U.S. patent application number 10/144494 was filed with the patent office on 2002-12-05 for synthetic absorbable autoclaveable monofilament fibers and brachytherapy seed spacers.
Invention is credited to Andjelic, Sasa, Jamiolkowski, Dennis D., Karl, John J., Keilman, Kenneth Michael, Popadiuk, Nicholas.
Application Number | 20020180096 10/144494 |
Document ID | / |
Family ID | 23859925 |
Filed Date | 2002-12-05 |
United States Patent
Application |
20020180096 |
Kind Code |
A1 |
Karl, John J. ; et
al. |
December 5, 2002 |
Synthetic absorbable autoclaveable monofilament fibers and
brachytherapy seed spacers
Abstract
The present invention is directed to absorbable, autoclaveable,
monofilament fibers prepared from absorbable glycolide-rich
polymers, in which the fibers are oriented in the total draw ratio
range 4.1 to 5.9X, and are annealed at a temperature between about
165.degree. C. and about 185.degree. C; to brachytherapy seed
spacers manufactured from the absorbable, autoclaveable,
glycolide-rich polymers, monofilament fibers; and to methods of
manufacturing such fibers and brachytherapy seed spacers.
Inventors: |
Karl, John J.; (Hopatcong,
NJ) ; Popadiuk, Nicholas; (Hillsborough, NJ) ;
Jamiolkowski, Dennis D.; (Long Valley, NJ) ; Keilman,
Kenneth Michael; (Raritan, NJ) ; Andjelic, Sasa;
(New York, NY) |
Correspondence
Address: |
AUDLEY A. CIAMPORCERO JR.
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
23859925 |
Appl. No.: |
10/144494 |
Filed: |
May 13, 2002 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10144494 |
May 13, 2002 |
|
|
|
09468463 |
Dec 21, 1999 |
|
|
|
6419866 |
|
|
|
|
Current U.S.
Class: |
264/148 ;
264/210.5; 264/210.8 |
Current CPC
Class: |
D01F 6/62 20130101; D01F
6/84 20130101; A61N 2005/1023 20130101 |
Class at
Publication: |
264/148 ;
264/210.5; 264/210.8 |
International
Class: |
D01D 005/098; D01D
010/02 |
Claims
We claim:
1. A process for the manufacture of a monofilament fiber,
comprising the steps of: extruding a polymer comprising 100 to
about 80 mole percent polymerized glycolide to form a monofilament
fiber, orienting the extruded monofilament fiber to a total draw
ratio of 4.1 to 5.9X; and annealing the oriented monofilament fiber
at a temperature of about 165.degree. to about 185.degree. C.
2. The process of claim 1 wherein the polymer comprises up to about
20 mole percent polymerized monomer selected from the group
consisting of L(-)-lactide, D(+)-lactide, meso-lactide,
p-dioxanone, trimethylene carbonate and epsilon-caprolactone.
3. The process of claim 2 wherein the polymer comprises about 10
mole percent polymerized lactide and about 90 mole percent
polymerized glycolide.
4. The process of claim 1 wherein the total draw ratio is about 4.5
to about 5.5X.
5. The process of claim 1 wherein the monofilament fiber is
annealed at a temperature of about 170.degree. C. to about
180.degree. C.
6. The process of claim 4 wherein the monofilament fiber is
annealed at a temperature of about 170.degree. C. to about
180.degree. C.
7. An absorbable, autoclaveable, monofilament fiber prepared by the
process of: extruding a polymer comprising 100 to about 80 mole
percent polymerized glycolide to form a monofilament fiber,
orienting the extruded monofilament fiber to a total draw ratio of
4.1 to 5.9X; and annealing the oriented monofilament fiber at a
temperature from about 165.degree.to about 185.degree. C.
8. The fiber of claim 7 wherein the polymer comprises up to about
20 mole percent polymerized monomer selected from the group
consisting of L(-)-lactide, D(+)-lactide, meso-lactide,
p-dioxanone, trimethylene carbonate and epsilon-caprolactone.
9. The fiber of claim 8 wherein the polymer comprises about 10 mole
percent polymerized lactide and about 90 mole percent polymerized
glycolide.
10. The fiber of claim 7 wherein the total draw ratio is about 4.5
to about 5.5X.
11. The fiber of claim 7 wherein the monofilament fiber is annealed
at a temperature from about 170.degree. C. to about 1 80.degree.
C.
12. The fiber of claim 10 wherein the monofilament fiber is
annealed at a temperature of about 170.degree. C. to about
180.degree. C.
13. A brachytherapy seed spacer comprising an absorbable,
autoclaveable monofilament fiber prepared by the process of:
extruding a polymer comprising 100 to about 80 mole percent
polymerized glycolide to form a monofilament fiber, orienting the
extruded monofilament fiber to a total draw ratio of 4.1 to 5.9X;
and annealing the oriented monofilament fiber at a temperature of
about 165.degree. to about 185.degree. C.
