Aug. 9, 2002, and entitled "Embolization,"
and U.S. patent application Ser. No. 10/615,276, filed Jul. 8,
2003, and entitled "Agent Delivery Particle," which are both
incorporated herein by reference.
TECHNICAL FIELD
[0002] The invention relates to embolization.
BACKGROUND
[0003] Therapeutic vascular occlusions (embolizations) are used to
prevent or treat pathological conditions in situ. Compositions
including embolic particles are used for occluding vessels in a
variety of medical applications. Delivery of embolic particles
through a catheter is dependent on size uniformity, density and
compressibility of the embolic particles.
SUMMARY
[0004] In one aspect, the invention features a polymeric particle
having a diameter of about 500 microns or less. The particle has a
first density of pores in an interior region and a second density
of pores at a surface region. The first density is different from
the second density.
[0005] In another aspect, the invention features a polymeric
particle having a diameter of about 500 microns or less. The
particle has a first average pore size in an interior region and a
second average pore size at the surface region. The first average
pore size is different from the second average pore size.
[0006] In a further aspect, the invention features a composition
that includes a plurality of particles in a carrier fluid. At least
some of the plurality of particles have a diameter of about 500
microns or less. At least some of the particles having a diameter
of about 500 microns or less have a first density of pores in an
interior region and a second density of pores at a surface region.
The first density is different from the second density.
[0007] In one aspect, the invention features a composition that
includes a plurality of particles in a carrier fluid. At least some
of the plurality of particles have a diameter of about 500 microns
or less. At least some of the particles having a diameter of about
500 microns or less have a first average pore size in an interior
region and a second average pore size at a surface region. The
first average pore size is different from the second average pore
size.
[0008] In another aspect, the invention features a method that
includes passing a solution that contains a base polymer and a
gelling precursor through an orifice having a diameter of about 200
microns or less (e.g., about 100 microns or less, about 10 microns
or more) to form drops containing the base polymer and the gelling
precursor. The method also includes forming particles containing
the base polymer and the gelling precursor from the drops
containing the base polymer and the gelling precursor.
[0009] In a further aspect, the invention features a method that
includes heating a solution that contains a base polymer and a
gelling precursor to a temperature of at least about 50.degree. C.
(e.g., about 65.degree. C. or more, about 75.degree. C. or more,
about 85.degree. C. or more, about 95.degree. C. or more, about
105.degree. C. or more, about 115.degree. C. or more, about
121.degree. C.). The method also include forming particles
containing the base polymer and the gelling precursor from the
solution containing the base polymer and the gelling precursor.
[0010] In one aspect, the invention features a method that includes
passing a solution containing a base polymer and a gelling
precursor through an orifice while vibrating the orifice at a
frequency of about 0.1 KHz or more (e.g., about 0.8 KHz or more,
about 1.5 KHz or more) to form drops containing the base polymer
and the gelling precursor. The method also includes forming
particles containing the base polymer and the gelling precursor
from the drops containing the base polymer and the gelling
precursor.
[0011] In another aspect, the invention features a method that
includes forming drops containing the base polymer and the gelling
precursor, and contacting the drops with a gelling agent to form
particles containing the base polymer and the gelling precursor.
The gelling agent is at a temperature greater than room temperature
(e.g., a temperature of about 30.degree. C. or more).
[0012] In a further aspect, the invention features a method that
includes forming drops containing a base polymer and a gelling
precursor, and contacting the drops with a gelling agent to form
particles containing the base polymer and the gelling precursor.
The gelling agent is contained in a vessel, and the method further
includes bubbling a gas through the gelling agent, disposing a mist
containing the gelling agent between a source of the drops and the
vessel, including a surfactant in the mixture containing the
gelling agent, and/or stirring the gelling agent.
[0013] In one aspect, the invention features a method that includes
administering to a subject a therapeutically effective amount of a
composition including a plurality of particles in a carrier fluid.
At least some of the plurality of particles have a diameter of
about 500 microns or less. At least some of the particles having a
diameter of about 500 microns or less have a first density of pores
in an interior region and a second density of pores at a surface
region. The first density is different from the second density.
[0014] In another aspect, the invention features a method that
includes administering to a subject a therapeutically effective
amount of a composition including a plurality of particles in a
carrier fluid. At least some of the plurality of particles have a
diameter of about 500 microns or less. At least some of the
particles having a diameter of about 500 microns or less have a
first average pore size in an interior region and a second average
pore size at a surface region. The first average pore size is
different from the second average pore size.
[0015] Embodiments may also include one or more of the
following.
[0016] The first density can be greater than the second
density.
[0017] The first average pore size can be greater than the second
average pore size.
[0018] A particle can have a diameter of about 10 microns or more.
A particle can have a diameter of about 100 microns or more and/or
a diameter of about 300 microns or less. A particle can have a
diameter of about 300 microns or more.
[0019] A particle can include at least one polymer selected from
polyvinyl alcohols, polyacrylic acids, polymethacrylic acids, poly
vinyl sulfonates, carboxymethyl celluloses, hydroxyethyl
celluloses, substituted celluloses, polyacrylamides, polyethylene
glycols, polyamides, polyureas, polyurethanes, polyesters,
polyethers, polystyrenes, polysaccharides, polylactic acids,
polyethylenes, polymethylmethacrylates, polycaprolactones,
polyglycolic acids, and poly(lactic-co-glycolic) acids.
[0020] A particle can be at least partially coated with a
substantially bioabsorbable material.
[0021] A particle can have a density of from about 1.1 grams per
cubic centimeter to about 1.4 grams per cubic centimeter.
[0022] A particle can have a sphericity of about 0.9 or more.
[0023] After compression to about 50 percent, a particle has a
sphericity of about 0.9 or more.
[0024] A particle can include about 2.5 weight percent or less
polysaccharide (e.g., alginate). An alginate can have a guluronic
acid content of about 60 percent or greater.
[0025] A particle can be substantially insoluble in DMSO.
[0026] A particle can be substantially free of animal-derived
compounds.
[0027] A carrier fluid can include a saline solution, a contrast
agent or both.
[0028] A plurality of particles can have a mean diameter of about
500 microns or less and/or about 10 microns or more. A plurality of
particles can have a mean diameter of about 100 microns or more
and/or a mean diameter of about 300 microns or less. A plurality of
particles can have a mean diameter of about 300 microns or
more.
[0029] A method can include heating the solution to a temperature
of at least about 50.degree. C. before passing the solution through
the orifice.
[0030] A method can include vibrating the nozzle orifice at a
frequency of at least about 0.1 KHz as the solution passes
therethrough.
[0031] A method can further include contacting the drops with a
gelling agent to gel the gelling precursor to form particles
comprising the base polymer and gelled gelling precursor.
[0032] A method can further include removing at least some of the
gelled gelling precursor from the particles.
[0033] A composition can be administered by percutaneous
injection.
[0034] A composition can be administered by a catheter.
[0035] A composition can be introduced into the subject using a
lumen having a diameter that is smaller than a mean diameter of the
plurality of particles.
