A METHOD FOR PRODUCING A BIODEGRADABLE AND BIOABSORBABLE COPOLYMER
TECHNICAL FIELD
The present invention relates to a biodegradable and
bioabsorbable polymer having a low metal catalyst- content
(residual content), and a process for producing the same.
Specifically, the invention relates to a technique for reducing
the content of the metal catalyst in the biodegradable and
bioabsorbable polymer obtained after synthesis using the metal
catalyst.
BACKGROUND ART
Known examples of biodegradable ; arid bioabsorbable
"polymers include polylactic ". . aqid> pSlyglycolic . -acid,
.polycaprolactone, tsrimethylene carbonate, pol^dioxane>. copolymers
^thereof, and the like. They are degradable and..absorbable-in vivq,
_ and are thus used in medical implant applications such as sutures*,
•bone-joining materials, etc..
Since a heavy metal-based catalyst such-as tin octylate
is widely used-for the' synthesis of • such a polymer compound, the
metal catalyst remains in the synthesized'polymer'compound..' When,
the polymer compound is used as a material for a medical implant
application, the metal catalyst is exposed to the body with the
degradation of the polymer. The metal catalyst, which varies
'according to species, may have harmful effects on the human- body
suc£< as immunotoxicity, genetic toxicity, neurotoxicity, "etc.
when present at a certain concentration or more. Therefore, when
the polymer is used in a medical implant application, the metal
.•qatalysl: residual -content -:mus't' be'reduced as much as possible'.'1
On the other hand, polymers" for implant applications
require features of a certain level or more* of- molecular weight, -
strength, etc. In "order to obtain such polymers, a metal catalyst
of a certain amount." or more . must be added during the
polymerization process; it is thus required to remove the metal
catalyst remaining in the polymer After the polymerization
reaction. However,, removal of the metal catalyst is not easy, and.
is often accompanied by industrial difficulties.
For example, in a method described in Patent Document 1,
a polymer compound is first dissolved in an organic solvent, and
a metal catalyst is then removed by reprecipitation. This method,
however, requires a large amount of solvent, and causes a drastic
drop in molecular weight due to the polymer dissolution.
Therefore, this is not appropriate for producing materials (e.g.,
medical devices) that require strength of. a certain level or more.
Furthermore, since the polymer tends to contain many air bubbles
-when^reprecipitated, the molded product of the polymer is also
likel-y to contain -bubbles. Thus, it is not suitable, for
industrial manufacture.
Patent Document' 2 discloses a method for producing
copolymers o^ lacti&e and e-caprolactone; however, it- does; not
disclose the - final metal catalyst Content. The publication
discloses that the catalyst is used in an amount of 10"7 to-. 10~3
mol/mal relative to the-'monomers;-, however, the Examples merely
disclose that a catalyst' is added in an amount of 10"5 mol 'Cmetal
content: 22 ppm) per-mol 5-f monomer. The, further reduction bf the
metal :eatalyst content.,is not specifically disclosed.
Patent Document-- 3 discloses a method for obtaining a
biodegradable and bioabsorbable polymer having a high molecular
weight by adding 1 to 20Lppm of a metal catalyst and 0.01 t-b 0.5
wt% of higher alcohol --to lactide an.d caprolactone, and by
conducting polymerization under reduced pressure for 10 to 40
days. However, since the end of the polymer obtained by this
method is modified with a higher alcohol, it is considered that
the ^ polyme'r Has"'" different'' propertie'% ""(eVg.Y absorbability,
safety) than previously used bioabsorfc>able polymers, and thus
various examinations are required. Furthermore, since the metal
catalyst content used is too small, a long_ polymerization period
is required. It is therefore not industrially preferable.
Patent Document 1:
Japanese Unexamined Patent Publication No. S60-501217, see
Example I, etc.
