Surgical suture abstract
A triblock terpolymer with a structure ABA formed from a biodegradable
hard segment A and a biodegradable soft segment B has as the soft
segment a statistical terpolymer with a completely amorphous structure.
A process for its production comprises chemically reacting the hard
segment monomer with hydroxy terminal groups of the soft segment
B. The absorbable polymer is suitable for the production of a surgical
suture material, which is wholly or partly formed from the polymer.
Surgical suture claimsWhat is claimed is:
1. A surgical suture material comprising a triblock terpolymer
having an ABA structure formed from a biodegradable hard segment
A and a biodegradable soft segment B, in which the soft segment
B is dihydroxy-terminated and chemically bound to the two hard segments
A, wherein the soft segment B is a random terpolymer having an amorphous
structure, the hard segment blocks A contains a glycolide monomer
and represents 20 to 95 weight % of the triblock terpolymer, the
terpolymer of the soft segment B being formed from trimethylene
carbonate, .epsilon.-caprolactone and glycolide, with the trimethylene
carbonate present in an amount of 5 to 70 weight %, the .epsilon.-caprolactone
present in an amount of 5 to 70 weight % and the glycolide present
in an amount of 10 to 70 weight %, and with the trimethylene carbonate
and .epsilon.-caprolactone being present in a weight ratio of between
80:20 and 20:80 wherein the terpolymer has a glass transition temperature
in the range of -10 to +25.degree. C. and a melting point which
is at least 164.5.degree. C.
2. The surgical suture material according to claim 1 wherein the
hard segment block represents 40 to 60 weight % of the triblock
terpolymer.
3. A surgical suture material wholly or partly formed from a triblock
terpolymer according to claim 2.
4. The surgical suture material of claim 3 in the form of a monofilament
or multifilament thread.
5. The surgical suture material of claim 1 in the form of a monofilament
or multifilament thread.
6. A process for the production of a surgical suture material comprising
a triblock terpolymer having an ABA structure of a biodegradable
hard segment A and a biodegradable soft segment B, wherein the soft
segment is a dihydroxy-terminated random terpolymer with an amorphous
structure and wherein the terpolymer has a glass transition temperature
in the range of -10 to +25.degree. C. and a melting point which
is at least 164.5.degree. C., comprising the steps of:
preparing the soft segment B by statistically copolymerizing 5
to 70 weight percent trimethylene carbonate, 5 to 70 weight percent
.epsilon.-caprolactone and 10 to 70 weight percent glycolide, wherein
the weight ratio of trimethylene carbonate and .epsilon.-caprolactone
is between 80:20 and 20:80 optionally in the presence of a catalyst
or a bifunctional initiator, at a temperature above 150.degree.
C. so that the mixture is a melt, with stirring and with an over
pressure of between 1 and 2 bars for a sufficient time to produce
the soft segment;
recovering the dihydroxy-terminated soft segment;
chemically reacting the dihydroxy-terminated soft segment with
glycolide by repeated melting of the soft segment with glycolide
at a temperature of between 200 and 250.degree. C., optionally in
the presence of a catalyst or a bifunctional initiator, with stirring
and with an over pressure of between 1 and 2 bars, for a sufficient
time to produce the triblock terpolymer; and
recovering the triblock terpolymer as the suture material.
7. The process according to claim 6 wherein the soft segment is
produced by random copolymerization of trimethylene carbonate, .epsilon.-caprolactone
and glycolide, containing 10 to 40 weight % trimethylene carbonate,
10 to 40 weight % .epsilon.-caprolactone and 30 to 50 weight % glycolide.
8. The process according to claim 6 wherein the triblock terpolymer
is treated with .gamma. rays to shorten the degradation time of
the polymer.
9. The process according to claim 6 wherein the soft segment is
recovered by discharging the soft segment from the reactor, cooling
the soft segment, comminuting the soft segment and then drying the
soft segment, and the triblock terpolymer is recovered by discharging
the triblock terpolymer from the reactor, cooling the triblock terpolymer,
comminuting the triblock terpolymer, and then drying triblock terpolymer.
10. A process for the production of a surgical suture material
comprising a triblock terpolymer having a structure ABA having a
biodegradable hard segment A and a biodegradable soft segment B,
wherein the soft segment is a dihydroxy-terminated random terpolymer
with a completely amorphous structure and wherein the terpolymer
has a glass transition temperature of -10 to +25.degree. C. and
a melting point of at least 164.5.degree. C., comprising the steps
of:
preparing the soft segment B in a polymerization reactor by statistically
copolymerizing 5 to 70 weight percent trimethylene carbonate, 5
to 70 weight percent .epsilon.-caprolactone, and 10 to 70 weight
percent glycolide, wherein the weight ratio of trimethylene carbonate
and .epsilon.-caprolactone is between 80:20 and 20:80 optionally
in the presence of a catalyst or a bifunctional initiator, at a
temperature between 200 and 210.degree. C. so that the mixture is
a melt with stirring and with an over pressure of between 1 and
2 bars for a sufficient time to produce the soft segment;
chemically reacting the dihydroxy-terminated soft segment with
glycolide by adding to the melted soft segment in the polymerization
reactor glycolide monomer as a melt under an argon counterflow,
with vigorous stirring, raising the temperature to about 230.degree.
C. in less than 15 minutes, reducing the temperature to 220.degree.
C. and allowing the reaction to proceed for sufficient time to form
the triblock terpolymer; and
recovering the triblock terpolymer as the suture material.
11. The process according to claim 10 wherein the soft segment
is produced by random copolymerization of trimethylene carbonate,
.epsilon.-caprolactone and-glycolide, containing 10 to 40 weight
% trimethylene carbonate, 10 to 40 weight .epsilon.-caprolactone
and 30 to 50 weight % glycolide.
12. The process according to claim 10 wherein the triblock terpolymer
is treated with .gamma. rays to shorten the degradation time of
the polymer.