[0036] A composition can be used to treat a cancer condition. The
cancer condition can be, for example, ovarian cancer, colorectal
cancer, thyroid cancer, gastrointestinal cancer, breast cancer,
prostate cancer and/or lung cancer. Treating the cancer condition
can include at least partially occluding a lumen providing
nutrients to a site of the cancer condition with at least some of
the plurality of particles.
[0037] A method can include at least partially occluding a lumen in
the subject with at least some of a plurality of particles.
[0038] Embodiments of the invention may have one or more of the
following advantages. Some disorders or physiological conditions
can be mediated by delivery of embolic compositions. Embolic
compositions can be used, for example, in treatment of fibroids,
tumors (e.g., hypervascular tumors), internal bleeding, and/or
arteriovenous malformations (AVMs). Examples of fibroids can
include uterine fibroids which grow within the uterine wall, on the
outside of the uterus, inside the uterine cavity, between the
layers of broad ligament supporting the uterus, attached to another
organ or on a mushroom-like stalk. Internal bleeding includes
gastrointestinal, urinary, renal and varicose bleeding. AVMs are,
for example, abnormal collections of blood vessels which shunt
blood from a high pressure artery to a low pressure vein. The
result can be hypoxia and malnutrition of those regions from which
the blood is diverted.
[0039] Spherical embolic particles in the embolic compositions can
be tailored to a particular application by, for example, varying
particle size, porosity gradient, compressibility, sphericity and
density of the particles. In embodiments in which the spherical
embolic particles have a substantially uniform size, the particles
can, for example, fit through the aperture of a catheter for
administration by injection to a target site, without partially or
completely plugging the lumen of the catheter. The spherical
embolic particles have a mean diameter of about 1200 microns or
less (e.g., from about 100 microns to about 500 microns). Size
uniformity of .+-.15 percent of the spherical embolic particles
allows the particles to stack evenly in the cylindrical lumen of
the blood vessel to completely occlude the blood vessel lumen.
Suspensions containing the embolic particles at a density of about
1.1 grams per cubic centimeter to about 1.4 grams per cubic
centimeter can be prepared in calibrated concentrations of the
embolic particles for ease of delivery by the physician without
rapid settlement of the suspension. Control in sphericity and
uniformity of the embolic particles can result in reduction in
aggregation caused, for example, by surface interaction of the
particles. In addition, the embolic particles are relatively inert
in nature.
[0040] Features and advantages are in the description, drawings,
and claims.
DESCRIPTION OF DRAWINGS
[0041] FIG. 1A is a schematic illustrating injection of an embolic
composition including embolic particles into a vessel, while FIG.
1B is an enlarged view of the region 1B in FIG. 1A;
[0042] FIG. 2A is a light micrograph of a collection of hydrated
embolic particles, while FIG. 2B is a scanning electron microscope
(SEM) photograph of an embolic particle surface and FIGS. 2C-2E are
cross-sections of embolic particles;
[0043] FIG. 3A is a schematic of the manufacture of an embolic
composition while FIG. 3B is an enlarged schematic of region 3B in
FIG. 3A;
[0044] FIG. 4 is a photograph of gel-stabilized drops;
[0045] FIG. 5 is a graph of embolic particle size uniformity;
[0046] FIG. 6 is a graph of embolic particle size uniformity;
[0047] FIG. 7 is a schematic of an injection pressure testing
equipment;
[0048] FIG. 8 is an infrared spectrum of embolic particles; and
[0049] FIG. 9 is an infrared spectrum of embolic particles.
DETAILED DESCRIPTION
Composition
[0050] Referring to FIGS. 1A and 1B, an embolic composition,
including embolic particles 111 and a carrier fluid, is injected
into a vessel through an instrument such as a catheter 150.
Catheter 150 is connected to a syringe barrel 110 with a plunger
160. Catheter 150 is inserted, for example, into a femoral artery
120 of a patient. Catheter 150 delivers the embolic composition to,
for example, occlude a uterine artery 130 leading to a fibroid 140.
Fibroid 140 is located in the uterus of a female patient. The
embolic composition is initially loaded into syringe 110. Plunger
160 of syringe 110 is then compressed to deliver the embolic
composition through catheter 150 into a lumen 165 of uterine artery
130.
[0051] Referring particularly to FIG. 1B which is an enlarged view
of section 1B of FIG. 1A, uterine artery 130 is subdivided into
smaller uterine vessels 170 (e.g., having a diameter of about 2
millimeters or less) which feed fibroid 140. The embolic particles
111 in the embolic composition partially or totally fill the lumen
of uterine artery 130, either partially or completely occluding the
lumen of the uterine artery 130 that feeds uterine fibroid 140.
[0052] In general, the particles are substantially formed of a
polymer, such as a highly water insoluble, high molecular weight
polymer. An example of such a polymer is a high molecular weight
polyvinyl alcohol (PVA) that has been acetalized. The embolic
particles can be substantially pure intrachain 1,3-acetalized PVA
and substantially free of animal derived residue such as collagen.
In embodiments, the particles include a minor amount (e.g., about
2.5 weight percent or less, about one weight percent or less, about
0.2 weight percent or less) of a gelling material (e.g., a
polysaccharide, such as alginate).
[0053] FIG. 2A shows an embodiment in which the embolic particles
have a substantially uniform spherical shape and size. FIG. 2B
shows an embodiment in which an embolic particle has a well-defined
outer spherical surface including relatively small, randomly
located pores. The surface appears substantially smooth, with a
surface morphology including larger features, such as crevice-like
features. FIGS. 2C-2E show scanning electron micrograph (SEM)
images of cross-sections through embolic particles in which the
bodies of the particles define pores which provide compressibility
and other properties to the embolic composition. Pores near the
center of the particle are relatively large, and pores near the
surface of the particle are relatively small.
[0054] The region of small pores near the surface of the embolic
particle is relatively stiff and incompressible, which enhances
resistance to shear forces and abrasion. In addition, the variable
pore size profile can produce a symmetric compressibility and, it
is believed, a compressibility profile. As a result, the particles
can be relatively easily compressed from a maximum, at rest
diameter to a smaller, compressed first diameter, although
compression to an even smaller diameter requires substantially
greater force. Without wishing to be bound by theory, it is
believed that a variable compressibility profile can be due to the
presence of a relatively weak, collapsible inter-pore wall
structure in the center region where the pores are large, and a
stiffer inter-pore wall structure near the surface of the particle,
where the pores are more numerous and relatively small. It is
further believed that a variable pore size profile can enhance
elastic recovery after compression. It is also believed that the
pore structure can influence the density of the embolic particles
and the rate of carrier fluid or body fluid uptake.