Patent Document 2:
Japanese Unexamined Patent Publication No. H6-501045
Patent Document 3: ;
Japanese Unexamined Patent Publication No. 2000-191753
DISCLOSURE OF THE INVENTION ->
The object of the present invention is to provide a
safe biodegradable and bioabsorbable polymer :having an extremely
low metal catalyst content,- while retaining the properties
desired for a medical implant or the like; and a process for
producing the same. The present invention^further aims to provide
a*, method for reducing the* ' content of a metal catalyst in a
biodegradable and absorbable polymer tha't* caii ; be applied on an
industrial scale.
Method for Solving the .Problems
The present inventors conducted extensive research to
achieve the above object si* As;:a result, \ they found that a
biodegradable and bioabsorbable ?-polymer that- is obtained by
copolymerizing lactide .(lactic .acid- cyclic"- dimer) and ecaprolactone
at a specified molar ratio in ..the presence of a
metal catalyst is capable'* of having a metal. catalyst content of
less than 1 ppm in terms "of a metal by washing;" the polymer with
the mixed solvent containing acetic acid and" isopropanol at a
specified volume ratio. V
Specifically, the present inventors found that the
metal catalyst can be effectively" removed, without causing a
drastic drop in ' molecular weight, ' by' copolymeri^ing' lact'ide
(lactic acid cyclic dimer) and e-caprolactone at a molar ratio
ranging from 40/60 to 60/40 using a metal catalyst to produce a
copolymer, and washing the copolymer with a mixed solvent
comprising acetic acid and isopropanol at a volume ratio ranging
from 25/75 to 45/55, and' drying the copolymer. Hereinafter, this
invention is sometimes referred to as "First Embodiment".
The present inventors further found that the metal
catalyst can be effectively removed, without causing a drastic
drop in molecular weight, by copolymerizing lactide (lactic acid
cyclic dimer) and s-caprolactone at a molar ratio ranging from
65/35 to 85/15 using a metal catalyst to produce a copolymer, and
washing the copoiyraer with a mixed solvent comprising acetic acid
and isopropanol at a volume ratio ranging from 45/55 to 55/45,
and drying---the copolymer. Hereinafter, this invention is
sometimes referred to as "Second Embodiment".
The,;-invention is explained below in full detail.
First Embodiment
1;. Biodegradable, and Bioabsorbable Polymer -
.The; biodegradable and . bioabsorbablej-/polymfex of the
'j&esent "invention is a- lactide/s-caprolactone "copolymer, which
comprises lactide and .s-caprolactone at a molar ratio ranging
from 40/.60 to 60/40, and preferably 45/55 to 55.Z45.
"7-\ . The ,- biodegradable and bioabsorbable,-. polymer of the «
invention has,, a weight average molecular weigtit (Mw>. of about
50,000 to about 800,000, and particularly aboutvl00,0Q5 to about
500,000. ; Within the range described above,:-\ the polymer . is
suitably used' .as a medical implant in view of .-properties such as
strength, degradability, and'processability.
A. metal included in the' biodegradable- and bioabsorbable
polymer is derived from a metal catalyst used in a polymerization .
reaction for producing the biodegradable and bioabsorbable :
polymer mentioned below. Examples of such metals include sodium,
potassium, aluminium, titanium, zinc-, tin, etc. For example, when
tin octylate-is used in the polymerization' reaction, tin will be
the main metal contained in the polymer.
The biodegradable and bioabsorbable polymer of the
present invention has an extremely low metal catalyst content of
less than 1 ppm in terms of a metal. The' content of the metal
catalyst (in terms of a metal) in the polymer is preferably 0.1
to 0.95 ppm, more preferably 0.1 to 0.7 ppm, and further
preferably 0.1.to 0.5 ppm. Thus, even when the biodegradable and
bioabsorbable polymer of the invention is used as a medical
implant, there is little possibility of causing -immunotoxicity,
genetic toxicity, neurotoxicity, etc. in the human body.
The metal catalyst content (in terms of a metal) is
measured as follows. A sulfuric acid/nitric acid mixture (1:1,
volume ratio) is added to the polymer, and then heated to degrade
an organic component. Metal -..in the resulting mixture is
quantified using a plasma emission spectrometry machine with
reference to va metal standard solution. • Test Example 1-1(1)
illustrates a -<• measurement example .in which tin octylate is used
as a catalyst..