14. The seed spacer of claim 13 wherein the polymer comprises up to
about 20 mole percent polymerized monomer selected from the group
consisting of L(-)-lactide, D(+)-lactide, meso-lactide,
p-dioxanone, trimethylene carbonate and epsilon-caprolactone.
15. The seed spacer of claim 14 wherein the polymer comprises about
10 mole percent polymerized lactide and about 90 mole percent
polymerized glycolide.
16. The seed spacer of claim 13 wherein the total draw ratio is
about 4.5 to about 5.5X.
17. The seed spacer of claim 13 wherein the monofilament fiber is
annealed at a temperature from about 170.degree. C. to about
180.degree. C.
18. The seed spacer of claim 16 wherein the monofilament fiber is
annealed at a temperature from about 170.degree. C. to about
180.degree. C.
19. A process for the manufacture of a brachytherapy seed spacer,
comprising the steps of: extruding a polymer comprising 100 to
about 80 mole percent polymerized glycolide to prepare a mono
filament fiber, orienting the extruded monofilament fiber to a
total draw ratio of 4.1 to 5.9X, annealing the oriented
monofilament fiber at a temperature from about 165.degree. to about
185.degree. C; and cutting the annealed, oriented monofilament
fiber to a pre-determined dimension effective for use as the
brachytherapy seed spacer.
20. The process of claim 19 wherein the polymer comprises up to
about 20 mole percent polymerized monomer selected from the group
consisting of L(-)-lactide, D(+)-lactide, meso-lactide,
p-dioxanone, trimethylene carbonate and epsilon-caprolactone.
21. The process of claim 20 wherein the polymer comprises about 10
mole percent polymerized lactide and about 90 mole percent
polymerized glycolide.
22. The process of claim 19 wherein the total draw ratio is about
4.5 to about 5.5X.
23. The process of claim 19 wherein the monofilament fiber is
annealed at a temperature from about 170.degree. C to about
180.degree. C.
24. The process of claim 22 wherein the monofilament fiber is
annealed at a temperature from about 170.degree. C to about
180.degree. C.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to synthetic, absorbable mono
filament fibers of glycolide-based polymers, especially
poly(lactide-co-glycolide) copolymers, that are useful in the
fabrication of brachytherapy seed spacers in brachytherapy seed
delivery systems.
BACKGROUND OF THE INVENTION
[0002] Prostatic cancer has been estimated to affect as many as one
in three men. In the U.S. alone, this implies an estimated
fifty-million patients who are candidates for treatment of
prostatic cancer. Prior methods of treatment include surgical
intervention, external radiotherapy, and other brachytherapy
(interstitial radiation) techniques. A general discussion of the
localized use of radiation therapy is found in Bagshaw, M. A.,
Kaplan, I. D. and Cox, R. C., Radiation Therapy for Localized
Disease, CANCER 71: 939-952, 1993. Disadvantages associated with
surgical intervention include impotence and incontinence. External
radiotherapy may have deleterious effects on surrounding normal
tissues (e.g., the bladder, the rectum, and the urethra). In
contrast, brachytherapy diminishes complications such as impotence
and incontinence, and allows a higher and more concentrated
radiation dose to be delivered to the prostate gland as compared to
external radiotherapy. An additional advantage of brachytherapy is
that treatment can be accomplished within a matter of days as
compared to weeks, greatly reducing radiation exposure of the
adjacent organs.
[0003] Prostate brachytherapy can be divided into two categories,
based upon the radiation level used. The first category is
temporary implantation, which uses high activity sources, and the
second category is permanent implantation, which uses lower
activity sources. These two techniques are described in Porter, A.
T. and Forman, J. D., Prostate Brachytherapy, CANCER 71: 953-958,
1993. The predominant radioactive sources used in prostate
brachytherapy include iodine-125, palladium-103, gold-198,
ytterbium-169, and iridium-192. Prostate brachytherapy can also be
categorized based upon the method by which the radioactive material
is introduced into the prostate. For example, an open or closed
procedure can be performed via a suprapubic or a perineal
retropubic approach.
[0004] Prostate cancer is a common cancer for men. While there are
various therapies to treat this condition, one of the more
successful approaches is to expose the prostate gland to radiation
by implanting radioactive seeds. The seeds are implanted in rows
and are carefully spaced to match the specific geometry of the
patient's prostate gland and to assure adequate radiation dosages
to the tissue. Current techniques to implant these seeds include
loading them one at a time into the cannula of a needle-like
insertion device, which may be referred to as a brachytherapy
needle. Between each seed may be placed a spacer. In this
procedure, a separate brachytherapy needle is loaded for each row
of seeds to be implanted.