[0055] In some embodiments, the embolic particles can be delivered
through a catheter having a lumen with a cross-sectional area that
is smaller (e.g., about 50 percent or less) than the uncompressed
cross-sectional area of the particles. In such embodiments, the
embolic particles are compressed to pass through the catheter for
delivery into the body. Typically, the compression force is
provided indirectly, by depressing the syringe plunger to increase
the pressure applied to the carrier fluid. In general, the embolic
particles are relatively easily compressed to diameters sufficient
for delivery through the catheter into the body. The relatively
robust, rigid surface region can resist abrasion when the embolic
particles contact hard surfaces such as syringe surfaces, hard
plastic or metal stopcock surfaces, and the catheter lumen wall
(made of, e.g., Teflon) during delivery. Once in the body, the
embolic particles can substantially recover to original diameter
and shape for efficient transport in the carrier and body fluid
stream. At the point of occlusion, the particles can again compress
as they aggregate in the occlusion region. The embolic particles
can form a relatively dense occluding mass. The compression in the
body is generally determined by the force provided by body fluid
flow in the lumen. In some embodiments, the compression may be
limited by the compression profile of the particles, and the number
of embolic particles needed to occlude a given diameter may be
reduced.
[0056] In some embodiments, among the particles delivered to a
subject, the majority (e.g., about 50 percent or more, about 60
percent or more, about 70 percent or more, about 80 percent or
more, about 90 percent or more) of the particles have a diameter of
about 1500 microns or less (e.g., about 1200 microns or less, about
900 microns or less, about 700 microns or less, about 500 microns
or less, about 300 microns or less) and/or about 10 microns or more
(e.g., about 100 microns or more, about 300 microns or more, about
400 microns or more, about 500 microns or more, about 700 microns
or more, about 900 microns or more).
[0057] In certain embodiments, the particles delivered to a subject
have a mean diameter of about 1500 microns or less (e.g., about
1200 microns or less, about 900 microns or less, about 700 microns
or less, about 500 microns or less, about 300 microns or less)
and/or about 10 microns or more (e.g., about 100 microns or more,
about 300 microns or more, about 400 microns or more, about 500
microns or more, about 700 microns or more, about 900 microns or
more). Exemplary ranges for the mean diameter of particles
delivered to a subject include from about 100 microns to about 300
microns, from about 300 microns to about 500 microns, from about
500 microns to about 700 microns, and from about 900 microns to
about 1200 microns. In general, a collection of particles has a
mean diameter in approximately the middle of the range of the
diameters of the individual particles, and a variance of about 20
percent or less (e.g. about 15 percent or less, about 10 percent or
less).
[0058] In some embodiments, the mean size of the particles
delivered to a subject can vary depending upon the particular
condition to be treated. As an example, in embodiments in which the
particles are used to treat a liver tumor, the particles delivered
to the subject can have a mean diameter of about 500 microns or
less (e.g., from about 100 microns to about 300 microns, from about
300 microns to about 500 microns). As another example, in
embodiments in which the particles are used to treat a uterine
fibroid, the particles delivered to the subject can have a mean
diameter of about 1200 microns or less (e.g., from about 500
microns to about 700 microns, from about 700 microns to about 900
microns, from about 900 microns to about 1200 microns).
[0059] As shown in FIG. 2C, in some embodiments a particle can be
considered to include a center region, C, from the center c' of the
particle to a radius of about r/3, a body region, B, from about r/3
to about 2 r/3 and a surface region, S, from 2r/3 to r. The regions
can be characterized by the relative size of the pores in each
region, the density of the pores (the number of pores per unit
volume) in each region, and/or the material density (density of
particle material per unit volume) in each region.
[0060] In general, the mean size of the pores in region C of a
particle is greater than the mean size of the pores at region S of
the particle. In some embodiments, the mean size of the pores in
region C of a particle is greater than the mean size of the pores
in region B the particle, and/or the mean size of the pores in
region B of a particle is greater than the mean size of the pores
at region S the particle. In some embodiments, the mean pore size
in region C is about 20 microns or more (e.g., about 30 microns or
more, from about 20 microns to about 35 microns). In certain
embodiments, the mean pore size in region B is about 18 microns or
less (e.g. about 15 microns or less, from about 18 microns to about
two microns). In some embodiments, the mean pore size of the pores
in region S is about one micron or less (e.g. from about 0.1 micron
to about 0.01 micron). In certain embodiments, the mean pore size
in region B is from about 50 percent to about 70 percent of the
mean pore size in region C, and/or the mean pore size at region S
is about 10 percent or less (e.g., about two percent or less) of
the mean pore size in region B. In some embodiments, the surface of
a particle and/or its region S is/are substantially free of pores
having a diameter greater than about one micron (e.g., greater than
about 10 microns). In certain embodiments, the mean pore size in
the region from 0.8r to r (e.g., from 0.9r to r) is about one
micron or less (e.g., about 0.5 micron or less, about 0.1 micron or
less). In some embodiments, the region from the center of the
particle to 0.9r (e.g., from the center of the particle to 0.8r)
has pores of about 10 microns or greater and/or has a mean pore
size of from about two microns to about 35 microns. In certain
embodiments, the mean pore size in the region from 0.8r to r (e.g.,
from 0.9r to r) is about five percent or less (e.g., about one
percent or less, about 0.3 percent or less) of the mean pore size
in the region from the center to 0.9r. In some embodiments, the
largest pores in the particles can have a size in the range of
about one percent or more (e.g., about five percent or more, about
10 percent or more) of the particle diameter. The size of the pores
in a particle can be measured by viewing a cross-section as in FIG.
2C. For irregularly shaped (nonspherical) pores, the maximum
visible cross-section is used. In FIG. 2C, the SEM was taken on wet
particles including absorbed saline, which were frozen in liquid
nitrogen and sectioned. FIG. 2B was taken prior to sectioning. In
FIGS. 2D-2E, the particle was freeze-dried prior to sectioning and
SEM analysis.
[0061] Generally, the density of pores in region C of a particle is
greater than the density of pores at region S of the particle. In
some embodiments, the density of pores in region C of a particle is
greater than the density of pores in region B of the particle,
and/or the density of pores in region B of a particle is greater
than the density of pores at region S of the particle.
[0062] In general, the material density in region C of a particle
is less than the material density at region S of the particle. In
some embodiments, the material density in region C of a particle is
less than the material density in region B of the particle, and/or
the material density in region B of a particle is less than the
material density at region S of the particle.
[0063] In general, the density of a particle (e.g., as measured in
grams of material per unit volume) is such that it can be readily
suspended in a carrier fluid (e.g., a pharmaceutically acceptable
carrier, such as a saline solution, a contrast solution, or a
mixture thereof) and remain suspended during delivery. In some
embodiments, the density of a particle is from about 1.1 grams per
cubic centimeter to about 1.4 grams per cubic centimeter. As an
example, for suspension in a saline-contrast solution, the density
can be from about 1.2 grams per cubic centimeter to about 1.3 grams
per cubic centimeter.
[0064] In certain embodiments, the sphericity of a particle after
compression in a catheter (e.g., after compression to about 50
percent or more of the cross-sectional area of the particle) is
about 0.9 or more (e.g., about 0.95 or more, about 0.97 or more). A
particle can be, for example, manually compressed, essentially
flattened, while wet to about 50 percent or less of its original
diameter and then, upon exposure to fluid, regain a sphericity of
about 0.9 or more (e.g., about 0.95 or more, about 0.97 or
more).