2. Production--.of- Biodegradable;. ancW Bioabsorbable Polymer
• The ^-biodegradable .^and,:.bioabsorbable polymer of the;
present invention having a low metal catalyst content is produced
by polymerizing lactide and j>-caprolactone in the presence of a
metal catalyst to produce a copolymer, washing the copolymer with
a mixed s.olvent comprising acetic acid and isopropanol at a
volume ratio U ranging from -: 25/75- to 45/55, and drying the
copolymer.- According to the- production method, the metal catalyst
content (in ./terms .of a .metal).: in the biodegradable and
bioabsorbable polymer can be'reduced to less than 1 ppm.
The--production method ^explained in detail below.
(1) Production of Copolymer *--
The copolymer is produced by copolymerizing lactide and
s-caprolactone in the presence of a metal catalyst.
A lactic acid forming the-lactide may be any one of the
following: 'E-fbrm/" D-f orra',"or' -DL-form>i bat • is-preferably L-form.
Examples of metal catalysts include those containing
sodium, potassium, aluminium, titanium, zinc, tin, or like groups.
Specific examples include sodium ethoxide, potassium-t-butoxide,
triethylaluminum, tetrabutyl titanate,' tin •octylate (II), tin 2-
ethylhexanoate, triphenyltin acetate, .tin oxide, dibutyltin oxide,
tin oxalate, tin chloride, dibutyltin dilaurate, etc. Of these,
tin octylate (II) . is preferable in view of reactivity and safety
in the polymerization reaction.
The used amount of the metal catalyst is about 100 to
about 1,-000 ppm (about 29 to about 290 ppm in terms of a metal) ,
and preferably about 200 to about 700 ppm (48 to 203 ppm in terms
of a metal) relative to the mixture weight content of lactide and
s-caprolactone. '-'.
- - •=- By using the metal catalyst in the range-:- described
above, a copolymer that has a molecular weight, strength, or like
properties suitable for implant applications can be produced in a
shorter period of time. When the -amount of metal- catalyst to be
added is too small,, a large number, of monomers remain unxeacted,,
.dr- the reaction requires too much .--time, .resulting inva polymer
'.that is unsuitable for industrial m|^'ufactiire. Further^ };a polymer
'having a large polymerization -degree (a &Lgh rnot;ecula'r weight)- -
cannot be obtained, and it is thus ..'-'not preferable.'1 v~;'. *
&£•• The copolymer can be produced by.^ubjecting. lactide and."
's-caprolactone to a publicly known A polymerization re'aetion such
'as bulk polymerization, in the jb'r-3sence-/: of a metals -'catalyst-,
Specifically, the lactide and e~caprolactone are Introduced in a"
"reaction vessel, and then the met-g.1 catalyst -is _ add'e'd thereto
'such that the metal catalyst is contained-: in an amount: of about
-200 to about 700 ppm (48 to 203 ppm in terms of 'a metal). Bulk
polymerization is then carried out- under a nitrogen atmosphere,
Or under reduced pressure according to a known method for 2 to 20
days at 110 to 180°C. *r.
The weight average molecular weight (Mw) of the
resulting lactic acid-s-caprolactone" copolymer is about 50,000 to
about' 8dO,6~0tf; '^nd'preTeYab^ about 500,000.
At this stage, the content of the metal catalyst (in
terms of a metal) in the copolymer is equivalent to the content
of the metal derived from the metal catalyst used in the
polymerization reaction, i.e., 48 to 203 ppm.
(2) Washing of Copolymer
The metal catalyst content (in terms of a metal) is
reduced to less than 1 ppm by washing the .copolymer obtained
above in step (1) in a mixed solvent containing acetic acid and
isopropanol at a volume ratio of 25/75 to 45/55, at lower than
40°C.