[0005] Although seed spacers may be made from a variety of
materials, both absorbable and non-absorbable, there are advantages
if the material is absorbable. These advantages include minimizing
or eliminating any effects due to the long-term presence of the
material in the body. Absorbable materials include catgut,
collagen, and synthetic absorbable polymers. Catgut and collagen
usually degrade by an enzymatic mechanism, as opposed to a chemical
mechanism such as reaction with water, that is, hydrolysis. The
preferred method of sterilization for brachytherapy seeds and
spacers is steam sterilization (autoclaving). When catgut is used
as a seed spacer material, the autoclaving process utilized may
make the spacer soft, presumably by the plastisizing effects of the
water which these materials uptake during exposure. Besides not
retaining physical characteristics, catgut seed spacers also can
change shape when exposed to autoclaving. Present-day synthetic
absorbable materials do not uptake as much water as catgut or
collagen. They do, however, degrade by a hydrolysis mechanism. It
is well known that these hydrolysis reactions occur at faster rates
at higher temperatures. As the preferred sterilization method for
brachytherapy seeds and spacers is steam sterilization
(autoclaving), it is surprising that synthetic materials known to
date can effectively function in these applications. Indeed, based
on the knowledge that synthetic absorbable polymers generally
degrade by chemical hydrolysis, most would not even consider them
for use as medical devices that would be sterilized by
autoclaving.
[0006] One approach to minimizing the effects of steam
sterilization on the premature degradation of seed spacers made
from synthetic absorbable polymers would be to consider those
synthetic absorbable polymers that are much more resistant to
hydrolysis. Such a material is polylactide. This material has a
much higher probability of maintaining mechanical properties
required for use in brachytherapy seed delivery devices after it
has been exposed to autoclaving, compared to, for instance,
polyglycolide. Yet, because polylactide takes so much longer to
absorb in the body, it is not generally a material of choice. The
high-lactide polymer, 95/5 poly(lactide-co-glycolide), used in the
production of certain long-term commercial suture materials useful
in certain orthopedic surgical procedures, also takes too long to
absorb in the brachytherapy procedures.
[0007] Other problems exist with certain synthetic absorbable
polymers. For instance, the synthetic absorbable polymer
poly(p-dioxanone), although known to retain its strength for much
longer time periods than polyglycolide, is too low melting to be
suitable for sterilization by autoclaving. As such, proper
selection of material is an important criterion in the manufacture
of monofilament fibers having properties suitable for use as
brachytherapy seed spacers.
[0008] In addition to material selection, we have found that the
process of manufacture is an important factor. Although injection
molding appears to be an entirely suitable manufacturing process to
make seed spacers, if injection molding most synthetic absorbable
polymers is utilized as the manufacturing process, the spacers so
produced tend to break down excessively during the sterilization
process, retaining very little strength. We have found a process of
making brachytherapy seed spacers from glycolide-rich synthetic
absorbable polymers entailing a preferred extrusion, drawing, and
annealing process to provide monofilament fibers with suitable
properties which can be cut to length.
[0009] Monofilament fiber, for use in many applications, needs to
be particularly straight, devoid of curves or bows, to allow proper
functioning. One such application is brachytherapy seed spacers. If
the seeds are curved or bowed, they may jam the applier during
application of the seed/seed spacer assembly. Additionally,
undesirable dimensional spacing variation may result if the seeds
are curved initially, or worse yet, curve or bow irreproducibily
once in the assembly, as this may initially go undetected. Since
the function of brachytherapy seed spacers is to help position
radioactive seeds to provide radioactivity in spatially suitable
pattern, the seeds must be sufficiently dimensionally accurate and
stable. Fibers made by some spinning processes are not straight
after extrusion and drawing. They tend to retain some coil memory.
Even after rack annealing, fibers made by some processes still can
be curved due to residual coil memory.
[0010] Other various process conditions may adversely affect the
properties required of the fibers for use as brachytherapy seed
spacers. Upon sterilization by autoclaving, too much undesirable
shrinkage in length may occur or the parts may undergo warping or
bending.
[0011] Besides the "brooming" that may be experienced upon cutting
fibers to length, some fabricated devices, i.e. seed spacers, also
may "broom" or split during surgery under mechanical loading. Too
much undesirable shrinkage in length, warping or bending upon
autoclaving sterilization, or "brooming" or collapse during loading
are failures that are particularly troublesome, as they occur at a
point when they are difficult to detect or worse yet, during the
actual surgical procedure.
[0012] It would be advantageous to develop a synthetic, absorbable
monofilament fiber that both is absorbable by the body and
maintains mechanical properties such that the fibers are suitable
for use as brachytherapy seed spacers in brachytherapy seed
delivery systems. It also would be advantageous to provide robust
processes for reliably making such synthetic absorbable
monofilament fibers having absorbability and mechanical strength
suitable for use as brachytherapy seed spacers.
[0013] According to the present invention, a manufacturing process
is provided for the production of a synthetic, absorbable,
monofilament fiber suitable for the fabrication of medical devices
that require autoclaving as the means of sterilization, such as
seed spacers. We have discovered unexpectedly that monofilament
fibers prepared from certain glycolide-rich copolymers, which
fibers have been oriented in a total draw ratio of 4.1 to 5.9X, and
have been annealed between about 165.degree. C. and 185.degree. C.,
can undergo a sterilizing autoclave cycle and still retain
sufficient properties so as to allow their use in certain medical
procedures, including brachytherapy.