13. The process according to claim 10 wherein the triblock terpolymer
is recovered by discharging the triblock terpolymer from the reactor,
cooling the triblock terpolymer, comminuting the triblock terpolymer,
and the drying triblock terpolymer.
Surgical suture description
TECHNICAL FIELD
The present invention relates to a triblock terpolymer of absorbable
synthetic polymer, its use in surgical suture material and processes
for the production thereof.
BACKGROUND OF THE INVENTION
Absorbable synthetic polymers usable for medical products such
as e.g. surgical suture material or implants, include conventional
homopolymers of polyglycolic acid or polylactic acid, as well as
their copolymers. Particularly in the case of suture materials monofilament
products have the advantage compared with braided multifilament
structures, that they have a smooth, homogeneous surface. This facilitates
the course of the thread and reduces the occurrence of capillarities.
Thus, no coatings need be applied in order to improve the compactness
of the thread and the pull-through forces through the tissue to
be sewn are reduced due to the smooth structure.
A disadvantage of the known polymers for suture material is their
high flexural strength, partly linked with an inadequate transverse
tensile strength, which leads to a poor knotting behaviour and limits
the use for surgical sutures.
Therefore developments have led to the use of block copolymers,
e.g. the structure AB, ABA or ABAB, in which at least one block
constitutes a so-called soft segment. It is known to produce soft
segments by homopolymerization or copolymerization of monomers,
such as e.g. trimethylene carbonate (13-dioxan-2-one) TMC, .epsilon.-caprolactone
or p-dioxanone (14-dioxan-2-one). The soft segments are reacted
with hard segments, whose monomers are typically chosen from glycolide
and/or lactide, to the corresponding block copolymers.
Among the commercially marketed long term-absorbable suture materials
reference is made to the block copolymer of glycolide and trimethylene
carbonate disclosed in European patent 98394 Al of the American
Cyanamid Company. A crystalline copolymer of glycolide and .epsilon.-caprolactone
described in European patent EP 441322 A1 of ETHICON Inc. constitutes
a short term-absorbable polymer material.
European patent EP 626404 A2 of United States Surgical Corporation
(USSC) claims absorbable block copolymers of glycolide, p-dioxanone
and trimethylene carbonate, in which the soft segment is formed
solely from p-dioxanone and TMC.
U.S. Pat. No. 5431679 of United States Surgical Corporation describes
a block copolymer, which comprises a block of glycolide ester units
and a block of statistical copolymers of 13-dioxan-2-one and caprolactone.
SUMMARY OF THE INVENTION
The problem of the present invention is to provide an absorbable
synthetic polymer in the form of a triblock terpolymer, which has
a good degradation and absorption behaviour in vivo combined with
good mechanical characteristics, which is easy and inexpensive to
manufacture and which can be easily and reliably used for surgical
suture material.
This problem is solved by a triblock terpolymer with a structure
ABA of a biodegradable hard segment A and a biodegradable soft segment
B, in which the soft segment B is dihydroxy-terminated and to it
is chemically bound both hard segments and which is characterized
in that the soft segment is a statistical terpolymer with a completely
amorphous structure.
The completely amorphous structure of the soft segment can advantageously
influence the in vivo degradability. The degradation behaviour of
the soft segment approaches that of the hard segment in that it
also contains the rapidly degradable glycolide. As a result of its
completely amorphous nature, it has surprisingly been found that
there is a relatively rapid degradation behaviour, which can be
attributed to a faster diffusion of the hydrolysis solution or the
body fluids than can be the case in crystalline ranges. With regards
to the structural features there is also an increased compatibility
of soft segment and hard segment. This leads to a balanced absorption
behaviour in vivo of the hard and soft segments in the triblock
terpolymer.
The structure of the triblock terpolymers according to the invention
has an advantageous effect on the characteristics of products produced
there-from. Examples are favourable mechanical characteristics such
as good flexibility, e.g. low flexural strength, good modulus behaviour
and good knotting characteristics, such as are in particular desired
in applications in the medical sector, such as for surgical sewing
or suture threads.
DETAILED DESCRIPTION OF THE INVENTION
In the triblock terpolymer according to the invention the hard
segment A can in particular be a homopolymer. In the case of the
triblock terpolymer the terpolymer in the soft segment B can contain
a monomer, which is contained in the hard segment A. Advantageously,
in the block terpolymer, the percentage of hard segment blocks A
is 20 to 95 wt. %, particularly 20 to 80%, preferably 40 to 60 wt.
% of the triblock terpolymer and the residue is soft segment B.
The triblock terpolymer in the soft segment B can be characterized
in that it is formed from trimethylene carbonate, .epsilon.-caprolactone
and glycolide. In particular, trimethylene carbonate can be contained
in a percentage of 5 to 70 wt. %, .epsilon.-caprolactone in a percentage
of 5 to 70 wt. % and glycolide in a percentage of 10 to 70 wt. %
in the terpolymer according to the invention. The percentages by
weight of the components trimethylene carbonate, .epsilon.-caprolactone
and glycolide are chosen in such a way that together they represent
100 wt. % of the terpolymer in the soft segment B. According to
the invention, the triblock polymer in the terpolymer preferably
contains 10 to 40 wt. % trimethylene carbonate, 10 to 40 wt. % .epsilon.-caprolactone
and 30 to 60 wt. % glycolide.
In the terpolymer of the soft segment B according to the invention
can be present trimethylene carbonate and .epsilon.-caprolactone
in a weight ratio between 80:20 and 20:80 particularly 70:30 and
30:70. The soft segment terpolymer preferably contains trimethylene
carbonate and .epsilon.-caprolactone in a weight ratio of 50:50.
In another embodiment the soft segment terpolymer can contain .epsilon.-caprolactone
in a higher proportion than trimethylene carbonate.