Manufacture
[0065] FIG. 3A shows an embodiment of a system for producing
embolic particles. The system includes a flow controller 300, a
drop generator 310, a gelling vessel 320, a reactor vessel 330, a
gel dissolution chamber 340 and a filter 350. As shown in FIG. 3B,
flow controller 300 delivers polymer solutions to a viscosity
controller 305, which heats the solution to reduce viscosity prior
to delivery to drop generator 310. The solution passes through an
orifice in a nozzle in drop generator 310, forming drops of the
solution. The drops are then directed into gelling vessel 320,
where the drops are stabilized by gel formation. The gel-stabilized
drops are transferred from gelling vessel 320 to reactor vessel
330, where the polymer in the gel-stabilized drops is reacted,
forming precursor particles. The precursor particles are
transferred to gel dissolution chamber 340, where the gel is
dissolved. The particles are then filtered in filter 350 to remove
debris, and are sterilized and packaged as an embolic composition
including embolic particles.
[0066] In general, a base polymer and a gelling precursor are
dissolved in water and mixed.
[0067] Examples of base polymers include polyvinyl alcohols,
polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates,
carboxymethyl celluloses, hydroxyethyl celluloses, substituted
celluloses, polyacrylamides, polyethylene glycols, polyamides,
polyureas, polyurethanes, polyesters, polyethers, polystyrenes,
polysaccharides, polylactic acids, polyethylenes,
polymethylmethacrylates, polycaprolactones, polyglycolic acids,
poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic)
acids) and copolymers or mixtures thereof A preferred polymer is
polyvinyl alcohol (PVA). The polyvinyl alcohol, in particular, is
typically hydrolyzed in the range of from about 80 percent to about
99 percent. The weight average molecular weight of the base polymer
can be, for example, in the range of from about 9000 to about
186,000 (e.g., from about 85,000 to about 146,000, from about
89,000 to about 98,000).
[0068] Gelling precursors include, for example, alginates, alginate
salts, xanthan gums, natural gum, agar, agarose, chitosan,
carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma,
gum arabic, gum ghatti, gum karaya, gum tragacanth, hyalauronic
acid, locust beam gum, arabinogalactan, pectin, amylopectin, other
water soluble polysaccharides and other ionically cross-linkable
polymers. A particular gelling precursor is sodium alginate. A
preferred sodium alginate is high guluronic acid, stem-derived
alginate (e.g., about 50 percent or more, about 60 percent or more
guluronic acid) with a low viscosity (e.g., from about 20
centipoise to about 80 centipoise at 20.degree. C.), which produces
a high tensile, robust gel.
[0069] In some embodiments, the base polymer (e.g., PVA, such as
high molecular weight PVA) can be dissolved in water by heating
(e.g., above about 70.degree. C. or more, about 121.degree. C.),
while the gelling precursor (e.g., an alginate) can be dissolved at
room temperature. The base polymer (e.g., PVA) can be dissolved by
mixing the base polymer and the gelling precursor (e.g., alginate)
together in a vessel which is heated, e.g., to a temperature of at
least about 50.degree. C. (e.g., about 65.degree. C. or more, about
75.degree. C. or more, about 85.degree. C. or more, about
95.degree. C. or more, about 105.degree. C. or more, about
115.degree. C. or more, about 121.degree. C.). In some embodiments,
the mixture can be heated in an autoclave. Alternatively, the base
polymer (e.g., PVA) can be disposed in water and heated. The
gelling precursor (e.g., alginate) can subsequently be added at
room temperature, to avoid exposing the alginate to high
temperature. Heat can also be applied, for example, by microwave
application.
[0070] In certain embodiments, such as when the base polymer is PVA
and the gelling precursor is alginate, the mixture can be from
about 6.5 weight percent to about 8.5 weight percent (e.g., about
eight weight percent, about seven weight percent) base polymer and
from about 1.5 weight percent to about 2.5 weight percent (e.g.,
about 1.75 weight percent, about two weight percent) gelling
precursor.
[0071] In some embodiments, the base polymer/gelling precursor
mixture can be introduced to a high pressure pumping apparatus,
such as a syringe pump (e.g., model PHD4400, Harvard Apparatus,
Holliston, Mass.), and then transferred to drop generator 310.
Alternatively or additionally, drop generator 310 can contain a
pressure control device that applies a pressure (e.g., from about
0.5 Bar to about 1.6 Bar) to the base polymer/gelling precursor
mixture (a pressure head) to control the rate at which the mixture
is transferred to drop generator 310.
[0072] The pressure can be selected, for example, based on the size
of the nozzle orifice and/or the desired viscosity of the base
polymer/gelling precursor mixture, and/or the desired size of the
particles. In general, for a given mixture, as the nozzle orifice
is decreased, the pressure is increased. Generally, for a given
mixture, as the desired viscosity of the mixture is decreased, the
temperature is increased. As an example, in embodiments in which
the nozzle orifice has a diameter of about 100 microns and the base
polymer/gelling precursor mixture has a viscosity of from about 60
centipoise to about 100 centipoise, the pressure can be about 1.55
Bar. As another example, in embodiments in which the nozzle orifice
has a diameter of about 200 microns and the base polymer/gelling
precursor mixture has a viscosity of from about 60 centipoise to
about 100 centipoise, the pressure can be about 0.55 Bar.
[0073] Referring to FIG. 3B, viscosity controller 305 is a heat
exchanger that circulates water at a predetermined temperature
about the flow tubing between the pump and drop generator 310. The
base polymer/gelling precursor mixture flows into viscosity
controller 305, where the mixture is heated so that its viscosity
is lowered to a desired level. Alternatively or additionally, the
vessel containing the base polymer/gelling precursor mixture can be
disposed in a heated fluid bath (e.g., a heated water bath) to heat
the base polymer/gelling precursor mixture. In some embodiments
(e.g., when the system does not contain viscosity controller 305),
flow controller 300 and/or drop generator 310 can be placed in a
temperature-controlled chamber (e.g. an oven, a heat tape wrap) to
heat the base polymer/gelling precursor mixture.
[0074] The temperature to which the base polymer/gelling precursor
mixture is heated prior to transfer to drop generator 310 can be
selected, for example, based on the desired viscosity of the
mixture and/or the size of the orifice in the nozzle. In general,
for a given mixture, the lower the desired viscosity of the
mixture, the higher the temperature to which the mixture is heated.
Generally, for a given mixture, the smaller the diameter of the
nozzle, the higher the temperature to which the mixture is heated.
As an example, in embodiments in which nozzle has a diameter of
from about 150 microns to about 300 microns and the desired
viscosity of the mixture is from about 90 centipoise to about 200
centipoise, the mixture can be heated to a temperature of from
about 60.degree. C. to about 70.degree. C. (e.g., about 65.degree.