SUMMARY OF THE INVENTION
[0014] The present invention is directed towards monofilament
fibers prepared from polymers containing about 80 to 100 mole
percent, preferably about 85 to 100 mole percent, polymerized
glycolide monomer. The glycolide homopolymer also is known as
polyglycolide or as polyglycolic acid. Preferably the fibers are
prepared from polymers comprising 0 to about 15 mole percent
polymerized lactide monomer and 100 to about 85 mole percent
polymerized glycolide monomer, i.e. poly(lactide-co-glycolide).
Most preferably, the polymers comprise about 10 mole percent
polymerized lactide monomer and about 90 mole percent polymerized
glycolide monomer. The fibers are oriented at a total draw ratio
range of 4.1 to 5.9X, and are annealed at a temperature between
about 165.degree. C. and about 185.degree. C. Such fibers are
absorbable by the body and are capable of undergoing an autoclave
process used to sterilize brachytherapy seed spacers, while
retaining mechanical properties required for use as brachytherapy
seed spacers in brachytherapy seed delivery devices. The invention
also is directed to brachytherapy seed spacers prepared from the
monofilament fibers. The invention also is directed to methods of
manufacturing such fibers and brachytherapy seed spacers.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Polymers used in preparation of the monofilament fibers of
the present invention must be absorbable by the body when used as
brachytherapy seed spacers. By absorbable, it is meant that the
material does not simply dissolve away from the implant site, but
is converted to lower molecular weight species that are removed
from the site and usually from the body by biological means. The
conversion to lower molecular weight species, in the case of most
synthetic absorbable polymers, is effected by chain cleavage by
chemical hydrolysis. In the case of brachytherapy seed spacers, it
is preferable to have the devices "cleared" in no more than about
three or four months after the procedure.
[0016] In addition to being absorbable, the fibers prepared from
the polymers must possess certain mechanical properties in order to
be useful as brachytherapy seed spacers. In particular, the column
strength of the fiber, at a minimum, must be effective to prevent
the fiber from splitting or brooming upon cutting to length in the
manufacture of seed spacers. Preferably, the column strength of the
fiber, and subsequently the seed spacer, will be at least 3.5
pounds after autoclaving. The surface of the fiber must be
sufficiently smooth for use as brachytherapy seed spacers. In
addition, the fiber must be dimensionally stable and autoclaveable,
meaning that the fiber retains shape and dimension effective for
use as a seed spacer when subjected to an autoclaving process
suitable for sterilization of seed spacers and practiced in the
hospital environment.
[0017] As mentioned earlier, polylactide homopolymers have been
found to provide adequate mechanical properties, but are deficient
in that they take too long to be absorbed by the body. The melting
temperature of poly(p-dioxanone) polymer is too low to survive the
autoclave process. The synthetic absorbable polymers containing
polymerized glycolide that have glass transition temperatures below
room temperature and that have found commercial utility as
monofilament sutures, such as the segmented copolymers of glycolide
and caprolactone, generally do not have the mechanical properties
needed to function as seed spacers after being sterilized by
autoclaving. We have thus found that not all synthetic absorbable
polymers function equally as seed spacer materials.
[0018] It has been unexpectedly discovered that monofilament fibers
prepared from glycolide-rich polymers containing about 85 to 100
mole percent polymerized glycolide, preferably made from
poly(lactide-co-glycolide), comprising from 0/100 to about 15/85
mole percent lactide-glycolide, and most preferably, 10/90
poly(lactide-co-glycolide), in which the fibers have been oriented
in the total draw ratio range of 4.1 to 5.9X and in which the
fibers have been annealed at a temperature between about
165.degree. to about 185.degree. C., may be used to reliably
fabricate absorbable, autoclaveable brachytherapy seed spacers for
use in brachytherapy seed delivery devices. Despite being
absorbable in the body by virtue of a relatively facile reaction
rate with water; that is, relatively facile chemical hydrolysis,
seed spacers of the subject invention can withstand exposure to
water (steam) at the high temperatures, and for the time periods
necessary to sterilize by a conventional autoclaving cycle.
[0019] Polymers used to prepare fibers according to the present
invention generally are prepared from 100 to about 80 mole percent
glycolide monomer and from 0 to about 20 mole percent of a
copolymerizable comonomer. Exemplary comonomers may be selected
from the group consisting of L(-)-lactide, D(+)-lactide,
meso-lactide, p-dioxanone, trimethylene carbonate and
epsilon-caprolactone. If less than about 80 mole percent glycolide
is used, the fibers manufactured therefrom will not possess
sufficient mechanical properties required for use in brachytherapy
seed spacers. A preferred comonomer is lactide, especially at about
a 10 mole percent level. Other sequences may be incorporated in the
polymer, for instance, by adding an alpha,omega-dihydroxy compound
at the start of the polymerization.
[0020] Generally, the polymers of the present invention have
molecular weights, prior to extrusion, corresponding to inherent
viscosity (IV) values of about 1.0 to about 2.5 dL/g, as measured
in hexafluroisopropanol (HFIP) at 25.degree. C., at a concentration
of 0.1 g/dL. It is preferable that the IV values of the resins
range from 1.2 to 2.1 dL/g, more preferably between 1.3 and 2.0
dL/g, and most preferably between 1.4 and 1.7 dL/g. It should be
understood that if the molecular weight of the polymer were too
low, it would be very difficult to orient the fiber in the draw
ratio range required according to the present invention. If the
molecular weight is too high, difficulty in conveying the molten
resin during extrusion may result.