The triblock terpolymer according to the invention is in particular
characterized in that the monomer present both in the hard segment
A and the soft segment B is glycolide. Preferably the terpolymer
of the soft segment B is produced by statistical copolymerization
of trimethylene carbonate, .epsilon.-caprolactone and glycolide.
In the triblock terpolymer according to the invention advantageously
the soft segment B, as the middle block, is surrounded on either
side by hard segment blocks A. The hard segment is attached to both
ends of the soft segment by polymerization reaction at the OH-groups.
The formation of the hard segment can advantageously take place
by reacting the OH-terminated soft segment terpolymer with glycolide
monomers. A triblock terpolymer strand according to the invention
preferably comprises only one soft segment in the polymer strand.
Tests of the physical and physiological characteristics of the
triblock terpolymer according to the invention were performed, such
as e.g. relative to the microstructure, the glass transition range,
the melting behaviour and the inherent viscosity, as well as the
in vitro and in vivo degradation and the absorption behaviour. Unless
stated otherwise viscosity measurements take place in hexafluoroisopropanol
(HFIP) at 30.degree. C. and a concentration of c=0.8 g/dl. Measurements
of the glass transition temperatures (Tg), melting points (Tm) and
melting enthalpies (Hm) are performed by differential scanning calorimetry
(DSC) at a scanning rate of 10.degree. C./min. The in vitro degradation
was measured in the Sorensen buffer at pH 7.4 and a temperature
of 37.degree. C. and given as a percentage retention relative to
the original knot breaking strength.
The triblock terpolymer according to the present invention differs
from the conventional block polymers hitherto used e.g. for the
production of surgical suture material as a result of the modified
sequence of the monomer units in the macromolecular chain. This
also influences the interactions between the individual chain molecules
in a filament formed. As is well known to experts in the fibre technology
field, the physical and mechanical characteristics of a fibre are
dependent on the orientation and structure of the chain molecules,
particularly the formation of amorphous and crystalline ranges.
Preferably, the triblock terpolymer has an inherent viscosity of
0.5 to 1.5 dl/g, particularly 0.7 to 1.2 dl/g. The triblock terpolymer
according to the invention can also have a glass transition temperature
or point between -10.degree. C. and +25.degree. C. Preferably, the
soft segment B in the triblock terpolymer according to the invention
has a glass transition point between -30.degree. C. and +10.degree.
C. In particular, the triblock terpolymer is characterized in that
its structure is partly crystalline, the crystallinity being limited
to the hard segment. The melting enthalpy, a measure for the crystallinity
of a polymer, in the case of the triblock terpolymer according to
the invention is between 15 and 60 J/g, particularly between 15
and 50 J/g.
The absorbable triblock terpolymer according to the invention is
advantageously characterized by an accelerated absorbability in
living tissue. Its in vitro degradation time can be 5 to 30 days
(Sorensen buffer, 37.degree. C.).
It is to be assumed that the incorporation of a third monomer in
random distribution in the soft segment reduces the crystallization
tendency of the soft segment. In fact, tests by differential scanning
calorimetry (DSC), reveals that/the soft segment B is completely
amorphous in the structure. A suppression of the crystallization
in the soft segment leads to a desired improvement to the flexibility
of products produced from the triblock terpolymer according to the
invention. Measured values relative to the mechanical characteristics
of extruded filaments in two preferred embodiments of the inventive
polymer are given in tables 1 and 2.
The degradation of the polymer according to the invention takes
place in the body of an animal or human by metabolic processes.
Body and tissue fluids participate in the reaction. As a result
of hydrolysis the polymer chain is split up into smaller and more
readily soluble fragments. The fragments are then further degraded,
optionally accompanied by the participation of enzymatic processes.
The degradation products are transported away by the metabolic system
and, in the same way as other metabolic waste products, are eliminated
from the organism. It is important for a good compatibility of the
absorbable suture material with respect to the patient, that during
the degradation process no harmful metabolites are formed or concentrated.
Polyglycolic acid is in particular characterized that during its
decomposition in vivo no toxic decomposition products are formed.
The trimethylene carbonate and caprolactone used as comonomers according
to the invention are also characterized by a good compatibility
and the avoidance of toxic reactions.
Compared with glycolide, trimethylene carbonate and caprolactone
have much longer degradation times. This can lead to a widely differing
absorption behaviour of hard segment (e.g. glycolide) and soft segment
(e.g. TMC/caprolactone copolymer according to the prior art). Incompatible
polymers or polymer segments have a phase separation tendency, which,
as can be gathered from table 2 surprisingly leads to a deterioration
of the mechanical strength.
By polymerizing glycolide into the soft segment it is possible
to increase the compatibility between the hard segment and the soft
segment. This has an advantageous effect on the mechanical characteristics
of the polymer important in practice. This can also lead to a more
uniform degradation and absorption of the soft and hard segments
of the block copolymers in the living organism.
The degradation behaviour of the triblock terpolymer according
to the invention can be modified by varying the overall glycolide
percentage in the polymer. The degradation behaviour of the triblock
terpolymer according to the invention can also be modified by varying
the percentage of soft segment B in the triblock terpolymer (cf.
table 3). Another influencing factor, through whose variation it
is possible to modify the degradation behaviour in the inventive
polymer, is the intensity and duration of any .gamma. radiation.
Treatment with .gamma. rays can be linked with a partial molecular
weight deterioration, which leads to shortened degradation times.
It is possible in this way to adapt the characteristics of the triblock
terpolymer according to the invention to the advantageous requirements
in the individual case. In a possible embodiment of the invention,
a sterilization performed with the aid of .gamma. rays can be simultaneously
used for controlling the degradation behaviour of the surgical suture
materials produced from the polymer according to the invention.
It has been found that the triblock terpolymer with a structure
ABA formed from a hard segment A of biodegradable monomer and a
soft segment B of biodegradable monomer, in which the soft segment
is a statistical dihydroxyterminated terpolymer with an amorphous
structure, is suitable as an absorbable polymer for producing a
surgical suture material. The product provided for medical use is
then advantageously wholly or partly formed from the polymer.