C.). As another example, in embodiments in which the nozzle has a
diameter of from about 100 microns to about 200 microns and the
desired viscosity of the mixture is from about 60 centipoise to
about 100 centipoise, the mixture can be heated to a temperature of
from about 70.degree. C. to about 80.degree. C. (e.g., about
75.degree. C.).
[0075] Drop generator 310 generates substantially spherical drops
of a predetermined diameter by forcing a stream of the base
polymer/gelling precursor mixture through the nozzle orifice. The
nozzle is subjected to a periodic disturbance to break up the jet
stream of the mixture into drops of the mixture. The jet stream can
be broken into drops by vibratory action generated, for example, by
an electrostatic or piezoelectric element. The drop size can be
controlled, for example, by controlling the nozzle orifice
diameter, base polymer/gelling precursor flow rate, nozzle
vibration amplitude, and nozzle vibration frequency. In general,
holding other parameters constant, increasing the nozzle orifice
diameter results in formation of larger drops, and increasing the
flow rate results in larger drops. Generally, holding other
parameters constant, increasing the nozzle vibration amplitude
results in larger drops, and reducing the nozzle vibration
frequency results in larger drops. In general, the nozzle orifice
diameter can be about 500 microns or less (e.g., about 400 microns
or less, about 300 microns or less, about 200 microns or less,
about 100 microns or less) and/or about 50 microns or more. The
flow rate through the drop generator is typically from about one
milliliter per minute to about 12 milliliters per minute.
Generally, the nozzle frequency used can be about 0.1 KHz or more
(e.g., about 0.8 KHz or more, about 1.5 KHz or more, about 1.75 KHz
or more, about 1.85 KHz or more, about 2.5 KHz or more, from about
0.1 KHz to about 0.8 KHz). In general, the nozzle vibration
amplitude is larger than the width of the jet stream. The drop
generator can have a variable nozzle vibration amplitude setting,
such that an operator can adjust the amplitude of the nozzle
vibration. In some embodiments, the nozzle vibration amplitude is
set at between about 80 percent and about 100 percent of the
maximum setting.
[0076] In some embodiments, drop generator 310 can charge the drops
after formation, such that mutual repulsion between drops prevents
drop aggregation as the drops travel from drop generator 310 to
gelling vessel 320. Charging may be achieved, for example, by an
electrostatic charging device such as a charged ring positioned
downstream of the nozzle.
[0077] An example of a commercially available electrostatic drop
generator is the model NISCO Encapsulation unit VAR D (NISCO
Engineering, Zurich, Switzerland). Another example of a
commercially available drop generator is the Inotech Encapsulator
unit IE-50R/NS (Inotech AG, Dottikon, Switzerland).
[0078] Drops of the base polymer and gelling precursor mixture are
captured in gelling vessel 320. The distance between gelling vessel
320 and the orifice of the nozzle in drop generator 310 is
generally selected so that the jet stream of the base
polymer/gelling precursor mixture is substantially broken up into
discrete drops before reaching gelling vessel 320. In some
embodiments, the distance from the nozzle orifice to the mixture
contained in gelling vessel 320 is from about five inches to about
six inches.
[0079] The mixture contained in gelling vessel 320 includes a
gelling agent which interacts with the gelling precursor to
stabilize drops by forming a stable gel. Suitable gelling agents
include, for example, a divalent cation such as alkali metal salt,
alkaline earth metal salt or a transition metal salt that can
ionically cross-link with the gelling agent. An inorganic salt, for
example, a calcium, barium, zinc or magnesium salt can be used as a
gelling agent. In embodiments, particularly those using an alginate
gelling precursor, a suitable gelling agent is calcium chloride.
The calcium cations have an affinity for carboxylic groups in the
gelling precursor. The cations complex with carboxylic groups in
the gelling precursor, resulting in encapsulation of the base
polymer in a matrix of gelling precursor.
[0080] Without wishing to be bound by theory, it is believed that
in some embodiments (e.g., when forming particles having a diameter
of about 500 microns or less), it can be desirable to reduce the
surface tension of the mixture contained in gelling vessel 320.
This can be achieved, for example, by heating the mixture in
gelling vessel 320 (e.g., to a temperature greater than room
temperature, such as a temperature of about 30.degree. C. or more),
by bubbling a gas (e.g., air, nitrogen, argon, krypton, helium,
neon) through the mixture contained in gelling vessel 320, by
stirring (e.g., via a magnetic stirrer) the mixture contained in
gelling vessel 320, by including a surfactant in the mixture
containing the gelling agent, and/or by forming a mist containing
the gelling agent above the mixture contained in gelling vessel 320
(e.g., to reduce the formation of tails and/or enhance the
sphericity of the particles).
[0081] FIG. 4 shows a photo-image of the gelled particles. As
evident, a pore structure in the particle forms in the gelling
stage. The concentration of the gelling agent can affect pore
formation in the particle, thereby controlling the porosity
gradient in the particle. Adding non-gelling ions (e.g., sodium
ions) to the gelling solution can reduce the porosity gradient,
resulting in a more uniform intermediate porosity throughout the
particle. In embodiments, the gelling agent is, for example, from
about 0.01 weight percent to about 10 weight percent (e.g., from
about one weight percent to about five weight percent, about two
weight percent) in deionized water. In embodiments, particles,
including gelling agent and a pore structure, can be used in
embolic compositions.
[0082] Following drop stabilization, the gelling solution can be
decanted from the solid drops, or the solid drops can be removed
from the gelling solution by sieving. The solid drops are then
transferred to reactor vessel 330, where the base polymer in the
solid drops is reacted (e.g., cross-linked) to produce precursor
particles.
[0083] Reactor vessel 330 contains an agent that chemically reacts
with the base polymer to cause cross-linking between polymer chains
and/or within a polymer chain. The agent diffuses into the solid
drops from the surface of the particle in a gradient which, it is
believed, provides more cross-linking near the surface of the solid
drop than in the body and center of the drop. Reaction is greatest
at the surface of a solid drop, providing a stiff,
abrasion-resistant exterior. For polyvinyl alcohol, for example,
vessel 330 includes one or more aldehydes, such as formaldehyde,
glyoxal, benzaldehyde, aterephthalaldehyde, succinaldehyde and
glutaraldehyde for the acetalization of polyvinyl alcohol. Vessel
330 also includes an acid, for example, strong acids such as
sulfuric acid, hydrochloric acid, nitric acid and weak acids such
as acetic acid, formic acid and phosphoric acid. In embodiments,
the reaction is primarily a 1,3-acetalization:
##STR00001##
[0084] This intra-chain acetalization reaction can be carried out
with relatively low probability of inter-chain cross-linking, as
described in John G. Pritchard, "Poly(Vinyl Alcohol) Basic
Properties and Uses (Polymer Monograph, vol. 4) (see p. 93-97),
Gordon and Breach, Science Publishers Ltd., London, 1970, which is
incorporated herein by reference. Because the reaction proceeds in
a random fashion, some OH groups along a polymer chain might not
react with adjacent groups and may remain unconverted.