[0021] In a process for making monofilament fibers disclosed in
U.S. Pat. No. 4,671,280, entitled Surgical Fastening Device And
Method for Manufacture, in the name of Dorband et al., the contents
of which are hereby incorporated by reference in their entirety,
the fibers prepared from polymers comprising greater than 80 mole
percent polymerized glycolide are oriented in a total draw ratio of
7.4 X and annealed at 135.degree. C. On the other hand, fibers
according to the present invention must be oriented in a total draw
ratio of 4.1 to 5.9X, more preferably from about 4.5 to about 5.5.
When the total draw ratio is too low, the fibers exhibit
insufficient column strength retention after autoclaving when used
as a brachytherapy seed spacer. When the total draw ratio is too
high, the surface of the resulting fiber may be too rough for use
as a seed spacer, and/or the ends of the fibers may easily split
apart, or "broom", upon cutting to length or during mechanical
loading as occurs during introduction of a seed/seed spacer
assembly in surgery.
[0022] In order for the process used to manufacture fibers
according to the present invention to be robust, it should
consistently provide fiber having the mechanical properties
required for use in brachytherapy seed spacers, particularly
dimensional stability and surface smoothness. We surprisingly have
discovered that when the extruded, oriented monofilament fibers
comprising 100 to about 80 mole percent polymerized glycolide are
oriented to a total draw ratio between 4.1 to 5.9X and annealed at
a temperature between about 165.degree. C. and about 185.degree.
C., fibers that exhibit required dimensional stability and surface
smoothness consistently are provided. When the annealing
temperature is less than about 165.degree. C., e.g. about
155.degree. C., the fibers often exhibit insufficient mechanical
properties such as bowing. More preferably, the fibers are annealed
between about 170.degree. C. and about 180.degree. C. Even more
preferably, the fibers are annealed at about 175.degree. C.
[0023] Upon sterilization by autoclaving, too much undesirable
shrinkage in length may occur, or parts may undergo warping or
bending. Besides the "brooming" that may be experienced upon
cutting fibers to length, some fabricated devices, i.e. seed
spacers, also may "broom" or split during surgery under mechanical
loading. Fibers and spacers that exhibit too much undesirable
shrinkage in length, warping or bending upon autoclaving
sterilization, or "brooming", or collapse during loading are
considered ineffective for use in brachtherapy.
[0024] By "autoclaveable", it is meant that the fiber, in the form
of a seed spacer, maintains at least 3.5 lbs of column strength and
does not warp or bend during the autoclave cycle, thus preventing
its use as a brachytherapy seed spacer.
[0025] Although seed spacer diameters between about 30 and 40 mils
are particularly advantageous, it is to be understood that the
diameter of monofilament fibers of the subject invention can be as
low as about 20 mils and as high as about 60 mils or greater.
Generally the cross-section of the fibers will be circular, but
other shapes may be used to advantage. In the case of non-circular
cross-sections, corresponding cross-sectional areas will
dominate.
[0026] Processes for making the glycolide-rich fibers and
brachytherapy seed spacers of the present invention are set forth
herein.
Example 1
[0027] Polymers and Polymerization:
[0028] Generally the polymers of the present invention have
molecular weights, prior to extrusion, corresponding to inherent
viscosity (IV) values of about 1.0 to about 2.5 dL/g, as measured
in hexafluroisopropanol (HFIP) at 25.degree. C. at a concentration
of 0.1 g/dL. It is preferable that the IV values of the resins
range from 1.2 to 2. 1, more preferably between 1.3 and 2.0, and
most preferably between 1.4 and 1.7 dL/g. Preferably the polymer is
10/90 molar ratio poly(lactide-co-glycolide). In those cases in
which the polymerized glycolide content is very high, for instance
97 to 100 mole percent, the resins may be very difficult to
dissolve, even in HFIP, if they have been allowed to crystallize
significantly. Inherent viscosity measurements may then need to be
made after first melting a sample of the (dried) resin and then
quickly quenching it to avoid crystallization. Samples, so treated,
usually can be dissolved in HFIP of IV determinations.
[0029] The polymers of the present invention generally can be made
by the ring opening polymerization of the glycolide monomer, and in
the case of certain copolymers, monomers selected from the group
consisting of L(-)-lactide, D(+)-lactide, meso-lactide,
p-dioxanone, trimethylene carbonate and epsilon-caprolactone. These
other monomers may be used in any combination with glycolide
monomer, provided that the formed polymer resin suitable for
extrusion contains at least 80 mole percent glycolide. The
polymerizations can be conducted, by placing the monomer or
monomers, a catalyst such as stannous octoate, and an initiator
such as dodecanol, in a suitable reaction vessel, purging to
provide an inert atmosphere, and heating at a sufficient
temperature and time. The resulting polymer can be ground or
pelletized to produce resin suitable for "drying", that is, the
removal of unreacted monomers. Other sequences may be incorporated
in the polymer for instance, by adding an alpha,omega-dihydroxy
compound at the start of the polymerization. The final resin should
contain at least 85 mole percent glycolide sequences.