It has surprisingly been found that surgical suture materials can
be produced from the block polymer according to the invention, particularly
monofilaments for suture material, which have the very good characteristics
necessary for surgical material, particularly with respect to the
physical properties and practical handling.
As is apparent from the above description of the characteristics
of the polymer according to the invention, it is in particular characterized
by its biodegradability and favourable degradation behaviour, together
with its good mechanical characteristics, especially its flexibility,
for applications in the medical sector.
Advantageously, surgical suture material of absorbable synthetic
polymer in the form of a monofilament formed from the triblock terpolymer
of glycolide, trimethylene carbonate and caprolactone is suitable
for use for wound closure with accelerated absorption. The aforementioned
advantageous mechanical characteristics of monofilament suture or
sewing threads of triblock terpolymer allow an easy handling of
the suture material during the sewing of tissue in an animal or
human body, e.g. when fixing organs, closing tears in the body tissue
or closing surgical incisions. In particular, due to the formation
of a monofilament with a smoother thread surface than a multifilament
suture thread, the tissue to be treated can be protected against
damage caused by suture insertion. This limits the risk of patient-prejudicial
side-effects, such as e.g. delayed healing and tissue granuloma
formation. A good knotability and knot strength in conjunction with
a high initial tensile strength and flexibility allow a reliable
fixing and stabilization of the linked wound edges during the first
days following a surgical operation. In particular, during these
first days, regenerative, endogenous tissue can reliably be used
for natural wound healing, because the risk of tearing apart of
the wound edges during movement of the patient is reduced as a result
of the secure and reliable fixing.
The present invention also provides a process for the production
of a triblock terpolymer with a structure ABA formed from a hard
segment A of biodegradable monomer and a soft segment B of biodegradable
monomer, which is characterized in that the triblock terpolymer
is formed by chemically reacting the hard segment monomer with hydroxy
terminal groups of the soft segment B, which is a statistical, dihydroxy-terminated
terpolymer with an amorphous structure.
More particularly, in the case of the production process according
to the invention, the soft segment can be produced by statistical
copolymerization of trimethylene carbonate, .epsilon.-caprolactone
and glycolide, with 5 to 70 preferably 10 to 40 wt. % trimethylene
carbonate, 5 to 70 preferably 10 to 40 wt. % .epsilon.-caprolactone
and 10 to 70 preferably 30 to 50 wt. % glycolide. The percentages
by weight of the components trimethylene carbonate, .epsilon.-caprolactone
and glycolide are chosen in such a way that, together, they represent
100 wt. % of the terpolymer in the soft segment B.
The monomer mixture for producing the soft segment according to
the invention can have added to it in the conventional necessary
quantity, a suitable catalyst, such as e.g. tin octoate, as well
as a bifunctional initiator, e.g. diethylene glycol. The reaction
is performed as a melt polymerization at temperatures above 150.degree.
C. in a suitable heatable reactor equipped with a stirrer. In particular,
this polymerization reactor must be designed in such a way that
the resulting highly viscous melts are homogenized, the requisite
temperature ranges can be respected and the raw polymer can be substantially
completely discharged from the reactor.
The terpolymerization reaction can be performed according to standard
procedures, known to the expert, for the production of statistical
copolymers. Preferably, the reaction mixture is heated, accompanied
by constant thorough mixing, particularly to a temperature of 190
to 210.degree. C., preferably 205.degree. C. For the duration of
the reaction, an overpressure of 1 to 2 and preferably 1.5 bar argon
is applied. For a reaction duration of 2 to 6 hours, preferably
5 hours, the preintroduced monomers can react to a statistical terpolymer.
Advantageously, the process is characterized in that the reaction
rate during soft segment polymerization is above 95%.
In an embodiment of the process according to the invention, the
soft segment can be isolated after polymerization and reacted to
the triblock terpolymer following repeated melting on with glycolide.
For this purpose, at the end of the reaction, the raw terpolymer
of the soft segment B is discharged as melt and comminuted after
cooling.
The reaction of the soft segment terpolymer with glycolide monomer
to the triblock terpolymer takes place in known manner as a melt
polymerization in a suitable polymerization reactor, as described
hereinbefore for the production of the soft segment. Once again
it is possible to add in the standard, necessary quantity a suitable
catalyst, e.g. tin octoate, as well as a bifunctional initiator,
e.g. diethylene glycol. Preferably, the reaction mixture is heated
for a period of 0.5 to 1 hour to a temperature of 200 to 250.degree.
C., preferably 220 to 240.degree. C. The switching in of a stirrer
preferably takes place after reaching a temperature of approximately
130.degree. C. For the duration of the reaction an overpressure
of 1 to 2 and preferably 1.5 bar argon is applied. During the reaction
period of 1 to 3 hours, the triblock terpolymer with hard and soft
segments of structure ABA is formed. Subsequently the polymer is
discharged from the reactor and, after cooling, is comminuted and
dried in the usual way.
In another embodiment of the process according to the invention,
after polymerization the soft segment can be directly reacted in
situ with glycolide to the triblock terpolymer. The in situ polymerization
of the triblock terpolymer according to the invention takes place
as melt polymerization in a polymerization reactor, as described
hereinbefore for the aforementioned polymerization reactions. Firstly
the monomers glycolide, 13-dioxan-2-one and caprolactone are added
to the reactor in the quantities necessary for soft segment formation,
together with the necessary catalyst and initiator. Accompanied
by stirring, the mixture is heated at an argon overpressure of 1
to 2 bar for approximately 30 min to a temperature of 200 to 210.degree.