First, it is preferable that the copolymer be
pulverized using a grinder or the like into grains having an
average particle diameter of about 0.3 to about 4 mm in order to
improve the washing efficiency of the copolymer with a high metal
content. The average^particle diameter is measured using the
following -methods* Screening the particies using sieves- having
-various mesh sizes, and.calculating the average particle>,diameter
•based on the weight ratio of each of the screened portions; or-,
- taking a ^certain;.; amount, of the particles and observing the.
.diameter of.; each of .theyparticles by mear\s Qf a microscope^.;- ^~"
*" -^Ehe washing -solvent is- a- mixture comprising, acetic aci%
and^isopropanol. The"ons-xed solvent has a function of permeating.
.through the. pulverized-.polymer to." allow the acetic acid and metai;_
.catalyst--tfe, produce a^chelate complex, which is to be extracted,
in£§, the -:-: solution. *>!i-The volume rat;j_0 Qf acetic acid anpl
isbpropanofl in the mixed solvent is irj the range -:of -;^5/75 ta
45/55, ancl preferably .in the range Qf' 27/73 to- 43/5.7- If
necessary,;, a small amount of ethyl aCetate can be ,added in
addition to the isopropanol. In this case, the volumes-ratio of
the; isopropanol and ;the ethyl acetate is about 99/1 -,to about
70/30. The mixed solvent may be adjusteq to have a pH of about 2
to about 6. -i
The content (bath ratio) of the mixed solvent used in
the washing is, for example, not less than 1 L, preferably not
less; "than"T3T, and' more ^refe^ably* ihn the' range of about 3 to
about 10 L per washing, relative to 1 kg of dry weight of the
polymer. The washing method employed is SUch that the polymer is
immersed in the mixed solvent having a temperature of less than
40°C, and preferably about 15 to about 30°C, and then stirred.
The mixed solvent is changed 5 times -or more, and preferably
about 6 to about 12 times. The washing' process takes a total of
48 hours or more, and preferably about 48 to about 96 hours.
In the early stages of washing/ since a large amount of
metal catalyst remains in the polymer, it is preferable that the
bath ratio of the solvent be relatively increased (for example,
about 4 to about 8 L relative to 1 kg of dry weight of the
polymer) , and/or that the exchange time of the washing solvent be
shortened each time. During the latter halfl of the washing, it is
preferable that the bath ratio of the solvent be minimized (about
3 to about 6 L relative to 1 kg of dry weight of the polymer),
and/or that the washincj-time be prolonged.",;-;
Further, if ^necessary, it is preferable that the acetic
acid be removed washing:* the. polymer- with'a'sopropanol to prevent
the molecular weight re'ductidm'.after long storage.
The polymer?*a*fter wS-shing Undergoes a drying process.
"The drying "is conducted*-:at aboftt 15-t$.-about 60°C, arid: preferably
about 20 to about 5O°0£ri for 6/>hours o'r more,- and preferably for
"about 10 to 150 hour's^, to remove an- organic solvent. It is
preferable that pre-dr-ying ber- first 'preformed at \ about 20 to
about 35°C for about l'Onto about 30 hours'to remove- isopropanol,
"and then drying be: performed at about---35 €6": about 50°C for about
40 to about 100 hours .;'^Both drying processes are conducted under
normal to reduced pressure (fdr example, alDout 0.01 to about 0.1
Pa), and are preferably-conducted in vacuo^at about 0.01 to about
0.05 Pa. The molecular weight reduction.'-bf the polymer can be
prevented as much as possible by employing-sSuch drying conditions.
The biodegradable and bioafrsorbable polymer of the
present invention is produced in the aforementioned process. The
metal catalyst content (in terms of "a metal) of the biodegradable
'land bioabsbrbable:,3polymer 'is "less" than T' ppm"/ "preferably 0.1 to
0.95 ppm, more preferably 0.1 to 0.7 ppm, and further preferably
0.1 to 0.5 ppm.