[0030] Extrusion/Orientation:
[0031] Monofilament fibers of the present invention were extruded
using a one-inch horizontal extruder, with water quench
temperatures ranging from 20.degree. C. to 40.degree. C. (See Table
1). Typical extruder temperatures ranged from 225.degree. C. to
250.degree. C. although depending on the resin, temperatures may
range from about 200.degree. C. to about 265.degree. C. The
diameter of the extruder die was changed dependent on the amount of
orientation provided to the filament in the next stage. In the
experiments described, die diameters ranged from 200 to 220 mils.
The higher the draw ratio employed, the larger the die diameter was
selected so as to help keep the oriented fiber diameter fairly
constant. By way of example, for a final oriented fiber diameter of
35 mils, suitable die diameters may be as low as 140 mils to as
high as about 255 mils.
[0032] The filament was oriented in stages between godets with
in-line ovens located between the godets. The draw ratio between
the first and second set of godet rolls is between 4.5 and 5.0X,
with oven temperature between 50.degree. C. and 75.degree. C. The
third stage has an additional draw of between 1.01 to 1.2, with
oven temperatures between 50.degree. C. and 75.degree. C.
1 TABLE 1 Godet Oven Godet Oven Godet Elong Quench 1 1 2 2 3 Fiber
At Temp Height Speed/Temp Temp Speed Temp Speed Diameter Tensile
Break (.degree. C.) (in.) (Fpm/.degree. F.) (.degree. C.) (Fpm)
(.degree. C.) (Fpm) (Mils) (Lbs) (%) 20 0.25 20 -- -- -- -- 29.6
7.3 -- 20 0.25 20/127 RT 30 NA NA 29.8 11.1 209 20 0.25 20/145 RT
66 NA NA 28.3 37.7 88.8 20 0.25 20/125 RT 68 NA NA 27.8 29.7 54.5
20 0.25 20/137 RT 100 NA NA 28.7 20.4 32.5 20 0.5 20/150 RT 120 NA
NA 29.8 21.1 10.7 20 0.5 20/147 RT 100 NA NA 32.9 44.8 33.3 20 0.5
20/145 RT 100 NA NA 34.7 41.4 31.2 20 0.5 20/148 RT 120 NA NA 31.9
28.4 23.3 20 3.5 20/131 160 100 NA NA 36.2 90.7 50.1 20 2.5 20/131
160 100 NA NA 37.1 89.9 51.2 20 3.5 20/131 165 100 NA NA 37.0 91.8
53.2 20 1.0 20/131 160 100 NA NA 35.8 56.7 36.7 20 5.0 20/131 160
100 NA NA 36.7 89.0 52.7 20 3.5 20/131 165 100 170 110 35.3 89.1
44.0 20 3.5 15/RT.sup. 165 55 165 75 36.6 105.9 44.0 40 3.5
15/RT.sup. 165 55 165 75 35.5 111.1 41.3 40 2.0 15/RT.sup. 165 55
165 75 35.5 109.5 40.7 40 5.0 15/RT.sup. 165 55 165 75 36.2 109.0
42.4 40 3.5 15/RT.sup. 165 55 165 75 36.4 105.4 42.2 40 3.5
15/RT.sup. 165 55 165 75 36.0 100.6 44.1 40 3.5 15/RT.sup. 180 55
180 75 36.2 80.8 53.5 40 3.5 15/RT.sup. 165 55 165 75 35.8 98.6
43.5 RT = Room Temperature
[0033] Draw ratios between godets can be calculated by dividing the
linear speed of the later godet by that of the earlier godet,
provided there is no significant slippage of the fiber on the godet
rolls. That is, with godets 1, 2, and 3 running at 15, 55, 75 feet
per minute, respectively, the draw ratio between godets 1 and 2 is
55/15 or 3.67X, between godets 2 and 3 is 75/55 or 1.36. The total
draw ratio may be calculated by multiplying the respective
individual draw ratios, e.g. 3.67.times.1.36=5.0 for the above
example. If there is slippage on the godet rolls, fiber speeds will
be used to calculate draw ratio. In the case a fiber with a
circular cross-section, draw ratios can also be calculated from
diameter measurements of the fiber before and after a particular
drawing stage: the square root of the ratio of initial diameter to
that of the final diameter is the draw ratio. In general, for
fibers with circular or non-circular cross-sections, the ratio of
the initial cross-sectional area to that of the final
cross-sectional area is the draw ratio.
[0034] Annealing:
[0035] Once the extruded monofilament fiber is oriented, it may be
stored on a spool. It is then wound onto a standard rack with
minimum tension, for instance approximately one pound. Racks
approximately 36 inches in length are suitable. The filament
tension is controlled during winding of the fiber around the rack,
such that there may be about 5% change in length after annealing.