C. and is reacted under these conditions for 4 to 6 hours. For forming
the triblock terpolymer, a requisite quantity of the hard segment
monomer glycolide is added as melt. Reaction for hard segment formation
takes place under an argon counterflow and accompanied by vigorous
stirring. The temperature is increased in less than 15 min to approximately
230.degree. C., is then reduced to approximately 220.degree. C.
and these conditions are maintained until the reaction is completed
for approximately 1 to 2 hours. The finished triblock terpolymer
is discharged and, after cooling, comminuted and dried in the conventional
manner.
Using conventional melt spinning processes, products for use as
absorbable surgical suture materials can be produced from the triblock
terpolymers according to the invention. The triblock terpolymer
can be extruded to filaments in one embodiment of the process. In
a preferred embodiment the triblock terpolymer can be extruded in
a melt spinning process, e.g. a single-screw or a twin-screw extruder,
through suitable spinning nozzles to monofilaments. In the case
of melt spinning the nozzle temperature is in particular up to 30.degree.
C. above the melting point of the processed polymer.
Advantageously, for strengthening purposes, the filament formed
is extruded in a cooling bath, which contains water or a conventional
organic liquid, such as e.g. glycerin. The cooling bath temperature
can be in the range 2 to 60.degree. C., particularly 2 to 50.degree.
C. Preferably the filament is extruded in water at ambient temperature.
The distance between the spinning nozzle and the cooling bath is
between 0.5 and 30 cm, preferably between 1 and 10 cm.
In order to obtain the necessary mechanical characteristics, the
extruded filament can be stretched or drawn for orienting the molecular
chains. The strengthened spinning thread can either be drawn directly
or, following winding up or spooling, in a separate step using standard
methods. It is possible to carry out drawing either in heated, liquid
media such as e.g. water or glycerin baths, or using drawing ovens
and rails. Advantageously it can be drawn with a draw ratio of 1:4
to 1:10.
In order to ensure a permanent maintenance of the orientation,
the mechanical characteristics and the dimensional stability of
the filaments, the stretched or drawn polymer material can be set
or fixed by annealing. Setting takes place at temperatures in the
range 50 to 150.degree. C., preferably 70 to 130.degree. C. The
heat setting process duration is between 1 and 20 hours. Annealing
can take place with or without shrinkage of the filament. It is
particularly preferable for drawing and heat setting to take place
immediately following extrusion, particularly using a combined process.
Advantageously, for this purpose, use is made of a corresponding
equipment constituted by combined, suitable devices. In a preferred
embodiment of the invention monofilament or multifilament products
from the triblock terpolymer can be exposed for 1 to 20 hours, with
or without shrinkage, to a temperature of 50 to 150.degree. C. in
order to obtain dimensional stability.
The diameter of the monofilaments produced in this way can be in
the standard range 0.001 to 1.2 mm. Advantageously, the monofilaments
according to the invention are characterized by the aforementioned
mechanical characteristics.
As examples for uses in medical products mention is made of filaments
produced by spinning, which are used directly in the form of monofilaments
or multifilament thread structures and employed as surgical suture
material absorbable in the organism of the patient.
The polymers and medical products produced therefrom according
to the present invention can be dyed or undyed. For dyeing purposes,
it is possible to use the dyes authorized for absorbable medical
products by the US FDA (Food & Drug Administration), such as
e.g. D+C green No. 6 D+C violet No. 2 etc.
Triblock terpolymer filaments produced according to the invention
can be processed according to conventional methods to surgical suture
material, e.g. cut to suitable lengths. In particular, the polymer
material according to the invention can be appropriately sterilized.
An appropriate sterilization process can be chosen from conventional
physical or chemical methods for inactivating microorganisms, or
a combination of such methods. One possible sterilization process
comprises treatment with .gamma. radiation. Preferably, sterilization
of the inventive polymer material for medical products takes place
using ethylene oxide.
Advantageously, surgical suture material produced from the polymer
according to the invention, cut to appropriate lengths, can be suitably
packed in ready-for-use manner. According to a preferred embodiment,
the suture threads according to the invention can be made available
already equipped with surgical needles.
Due to the hydrolytic decomposability of the polymer material according
to the invention medical products, during the storage thereof, must
be protected against moisture and elevated temperatures, so that
the strength characteristics are fully maintained up to the time
of use. Advantageously, medical suture threads produced according
to the invention, are packed in ready-for-use state in dried form.
Appropriately this can be brought about by a moisture-proof pack,
particularly a pack of moisture-impermeable film material, preferably
as a vacuum pack. It is also achievable by the choice of a dry,
cool storage location.
The polymers according to the invention and the products produced
therefrom are in particular characterized by the following physical
properties. It is a semicrystalline triblock polymer, which is consequently
solid at ambient temperature and which has a firm consistence. The
triblock polymer has a melting point above 120.degree. C. There
is no phase separation between the hard and soft segments. This
is apparent from the glass transition temperature, Which for the
terpolymer according to the invention is -10 to +30.degree. C.,
particularly 0 to +15.degree. C. With several phases, separate detectable
glass transition points would exist.
The inherent viscosity of the triblock terpolymer according to
the invention is advantageously above 0.7 dl/g in HFIP (c=0.8g/l
at 30.degree. C.). The inherent viscosity can be up to 2.0 dl/g
for polymers usable in practice.
So that in the polymer according to the invention the residual
monomer content is low and simultaneously a high reaction or transformation
rate is obtained, the soft segment polymerization in the melt can
take place at over 150.degree. C., preferably above 170.degree.
C., up to 235.degree. C.
In the case where the polymer according to the invention is transformed
into threads and is in particular drawn or stretched, the knot breaking
strength changes during the degradation period. After 7 days it
is between 30 and 80%, preferably between 50 and 70% of the original
value. After 14 days the knot breaking strength is still between
5 and 50%, particularly between 20 and 40% of the original value,
as is apparent from measurements in the Sorensen buffer at pH 7.4
and 37.degree. C.