[0085] Adjusting for the amounts of aldehyde and acid used,
reaction time and reaction temperature can control the degree of
acetalization. In embodiments, the reaction time is from about five
minutes to about one hour (e.g., from about 10 minutes to about 40
minutes, about 20 minutes). The reaction temperature can be, for
example, from about 25.degree. C. to about 150.degree. C. (e.g.,
from about 75.degree. C. to about 130.degree. C., about 65.degree.
C.). Reactor vessel 330 can be placed in a water bath fitted with
an orbital motion mixer. The cross-linked precursor particles are
washed several times with deionized water to neutralize the
particles and remove any residual acidic solution.
[0086] The precursor particles are transferred to dissolution
chamber 340, where the gelling precursor is removed (e.g., by an
ion exchange reaction). In embodiments, sodium alginate is removed
by ion exchange with a solution of sodium hexa-metaphosphate (EM
Science). The solution can include, for example,
ethylenediaminetetracetic acid (EDTA), citric acid, other acids,
and phosphates. The concentration of the sodium hexa-metaphosphate
can be, for example, from about one weight percent to about 20
weight percent (e.g., from about one weight percent to about ten
weight percent, about five weight percent) in deionized water.
Residual gelling precursor (e.g., sodium alginate) can be measured
by assay (e.g., for the detection of uronic acids in, for example,
alginates containing mannuronic and guluronic acid residues). A
suitable assay includes rinsing the particles with sodium
tetraborate in sulfuric acid solution to extract alginate,
combining the extract with metahydroxydiphenyl colormetric reagent,
and determining concentration by UV/VIS spectroscopy. Testing can
be carried out by alginate suppliers such as FMC Biopolymer, Oslo,
Norway. Residual alginate may be present in the range of, for
example, from about 20 weight percent to about 35 weight percent
prior to rinsing, and in the range of from about 0.01 weight
percent to about 0.5 weight percent (e.g., from about 0.1 weight
percent to about 0.3 weight percent, about 0.18 weight percent) in
the particles after rinsing for 30 minutes in water at about
23.degree. C.
[0087] The particles are filtered through filter 350 to remove
residual debris. Particles of from about 100 microns to about 300
microns can filtered through a sieve of about 710 microns and then
a sieve of about 300 microns. The particles can then be collected
on a sieve of about 20 microns. Particles of from about 300 to
about 500 microns can filtered through a sieve of about 710 microns
and then a sieve of about 500 microns. The particles can then be
collected on a sieve of about 100 microns. Particles of from about
500 to about 700 microns can be filtered through a sieve of about
1000 microns, then filtered through a sieve of about 710 microns,
and then a sieve of about 300 microns. The particles can then be
collected in a catch pan. Particles of from about 700 to about 900
microns can be filtered through a sieve of 1000 microns and then a
sieve of 500 microns. The particles can then be collected in a
catch pan. Particles of from about 900 to about 1200 microns can
filtered through a sieve of 1180 microns and then a sieve of 710
microns. The particles can then be collected in a catch pan.
[0088] The particles are then packaged. Typically, from about one
milliliter to about five milliliters of particles are packaged in
from about five milliliters to about ten milliliters of saline. The
filtered particles then are typically sterilized by a low
temperature technique, such as e-beam irradiation. In embodiments,
electron beam irradiation can be used to pharmaceutically sterilize
the particles (e.g., to reduce bioburden). In e-beam sterilization,
an electron beam is accelerated using magnetic and electric fields,
and focused into a beam of energy. The resultant energy beam can be
scanned by means of an electromagnet to produce a "curtain" of
accelerated electrons. The accelerated electron beam penetrates the
collection of particles, destroying bacteria and mold to sterilize
and reduce the bioburden in the particles. Electron beam
sterilization can be carried out by sterilization vendors such as
Titan Scan, Lima, Ohio.
[0089] The embolic compositions can be used in the treatment of,
for example, fibroids, tumors, internal bleeding, AVMs,
hypervascular tumors, fillers for aneurysm sacs, endoleak sealants,
arterial sealants, puncture sealants and occlusion of other lumens
such as fallopian tubes. Fibroids can include uterine fibroids
which grow within the uterine wall (intramural type), on the
outside of the uterus (subserosal type), inside the uterine cavity
(submucosal type), between the layers of broad ligament supporting
the uterus (interligamentous type), attached to another organ
(parasitic type), or on a mushroom-like stalk (pedunculated type).
Internal bleeding includes gastrointestinal, urinary, renal and
varicose bleeding. AVMs are for example, abnormal collections of
blood vessels, e.g. in the brain, which shunt blood from a high
pressure artery to a low pressure vein, resulting in hypoxia and
malnutrition of those regions from which the blood is diverted.
[0090] The magnitude of a dose of an embolic composition can vary
based on the nature, location and severity of the condition to be
treated, as well as the route of administration. A physician
treating the condition, disease or disorder can determine an
effective amount of embolic composition. An effective amount of
embolic composition refers to the amount sufficient to result in
amelioration of symptoms or a prolongation of survival of the
patient. The embolic compositions can be administered as
pharmaceutically acceptable compositions to a patient in any
therapeutically acceptable dosage, including those administered to
a patient intravenously, subcutaneously, percutaneously,
intratrachealy, intramuscularly, intramucosaly, intracutaneously,
intra-articularly, orally or parenterally.
[0091] In some embodiments, a composition containing the particles
can be used to prophylactically treat a condition.
[0092] Compositions containing the particles can be prepared in
calibrated concentrations of the particles for ease of delivery by
the physician. Suspensions of the particles in saline solution can
be prepared to remain stable (e.g., to not precipitate) over a
duration of time. A suspension of the particles can be stable, for
example, for from about one minute to about 20 minutes (e.g. from
about one minute to about ten minutes, from about two minutes to
about seven minutes, from about three minutes to about six
minutes). The concentration of particles can be determined by
adjusting the weight ratio of the particles to the physiological
solution. If the weight ratio of the particles is too small, then
too much liquid could be injected into a blood vessel, possibly
allowing the particles to stray into lateral vessels. In some
embodiments, the physiological solution can contain from about 0.01
weight percent to about 15 weight percent of the particles. A
composition can include a mixture of particles, such as particles
having the pore profiles discussed above, particles with other pore
profiles, and/or non-porous particles.
[0093] While certain embodiments have been described, the invention
is not so limited.
[0094] As an example, particles can be used for embolic
applications without removal of the gelling agent (e.g. alginate).
Such particles can be prepared, for example, as described above,
but without removing the alginate from the particle after
cross-linking.
[0095] As another example, while substantially spherical particles
are preferred, non-spherical particles can be manufactured and
formed by controlling, for example, drop formation conditions. In
some embodiments, nonspherical particles can be formed by
post-processing the particles (e.g., by cutting or dicing into
other shapes).