The wound fiber is placed in the oven and the oven is purged with
nitrogen. While the annealing oven may be heated at a rate of about
1.degree. C. per minute, other heating rates may be used.
Alternately, the annealing cycle may include incremental hold times
at elevated temperatures prior to reaching the final temperature
between about 165.degree. C. and 185.degree. C. For instance, an
incremental hold time of 1 hour at 75.degree. C. can be used prior
to heating to the final temperature. After the heat cycle, the
material is cooled to ambient temperature, manually cut off the
rack into 30-inch strands and stored in a vacuum chamber until it
is ready to be cut into the final dimensions.
[0036] Column strength tests were performed on fibers in the
following manner: The test equipment was set up to have a
compression type load cell of at least 100 lbs. A stainless steel
tube that has an inside diameter that accommodates a stylet and
needle is used to compress the cut fiber (spacer). The tube is
clamped vertically such that the needle pushes the spacer in a
downward position. Once the position is set for the equipment, the
gauge length is "zeroed" to ensure that the stylet and pusher is
not overrun. The crosshead speed is set at 0.5 inch/second. The
maximum load and displacement at maximum load are recorded.
[0037] The fibers described in Table 2 were annealed at 145.degree.
C. prior to autoclaving and then evaluated for column strength
after autoclaving as set forth above. Some of the samples exhibited
unacceptable column strength after annealing or unacceptably rough
surface.
2 TABLE 2 Godet Godet 2 Oven Godet Oven Godet 1 Speed/ 1 3 2 4
Total Sample Speed Temp Temp Speed Temp Speed Draw Column Strength
ID (fpm) (fpm/.degree. C.) (.degree. C.) (fpm) (.degree. C.) (fpm)
Ratio Performance INDM 20.0 NA NA NA NA NA 1.0 Disintegrated during
XX1-1 autoclaving INDM 20.0 20/42 NA 30 NA NA 1.5 Disintegrated
during XX2-2 autoclaving INDM 20.0 20/42 NA 68 NA NA 3.4
Disintegrated during XX3-1 autoclaving INDM 14.76 20/50 50 62.4 50
72.5 4.8 Good - meets CS XX11-13 requirements INDM 20.0 20/47 NA
100 NA NA 5.0 Good - CS after XX4-1 Autoclaving = 16.16 lbs INDM
20.0 20/55 54 98.4 NA 100 5.0 Good - CS after XX7-1 Autoclaving =
20.39 lbs INDM 20.0 20/55 65 98 NA 100 5.0 Good - CS after XX7-5
Autoclaving = 19.27 lbs INDM 20.0 20/52 72 108 NA 110 5.5 Good - CS
after XX8-5 Autoclaving =28.99 lbs INDM 20.0 20/53 NA 120 NA NA 6.0
Not Tested Because XX6-5 Unacceptably Rough Surface
[0038] Annealed strands were evaluated against performance criteria
such as straightness, the ability to be cut easily without
splitting or brooming and column strength after autoclaving.
Results are presented in Table 3. It is noted that fibers annealed
at about 155.degree. C. or less exhibited inconsistent performance
results. Sample 2a, annealed at 145.degree. C., failed because it
did not meet the straightness criterion, i.e. it exhibited bowing.
Samples C, D, and G in Table 3, annealed at 155.degree. C., also
failed because they did not meet the straightness criterion.
3 TABLE 3 Oven Preheat Duration Set Duration Performance Temp Time
Temp Time CS Before CS After Sample (.degree. C.) (hrs) (.degree.
C.) (hrs) Straightness Autoclaving Autoclaving 1 75 1 145 6 Good
Good Good 2 -- -- 145 6 Good Good Good .sup. 2a -- -- 145 6 Failed
- CS not determined because Bowed sample failed "Straightness" 3 75
1 155 6 Good Good Good 4 -- -- 155 6 Good Good Good A -- -- 155 6
Good 13.86 12.24 B -- -- 155 6 Slight Bow 17.17 15.83 Fair C -- --
155 6 Failed - CS not determined because Bowed sample failed
"Straightness" D -- -- 155 6 Failed - CS not determined because
Bowed sample failed "Straightness" G -- -- 155 6 Failed - CS not
determined because Bowed sample failed "Straightness" E -- -- 175 6
Good 22.93 21.89 F -- -- 175 6 Good 20.36 18.23
[0039] We have unexpectedly discovered that monofilament fibers
prepared from glycolide-rich polymers described herein above and
that have been oriented in a total draw ratio of 4.1 to 5.9X and
that have been annealed at a temperature between about 165.degree.
to about 185.degree. C., may be used to reliably fabricate
absorbable, autoclaveable brachytherapy seed spacers for use in
brachytherapy seed delivery devices. Utilizing the fibers described
above, brachytherapy seed spacers were prepared as follows:
[0040] Cutting:
[0041] Fibers of the present invention may be cut in any manner
that will provide the dimensional requirements required for use as
brachytherapy seed spacers. This may include mechanical or thermal
means. An in-line cutting mechanism provides an economically
advantageous way of cutting. Cutting must be conducted so that it
does not "mushroom", crush, broom, or delaminate the fiber. Manual
cutting is possible and may be accomplished with a "razor blade" or
a "paper cutter" type of cutting mechanism. After cutting, the
fibers preferably are stored in a water-free environment, such as a
"nitrogen box" or a vacuum chamber. Simple cutting mechanisms
provide the advantage of capital cost avoidance regarding complex
equipment. The fibers of the subject invention have additional
advantage in that they can be cut by simply means without
"mushrooming", crushing, brooming, or delaminating, to allow their
use as brachytherapy seed spacers.