Moreover, with the drawn polymer material according to the invention,
particularly drawn threads, the elongation is between 15 and 60%,
preferably between 25 and 45%. The linear tensile strength is between
300 and 1000 N/mm.sup.2 particularly above 400 N/mm.sup.2. The
knot tensile strength is between 250 and 800 N/mm.sup.2 preferably
above 350 N/mm.sup.2.
For the triblock polymer according to the invention the modulus
of elasticity is between 500 and 3000 N/mm.sup.2 preferably below
1800 N/mm.sup.2. In the case of multifilament threads modulus of
elasticity values can be up to 7000 l/mm.sup.2 preferably less
than 5000/mm.sup.2.
EXAMPLES
Further features and details of the invention can be gathered from
the following description of preferred, exemplified embodiments.
The individual features can be implemented individually or in the
form of subcombinations. The examples merely serve to illustrate
the present invention, which is in no way restricted thereto.
Example 1
Dihydroxy-terminated Soft Segment of Composition G/TMC/CL=30/35/35.
In a reactor are placed 350 g of 13-dioxan-2-one (TMG), 350 g
of caprolactone (CL) and 300 g of glycolide (G), together with 0.2
g of tin octoate (solution in diethyl ether) and 1 g of diethylene
glycol. The ether is then drawn off in high vacuum at 50.degree.
C. After 1 hour an overpressure of 1.5 bar argon is applied and
the reactor heated to 205.degree. C., accompanied by stirring. This
temperature is maintained for 5 hours, after which the polymer is
discharged and analyzed. The inherent viscosity is 0.648 dl/g, and
the glass transition point -27.5.degree. C.
Example 2
Dihydroxy-terminated Soft Segment of Composition G/TMC/CL=40/30/30.
To a reactor are added 300 g of 13-dioxan-2-one, 300 g of caprolactone
and 400 g of glycolide, together with 0.2 g of tin octoate (solution
in diethyl ether) and 1 g of diethylene glycol. The reaction to
the polymer takes place in the same way as in example 1. The inherent
viscosity is 0.937 dl/g and the glass transition temperature -19.8.degree.
C.
Example 3
Dihydroxy-terminated Soft Segment of Composition G/TMC/CL:=50/25/25.
To a reactor are added 250 g of 13-dioxan-2-one, 250 g of caprolactone
and 500 g of glycolide, together with 0.2 g of tin octoate (solution
in diethyl ether) and 1 g of diethylene glycol. The reaction takes
place as in example 1. The inherent viscosity is 0.813 dl/g and
the glass transition point -9.3.degree. C.
Example 4
Triblock Terpolymer of Composition G/TMC/CL=72/14/14 with 40 wt.
% of soft Segment from Example 1.
To a reactor are added 600 g of glycolide and 400 g of the soft
segment of example 1 together with 0.1 g of tin octoate (solution
in diethyl ether). The ether is drawn off in high vacuum at 50.degree.
C. After applying an over-pressure of 1.5 bar argon, the reactor
is heated for 40 min to 240.degree. C. The switching in of a stirrer
takes place on reaching a temperature of 130.degree. C. The temperature
of 240.degree. C. is maintained for 70 min and the polymer is then
discharged. The inherent viscosity of the ABA triblock terpolymer
is 0.75 dl/g, the glass transition point is 9.5.degree. C. and the
melting point 182.3.degree. C.
Example 5
Triblock Terpolymer of Composition G/TMC/CL=73/13.5/13.5 with 45
wt. % of the Soft Segment of Example 2.
550 g of glycolide and 450 g of the soft segment from example 2
without additional catalyst addition, are placed in the reactor
and dried in high vacuum at 60.degree. C. for 16 hours. After applying
an overpressure of 1.5 bar argon, the reactor is heated to 235.degree.
C. for 35 min, the stirrer being switched in on reaching a temperature
of 130.degree. C. The temperature of 235.degree. C. is maintained
for 60 min and the polymer is then discharged.
The inherent viscosity of the ABA triblock terpolymer is 1.01 dl/g,
the glass transition temperature 9.8.degree. C. and the melting
point 180.1.degree. C.
Example 6
Triblock Terpolymer of Composition G/TMC/CL=73/13.5/13.5 with 54
wt. % Soft Segment of Example 3.
460 g of glycolide and 540 g of the soft segment from example 3
together with 0.05 g of tin octoate (solution in diethyl ether)
are placed in the reactor and dried in high vacuum for 16 hours
at 50.degree. C. After applying an overpressure of 1.5 bar argon,
the reactor is heated for 45 min to 230.degree. C., the stirrer
being switched in on reaching a temperature of 130.degree. C. After
10 min the temperature is reduced to 220.degree. C. and kept at
this level for 100 min. The polymer is then discharged.
The inherent viscosity of the ABA triblock terpolymer is 0.813
dl/g, the glass transition temperature 9.9.degree. C. and the melting
point 164.5.degree. C.
Example 7
In Situ Polymerization of a Triblock Terpolymer of Composition
G/TMC/CL=73/13.5/13.5 with 45 wt. % of a Soft Segment of Composition
G/TMC/CL=40/30/30.
In the first stage, 360 g of glycolide, 270 g of 13-dioxan-2-one
and 270 g of caprolactone, together with 0.9 g of diethylene glycol
and 0.2 g of tin octoate (solution in diethyl ether) are placed
in the reactor. After drying for 16 h at 50.degree. C. in high vacuum,
an overpressure of 1.5 bar argon is applied and the reaction mixture
is heated, accompanied by stirring, for 30 min to 205.degree. C.
This temperature is maintained for 5 h. In stage 2 there is an addition
of 1100 g of melted glycolide for forming hard segments, under an
argon counterflow and with vigorous stirring. Simultaneously the
temperature is raised for 10 min to 230.degree. C., then lowered
to 220.degree. C. and kept there for 90 min.
The polymer has an inherent viscosity of 1.02 dl/g, the glass transition
point is 2.1.degree. C. and the melting point 191.2.degree. C. A
sample of the soft segment taken prior to glycolide addition has
an inherent viscosity of 1.081 dl/g and the glass transition point
is -20.1.degree. C.