[0096] Moreover, in some embodiments the particles can include one
or more therapeutic agents (e.g., drugs). The therapeutic agent(s)
can be in and/or on the particles. Therapeutic agents include
agents that are negatively charged, positively charged, amphoteric,
or neutral. Therapeutic agents can be, for example, materials that
are biologically active to treat physiological conditions;
pharmaceutically active compounds; gene therapies; nucleic acids
with and without carrier vectors; oligonucleotides; gene/vector
systems; DNA chimeras; compacting agents (e.g., DNA compacting
agents); viruses; polymers; hyaluronic acid; proteins (e.g.,
enzymes such as ribozymes); cells (of human origin, from an animal
source, or genetically engineered); stem cells; immunologic
species; nonsteroidal anti-inflammatory medications; oral
contraceptives; progestins; gonadotrophin-releasing hormone
agonists; chemotherapeutic agents; and radioactive species (e.g.,
radioisotopes, radioactive molecules). Non-limiting examples of
therapeutic agents include anti-thrombogenic agents; antioxidants;
angiogenic and anti-angiogenic agents and factors;
anti-proliferative agents (e.g., agents capable of blocking smooth
muscle cell proliferation); anti-inflammatory agents; calcium entry
blockers; antineoplastic/antiproliferative/anti-mitotic agents
(e.g., paclitaxel, doxorubicin, cisplatin); antimicrobials;
anesthetic agents; anti-coagulants; vascular cell growth promoters;
vascular cell growth inhibitors; cholesterol-lowering agents;
vasodilating agents; agents which interfere with endogenous
vasoactive mechanisms; and survival genes which protect against
cell death. Therapeutic agents are described in co-pending U.S.
patent application Ser. No. 10/615,276, filed on Jul. 8, 2003, and
entitled "Agent Delivery Particle", which is incorporated herein by
reference.
[0097] In addition, in some embodiments (e.g., where the base
polymer is a polyvinyl alcohol and the gelling precursor is
alginate), after contacting the particles with the gelling agent
but before cross-linking, the particles can be physically deformed
into a specific shape and/or size. For example, the particles can
be molded, compressed, punched, and/or agglomerated with other
particles. After shaping, the base polymer (e.g., polyvinyl
alcohol) can be cross-linked, optionally followed by substantial
removal of the gelling precursor (e.g., alginate). Particle shaping
is described, for example, in co-pending U.S. patent application
Ser. No. 10/402,068, filed Mar. 28, 2003, and entitled "Forming a
Chemically Cross-Linked Particle of a Desired Shape and Diameter",
which is incorporated herein by reference.
[0098] Furthermore, in some embodiments the particles can be used
for tissue bulking. As an example, the particles can be placed
(e.g., injected) into tissue adjacent a body passageway. The
particles can narrow the passageway, thereby providing bulk and
allowing the tissue to constrict the passageway more easily. The
particles can be placed in the tissue according to a number of
different methods, for example, percutaneously, laparoscopically,
and/or through a catheter. In certain embodiments, a cavity can be
formed in the tissue, and the particles can be placed in the
cavity. Particle tissue bulking can be used to treat, for example,
intrinsic sphincteric deficiency (ISD), vesicoureteral reflux,
gastroesophageal reflux disease (GERD), and/or vocal cord paralysis
(e.g., to restore glottic competence in cases of paralytic
dysphonia). In some embodiments, particle tissue bulking can be
used to treat urinary incontinence and/or fecal incontinence. The
particles can be used as a graft material or a filler to fill
and/or to smooth out soft tissue defects, such as for
reconstructive or cosmetic applications (e.g., surgery). Examples
of soft tissue defect applications include cleft lips, scars (e.g.,
depressed scars from chicken pox or acne scars), indentations
resulting from liposuction, wrinkles (e.g., glabella frown
wrinkles), and soft tissue augmentation of thin lips. Tissue
bulking is described, for example, in co-pending U.S. patent
application Ser. No. 10/231,664, filed on Aug. 30, 2002, and
entitled "Tissue Treatment", which is incorporated herein by
reference.
[0099] The following examples are intended as illustrative and
nonlimiting.
Example 1
[0100] Particles were prepared as follows.
[0101] An aqueous solution containing eight weight percent
polyvinyl alcohol (99+ percent hydrolyzed, average M.sub.w
89,000-120,000 (Aldrich)) and two weight percent sodium alginate
(PRONOVA UPLVG, (FMC BioPolymer, Princeton, N.J.)) in deionized
water was prepared. The solution was heated to about 121.degree. C.
The solution had a viscosity of about 310 centipoise at room
temperature and a viscosity of about 160 centipoise at 65.degree.
C. Using a model PHD4400 syringe pump (Harvard Apparatus,
Holliston, Mass.), the mixture was fed into a model NISCO
Encapsulation unit VAR D drop generator (NISCO Engineering, Zurich,
Switzerland). Drops generated by the drop generator were directed
into a gelling vessel containing two weight percent calcium
chloride in deionized water, and stirred with a stirring bar. The
calcium chloride solution was decanted within about three minutes
to avoid substantial leaching of the polyvinyl alcohol from the
drops into the solution. The drops were added to a reaction vessel
containing a solution of four weight percent formaldehyde (37
weight percent in methanol) and 20 weight percent sulfuric acid
(95-98 percent concentrated). The reaction solution was stirred at
65.degree. C. for 20 minutes. Precursor particles were rinsed with
deionized water (3.times.300 milliliters) to remove residual acidic
solution. The sodium alginate was substantially removed by soaking
the precursor particles in a solution of five weight percent sodium
hexa-methaphosphate in deionized water for 0.5 hour. The solution
was rinsed in deionized water to remove residual phosphate and
alginate. The particles were filtered by sieving, as discussed
above, placed in saline (USP 0.9 percent NaCl) and sterilized by
irradiation sterilization.
[0102] Particles were produced at the nozzle diameters, nozzle
frequencies and flow rates (amplitude about 80 percent of maximum)
described in Table I.
TABLE-US-00001 TABLE I Flow Particle Nozzle Fre- Rate Size Diameter
quency (mL/ Density Sphe- Suspendability (microns) (microns) (kHz)
min) (g/mL) ricity (minutes) 500-700 150 0.45 4 -- 0.92 3 700-900
200 0.21 5 1.265 0.94 5 900-1200 300 0.22 10 -- 0.95 6
[0103] Suspendability was measured at room temperature by mixing a
solution of two milliliters of particles in five milliliters of
saline with contrast solution (Omnipaque 300, Nycomed,
Buckinghamshire, UK), and observing the time for about 50 percent
of the particles to enter suspension (i.e., not to have sunk to the
bottom or floated to the top of a container having a volume of
about ten milliliters and a diameter of about 25 millimeters).
Suspendability provides a practical measure of how long the
particles will remain suspended in use.
[0104] Measurements were also made of the amount of time that the
particles remained suspended in the contrast solution. The
particles remained in suspension for from about two to about three
minutes.