[0042] Sterilization by Autoclaving:
[0043] Different types of commercial autoclaving sterilizers are
available. Two major classes are known by some as the "pre-vacuum"
type and the "gravity-displacement" type. The pre-vacuum type of
sterilizer depends upon one or more pressure and vacuum excursions
at the beginning of the cycle to remove air. This method of
operation results in shorter cycle times for wrapped items because
of the rapid removal of air from the chamber (and the "load" or
items to be sterilized) by a vacuum system and because of a usually
higher operating temperature (for instance 132.degree. C. to
135.degree. C., or 250.degree. F. to 254.degree. F.). Typical
operating parameters for a pre-vacuum type of sterilizer are 3 to 4
minutes at 132.degree. C. to 135.degree. C. A gravity-displacement
type of sterilizer is one in which incoming steam displaces
residual air through a port or drain in or near the bottom of the
sterilizer chamber. Typical operating parameters for a
gravity-displacement type of sterilizer include 15 to 30 minutes at
121 to 123.degree. C.
[0044] Four types of sterilization cycles were used to sterilize
the samples: (1) pre-vacuum at 275.degree. F. (135.degree. C.) for
10 minutes; (2) gravity-displacement at 275.degree. F. (135.degree.
C.) for 15 minutes; (3) gravity-displacement at 275.degree. F. (1
35.degree. C.) for 25 minutes; (4) gravity-displacement at
254.degree. F. (123.3.degree. C.) for 30 minutes.
Example 2
[0045] Another method of manufacturing a dimensionally stable
absorbable spacer according to the present invention includes the
following steps. Using a typical horizontal extruder, such as a
one-inch 24:1 extruder, pellets of the polymer are melted and then
extruded through a die to form mono filaments. The filaments then
are quenched, for instance, using a heated water bath. More
particularly, the horizontal extruder includes a number of zones,
for instance, three zones, all which may be set independently at
temperatures of between about 200.degree. C. and about 260.degree.
C., and preferably between about 225.degree. C. and 250.degree. C.
As the polymer pellets are passed through the three zones, they
melt and the melted polymer is forced through a flange which is
heated to a temperature of between about 210.degree. C. and
265.degree. C. and preferably between about 230.degree. C. and
255.degree. C. After passing through the heated flange, the melted
polymer enters a pump, which has a temperature of between about
210.degree. C. and 265.degree. C. and preferably between about
232.degree. C. and 255.degree. C. Finally, the melted polymer is
forced through a die having a predetermined diameter of, for
example 0.22 inch. The polymer then forms a long rod, which is
suspended in air for approximately 2 to 4 inches and quenched in a
tank of water having a temperature of approximately 30.degree. C.
to 40.degree. C., thus completing the extrusion process.
Immediately following extrusion, or alternately after some time has
passed, the filaments may be oriented to about 5:1 draw ratio by
stretching them between heated godet rolls or by stretching them
between (optionally heated) godet rolls providing (additional)
heating means such as can be achieved with in-line ovens. It is
clear to those familiar with fiber manufacture that different means
of stretching a fiber to achieve a particular draw ratio are
available. In particular, the extruded rod may be oriented by
winding it around a first roller, which is turning at a rate of
approximately 4 to 6 meters per minute, which pulls the extruded
rod out of the bath. The extruded rod may then be wound around a
second roll that turns at a rate of 4 to 6 meters per minute. After
passing around the second roll, the extruded rod may be passed
through a first oven that is set at a temperature of approximately
50.degree. C. to 55.degree. C. After passing through the first
oven, the extruded rod may be passed around a third roll that is
turning at a rate of between 17 and 21 meters per minute. After
passing around the third roll, the extruded rod is passed through a
second oven that is set at a temperature of between 50.degree. C.
to 55.degree. C. After passing through the second oven, the
extruded rod is wound around a fourth roll that is turning at a
rate of between 24 and 31.5 meters per minute. Prior to cutting and
sterilizing, the rod must be annealed between about 165.degree. C.
and 185.degree. C.
[0046] It will be recognized that an absorbable, dimensionally
stable, autoclaveable seed spacer according to the present
invention may be modified to include certain types of medication
which may be absorbed as the spacer is absorbed. Such medications
might include, for example, anti-inflammatory, anti-cancer or
certain sustained-release drugs. A seed spacer according to the
present invention further may include markers or other materials
adapted to make the spacer visible to ultrasound or x-ray.
[0047] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. Accordingly, it is intended that the invention be
limited only by the spirit and scope of the appended claims.
* * * * *