Example 8
In Situ Polymerization of a Triblock Terpolymer of Composition
G/TMC/CL=73/13.5/13.5 with 54 wt. % of a Soft Segment of Composition
G/TMC/CL=50/25/25.
In the first stage, 540 g of glycolide, 270 g of 13-dioxan-2-one
and 270 g of caprolactone, together with 1.08 g diethylene glycol
and 0.216 g of tin octoate (solution in diethyl ether) are placed
in the reactor. After drying for 16 h at 50.degree. C. in high vacuum,
an overpressure of 1.5 bar argon is applied and the reaction mixture
is heated to 205.degree. C. for 30 min, accompanied by stirring.
This temperature is maintained for 5 h. In stage 2 1100 g of melted
glycolide are added for forming the hard segments, under an argon
counterflow and accompanied by vigorous stirring. Simultaneously
the temperature is raised for 10 min to 230.degree. C., then lowered
to 220.degree. C. and kept there for a further 80 min.
The polymer has an inherent viscosity of 0.99 dl/g, a glass transition
point of 10.4.degree. C. and a melting point of 183.6.degree. C.
Example 9
Extrusion of the ABA Triblock Terpolymer to the Monofilament.
The triblock terpolymer of example 7 is melted with a twin-screw
extruder at a screw speed of 21 r.p.m. and spun to monofilaments.
The L/D ratio of the nozzle capillaries is 24:1. The nozzle temperature
is 205.degree. C., i.e. above the melting point of the polymer (191.degree.
C.). For strengthening purposes, the extruded polymer strand is
drawn through a cooling bath with water at 20.degree. C. The distance
between the nozzle and the bath is 6 cm. The solid, monofilament
thread is wound up. For stretching or drawing purposes the monofilament
is subsequently passed over heated drawing rails. The first rail
is heated to 30.degree. C. and the second to 60.degree. C. The draw
ratio for the first path is 6.8:1 and for the second 1.32:1 which
gives a total draw ratio of 9.0:1. In order to obtain an adequate
dimensional stability, the drawn threads are then annealed in a
further process stage for 5 hours at 80.degree. C. The heat set
thread is then provided, for use as a surgical suture thread, with
a needle, followed by packing and sterilization. The mechanical
characteristics of the thread are given in table 1.
Example 10
Extrusion of the ABA Triblock Terpolymer to the Monofilament.
The triblock terpolymer of example 8 is spun to the monofilament
in accordance with example 9.
The process conditions for extrusion, drawing and annealing, together
with the mechanical characteristics of the monofilaments of examples
9 and 10 are given in the following table 1.
TABLE 1 ______________________________________ Extrusion Example
9 Example 10 ______________________________________ Polymer From
Ex. 7 From Ex. 8 Screw speed (r.p.m.) 21 22 Nozzle temperature (.degree.
C.) 205 185 Nozzle pressure (bar) 45 72 Capillary diameter (mtn)
1.8 1.8 Nozzle-bath spacing (cm) 6 4 Bath medium water water Bath
temperature (.degree. C.) 20 20 Draw-off speed (m/min) 10.0 8.0
Drawing Draw ratio 1 6.8:1 6:1 Temperature rail 1 (.degree. C.)
30 40 Draw ratio 2 1.32:1 1.1:1 Temperature oven 2 (.degree. C.)
60 80 Total draw 9.0:1 6.6:1 Filament diameter (mm) 0.352 0.472
Linear tensile strength (N) 49.5 73.5 Knot tensile strength (N)
34.6 49.3 Modulus of elasticity (N/mm.sup.2) 848 645 Elongation
(%) 29.2 30.3 Annealing (no shrinkage) Annealing time (h) 5 10 Annealing
temperature (.degree. C.) 80 100 Filament diameter (mm) 0.349 0.472
Linear tensile strength (N) 54.4 75.9 Knot tensile strength (N)
35.9 53.4 Modulus of elasticity (N/mm.sup.2) 1317.8 798.5 Elongation
(%) 24.9 32.7 ______________________________________
Example 11
In Situ Polymerization of a Triblock Terpolymer of Composition
G/TMC/CL=72/14/14 with 38 wt. % of a Soft Segment of Composition
G/TMC/CL=26/37/37.
In the first stage, 197.6 g glycolide, 281.2 g 13-dioxan-2-one
and 281.2 g caprolactone, together with 760 mg diethylene glycol
and 150 mg tin octoate (solution in diethyl ether) are placed in
the reactor and polymerized in accordance with example 7 with the
difference that in the second stage 1240 g of glycolide are added
and the reaction temperature is subsequently raised from 205.degree.
C. to 225.degree. C. and maintained for a further 90 min.
The inherent viscosity of the soft segment prior to glycolide addition
is 0.994 dl/g and its glass transition point is -26.9.degree. C.
The triblock terpolymer has an inherent viscosity of 0.883 dl/g
and a melting point of 215.3.degree. C. The occurrence of two separate
glass transition temperatures of -16.8.degree. C. and +28.3.degree.
C. is an indication of an at least partial incompatibility between
the hard and soft segments.
Example 12
In Situ Polymerization of a Triblock Terpolymer of Composition
G/TMC/CL=72/14/14 with 40 wt. % of a Soft Segment of Composition
G/TMC/CL=30/35/35.
In the first stage, 240.0 g glycolide, 280.0 g 13-dioxan-2-one
and 280.0 g caprolactone, together with 800 mg of diethylene glycol
and 160 mg tin octoate (solution in diethyl ether) are polymerized
with the same reaction performance as in example 10 and in the second
stage reacted with 1200 g glycolide to the triblock terpolymer.
The inherent viscosity of the soft segment prior to glycolide addition
is 1.112 dl/g and its glass transition point is -21.8.degree. C.