[0105] Omnipaque 300 is an aqueous solution of Iohexol, N.N.-Bis
(2,3-dihydroxypropyl)-T-[N-(2,3-dihydroxypropyl)-acetamide]-2,4,6-trilodo-
-isophthalamide. Omnipaque 300 contains 647 milligrams of iohexol
equivalent to 300 milligrams of organic iodine per milliliter. The
specific gravity of Omnipaque 300 is 1.349 of 37.degree. C., and
Omnipaque 300 has an absolute viscosity 11.8 centipoise at
20.degree. C.
[0106] Particle size uniformity and sphericity were measured using
a Beckman Coulter RapidVUE Image Analyzer version 2.06 (Beckman
Coulter, Miami, Fla.). Briefly, the RapidVUE takes an image of
continuous-tone (gray-scale) form and converts it to a digital form
through the process of sampling and quantization. The system
software identifies and measures particles in an image in the form
of a fiber, rod or sphere. Sphericity computation and other
statistical definitions are in Appendix A, attached, which is a
page from the RapidVUE operating manual.
[0107] Referring to FIG. 5, particle size uniformity is illustrated
for particles having a diameter of from about 700 microns to about
900 microns. The x-axis is the particle diameter, and the y-axis is
the volume-normalized percentage of particles at each particle
size. The total volume of particles detected was computed, and the
volume of the particles at each diameter was divided by the total
volume. The embolic particles had a distribution of particle sizes
with variance of less than about .+-.15 percent.
Example 2
[0108] Particles were prepared as follows.
[0109] An aqueous solution containing 7.06 weight percent polyvinyl
alcohol (99+ percent hydrolyzed, average M.sub.w 89,000-120,000
(Aldrich)) and 1.76 weight percent sodium alginate (PRONOVA UPLVG,
(FMC BioPolymer, Princeton, N.J.)) was prepared. The solution was
heated to about 121.degree. C. The solution had a viscosity of
about 140 centipoise at room temperature, and a viscosity of about
70 centipoise at 65.degree. C. Using a pressurized vessel, the
mixture was fed to a drop generator (Inotech Encapsulator unit
IE-50R/NS, Inotech Biosystems International, Inc.). Drops generated
by the drop generator were directed into a gelling vessel
containing two weight percent calcium chloride in deionized water,
and stirred with a stirring bar. The drops were collected within
about three minutes to avoid substantial leaching of the polyvinyl
alcohol from the drops into the solution. The drops were added to a
reaction vessel containing a solution of four weight percent
formaldehyde (37 weight percent in methanol) and 20 weight percent
sulfuric acid (95-98 percent concentrated). The reaction solution
was stirred at 65.degree. C. for 20 minutes. The precursor
particles were rinsed with deionized water (3.times.300
milliliters) to remove residual acidic solution. The sodium
alginate was substantially removed by soaking the precursor
particles in a solution of five weight percent sodium
hexa-methaphosphate in deionized water for half an hour. The
solution was rinsed in deionized water to remove residual phosphate
and alginate. The particles were filtered by sieving, placed in
saline (USP 0.9 percent NaCl) and sterilized by irradiation
sterilization.
[0110] The particles were produced at the nozzle diameters, nozzle
frequencies and pressures (amplitude about 80 percent of maximum)
described in Table II.
TABLE-US-00002 TABLE II Particle Nozzle Size Diameter Frequency
Pressure Flow Rate Suspendability (microns) (microns) (KHz) (Bar)
(mL/min) (minutes) 100-300 100 2.5 1.55 2.5 0.25 300-500 200 1.85
0.55 6.8 1
[0111] Suspendability was measured as described in Example 1.
[0112] Measurements were also made of the amount of time that the
particles remained suspended in the contrast solution. The
particles remained suspended in the contrast solution for about 20
minutes.
[0113] FIG. 6 shows particle size uniformity for particles having a
diameter of from about 300 microns to about 500 microns (see
discussion in Example 1). The embolic particles had a distribution
of particle sizes with a variance of less than about .+-.15
percent.
Example 3
[0114] Referring to FIG. 7, a catheter compression test was used to
investigate the injectability, and indirectly, the compressibility,
of the particles. The test apparatus included a reservoir syringe
610 and an injection syringe 620 coupled to a T-valve 630.
Reservoir syringe 610 was a 20 milliliter syringe while injection
syringe 620 was a three milliliter syringe. T-valve 630 was coupled
in series to a second T-valve 640. T-valve 640 was coupled to a
catheter 650 and a pressure transducer 660. Injection syringe 620
was coupled to a syringe pump 621 (Harvard Apparatus).
[0115] To test deliverability of the particles, syringes 610 and
620 were loaded with embolic composition in saline and contrast
agent (50/50 Omnipaque 300). The embolic composition in syringes
610 and 620 was intermixed by turning the T-valve to allow fluid
between the syringes to mix and suspend the particles. After
mixing, the embolic composition in syringe 620 flowed at a rate of
about ten milliliters per minute. The back pressure generated in
catheter 650 was measured by the pressure transducer 660 in
millivolts to measure the clogging of catheter 650. About one
milliliter of the particles was mixed in ten milliliters of
solution.
[0116] Results for several different catheters (available from
Boston Scientific, Natick, Mass.) and particle sizes are shown in
Table III. The baseline pressure was the pressure observed when
injecting carrier fluid only. The delivery pressure was the
pressure observed while delivering particles in carrier fluid. The
average was the average of the peak pressure observed in the three
runs.
TABLE-US-00003 TABLE III SIZE Inner Diameter Avg. Baseline Avg.
Delivery Total number (microns) Delivery Catheter (microns)
Pressure (psia) Pressure (psia) of Clogs 100-300 Spinnaker Elite
.RTM. 279 71.3 65.4 0 300-500 Spinnaker Elite .RTM. 330 54.6 52.6 0
500-700 RENEGADE .RTM. 533 32.610 33.245 0 700-900 FASTRACKER .RTM.
609 11.869 13.735 0 900-1200 GLIDECATH .RTM. 965 0.788 0.864 0
[0117] As evident, particles in each of the size ranges were
successfully delivered without clogging catheters with a lumen
diameter smaller than the largest particle size. The particles
exhibited a post-compression sphericity of about 0.9 or more.
Example 4
[0118] Solubility was tested by mixing particles in a solution of
solvent at room temperature for about 0.5 hour and observing the
mixture for visible signs of dissolution. The particles were
insoluble in DMSO (dimethylsulfoxide), HFIP
(hexafluoro-isopropanol), and THF (tetrahydrofuran).
Example 5
[0119] Particles had the following glass transition temperatures,
as measured by differential scanning calorimetry data (DSC):
TABLE-US-00004 Size (microns) Glass Transition Temperature
(.degree. C.) 100-300 107-108 300-500 110-111 500-700 109.30-110.14
900-1200 108.30-111.87
Example 6
[0120] FIGS. 8 and 9 show the ATR infrared spectra of dried
particles prepared according to Examples 1 and 2, respectively.
[0121] Other embodiments are in the claims.
* * * * *