The triblock terpolymer has an inherent viscosity of 0.91 dl/g
and a melting point of 209.4.degree. C. It is possible to detect
in the DSC a single, but wide glass transition of 11.3.degree. C.
Example 13
In Situ Polymerization of a Triblock Terpolymer of Composition
G/TMC/CL=72/14/14 with 43 wt. % of a Soft Segment of Composition
G/TMC/CL=35/32.5/32.5.
In the first stage, 301.0 g glycolide, 279.5 g 13-dioxan-2-one
and 279.5 g caprolactone, together with 900 mg diethylene glycol
and 180 mg tin octoate (solution in diethyl ether) in the same reaction
performance as in example 10 under polymerization and are reacted
in the second stage with 1140.0 g glycolide to the triblock terpolymer.
The inherent viscosity of the soft segment prior to glycolide addition
is 1.144 dl/g and the glass transition point is at -19.1.degree.
C. The triblock terpolymer has an inherent viscosity of 1.036 dl/g
and a melting point of 206.5.degree. C. A single glass transition
of 11.2.degree. C. is detectable in DSC.
Example 14
In Situ Polymerization of a Triblock Terpolymer of Composition
G/TMC/CL=70/15/15 with 50 wt. % of a Soft Segment of Composition
G/TMC/CL=40/30/30.
In the first stage, 400 g glycolide, 300 g 13-dioxan-2-one and
300 g caprolactone, together with 1000 mg diethylene glycol and
200 mg tin octoate (solution in diethyl ether), are polymerized
in an identical reaction performance to example 10 and reacted in
the second stage with 1000 g glycolide to the triblock terpolymer.
The inherent viscosity of the soft segment prior to glycolide addition
is 1.083 dl/g and the glass transition point -15.6.degree. C. The
triblock terpolymer has an inherent viscosity of 1.060 dl/g and
a melting point of 186.3.degree. C. A single glass transition of
5.1.degree. C. is detectable in DSC.
Processing of the polymers of examples 11 to 14 to monofilaments
and their characteristics.
The polymers of examples 11 to 14 were extruded in a similar manner
to examples 9 and 10 to monofilaments, followed by drawing and post-treatment.
Table 2 shows the mechanical characteristics of these fibres, as
a function of the composition of the soft segment and its proportion
in the triblock terpolymer.
TABLE 2 __________________________________________________________________________
Influence of the compatibility between the hard and soft segments
and influence of the soft segment percentage on the mechanical fibre
character- istics - comparison with commercial products and patents.
Polym. SS % Glycolide LTS Elong. Modulus KTS Ex. Ex. wt. % in SS
(wt. %) d (mm) (N/mm.sup.2) (%) (N/mm.sup.2) (N/mm.sup.2) __________________________________________________________________________
11a 11 38 26 0.500 476 38.7 2293 311 12a 12 40 30 0.441 461 46.2
2012 348 13a 13 43 35 0.475 595 37 1284 421 13b 13 43 35 0.211 660
36.4 1335 592 13c 13 43 35 0.360 642 41.7 1329 504 13d 13 43 35
0.262 542 36.9 902 433 14a 14 50 40 0.359 410 28.3 775 328 USSG
US-Pat. 35 0 0.301 383 21 -- 317 Monocryl USP 0 0.433 666 48.1 893
360 Biosyn USP 0 0.449 791 37.0 1530 405 __________________________________________________________________________
SS = soft segment d = thread diameter LTS = linear tensile strength
KTS = knot tensile strength -- = no information USSC = U.S. Pat.
No. 5431679
TABLE 3 ______________________________________ Influence of the
soft segment percentage and total glycolide content on the in vitro
degradation in the Sorensen buffer (pH 7.4 at 37.degree. C.). Total
KTS retention KTS retention SS % glycolide after 7 days after 14
days Ex. (wt. %) (wt. %) (%) (%) ______________________________________
12a 40 72 68.8 32.1 13a 43 72 66.6 31.3 14a 50 70 44.2 7.4 10 54
73 41.5 5.6 Monocryl 40.0 15.0 USP 0 Biosyn 64.8 44.1 USP 0 ______________________________________
Surprisingly thread lha only has only moderate strength characteristics,
although the hard segment percentage and therefore crystallinity
is highest.
Consequently the incompatibility between the hard and soft segments
has a negative effect on the mechanical characteristics. In addition,
the comparison with the thread of U.S. Pat. No. 5431679 whose
hard segments are also of glycolide, but whose soft segment is only
of trimethylene carbonate and caprolactone, shows that in the present
invention by polymerizing glycolide into the soft segment, the compatibility
with the hard segment is improved and the mechanical characteristics
are much better. It is also clear that an adequately low modulus,
which is an indication of the flexural slackness and therefore flexibility
of the thread, is obtained with a soft segment percentage of 43
wt. % or higher. However, the tensile strengths decrease on further
increasing the soft segment percentage, so that the polymer composition
of threads 13a to 13d represents the optimum.
On comparison of threads 12a and 13a with respect to the in vitro
degradation behaviour, it is clear that there are no differences
between a soft segment percentage of 40 and 43 wt. %, for the same
total glycolide percentage.
As among the monomers used, glycolide gives the fastest degradable
polymer, the degradation kinetics of thread 14a with a total glycolide
content of only 70 wt. % are surprising. Here the reduced crystallinity
due to the increase in the soft segment percentage appears to speed
up degradation, which also applies for example 10.
Thus, by means of the claimed polymer compositions, the degradation
kinetics can be varied within certain limits by varying a) the total
glycolide content and/or b) the soft segment percentage.
On comparing the degradation kinetics of the present invention
with the values of the commercial products Monocryl (Eticon) and
Biosyn (USSC), it can be seen that the range between them can be
covered. The longer degradation time compared with Monocryl in the
preferred embodiment of the invention is particularly advantageous
if a delayed wound healing process occurs. |