The weight average molecular , weight (Mw) of the
biodegradable and bioabsorbable polymer is about 50,000 to about
800,000, preferably about 100,000 to about 650,000, and more
preferably about 210,000 to about 500,000. Particularly, the
retention rate of the weight average molecular weight of the
copolymer after washing relative to that before washing is 75% or
more, and further 80% or more. According to the method of the
present invention, the molecular weight reduction during the
washing process can be suppressed as much as possible.
3. Application ..,-
•"j^'.The biodegradable and bioabsorbable polymer of the
present invention has an extremely low metal catalyst content of
less^thah->l ppm (in terms of a metal), andy known production
methods. -.
Second Embodiment
1. Biodegradable and Bioabsorbable Polymer
7-t-The biodegradable and bioabsorbable polymer, of the
present ^invention is a lactide/e-caprolactone copolymer, which
comprises lactide and s-caprolactone at a molar ratio ranging
from 65/35 to 85/15, and preferably -70/30 to 80/20.
"''" ' The biodegradable r and bioabsorbable polymer of the
invention has a weight average molecular weight (Mw) of about
50,000 to about 800,000, and particularly about 100,000 to about
500,000. Within the range described above, the polymer is
suitably used as a medical implant in" view of properties such as
strength, degradability, and processability.
A metal included in the biodegradable and bioabsorbable
polymer is derived from a metal catalyst used in a polymerization
reaction for producing the biodegradable and bioabsorbable
polymer mentioned below. Examples of such metals include sodium/
potassium/ aluminium/ titanium, zinc, tin, etc. For.example, when
tin octylate is used in the polymerization reaction, tin will be
the main metal contained in the polymer.
The biodegradable, and bioabsorbable polymer of the
present invention has an extremely low metal catalyst content of
less than -1 ppm in terms, of .a- metal. The content of the metalcatalyst
(ah terms of a metal-}--;;in the polymer is preferably 0.1-
to 0.95 -ppm, more preferably.- 0.1 to 0.7 ppm, and further,-,;-
preferablyf:-0.1 to>G.5 ppm=.v Thus,, even when the biodegradable,,.and;;.
bioabsorbable polymer of>vthe^-invention is used as a medical../;
implant, there is.^>little;>possi-bility of causing immunotoxicity/,:'*_-
genetic.: toxicity, neurotoxicity^- etc. in-the human body. . --••
'- - _?T_he metal catalyst"-^content (in terms of a metal )• is - -
measured a& follows. A sulfuric acid/nitric acid mixture (1:1£,
volume-ratio) is aWed to '-the;.polymer, and then heated to degrade^,-.
an organic;;., component.. . Metal in the resulting mixture is,:;/.
quantifiedv-;using r& plasma emission spectrometry machine .wittr.-,
reference -tp a metal standard, solution.' Test Example 11-1(1).:-:
illustrates a measurement example' in which tin octylate is usegV.
as a catalyst.
2. Production of Biodegradable, jand Bioabsorbable Polymer
The biodegradable .and bioabsorbable polymer of the
present invention having a low metal catalyst content is produced
by polymerizing lactide and 8-caprolactone in the presence of a
itietal 'catalyst to -produce' a^copolymer, 'washing the copolymer v/ith
a mixed solvent comprising acetic acid and isopropanol at a
volume ratio ranging from 45/55 to 55/45, and drying the
copolymer. According to the production method, the metal catalyst
content (in terms of a metal) in the biodegradable and
bioabsorbable polymer can be reduced to less than 1 pprn.
The production method is explained in detail below.
(1) Production_of Copolymer
The copolymer is produced by ^polymerizing lactide and
s-caprolactone in the presence of a metal catalyst.
A lactic acid forming the lactide may be any one of the
following: L-form, D-form, or DL-form, bat is preferably L-form.
Examples of metal catalysts include those containing
sodium, potassium, aluminium, titanium, zinc, tin, -ox like groups.
Specific examples include sodium ethoxide, potassium-t-butoxide,
triethylaluminum, tetrabutyl tltanate, t-in octylatei .(II), tin 2-
ethylhexanoate, triphenyltin acetate, tin oxide, dibutyltin oxide,
tin oxalate, tin chloride, dibutyltin c^ilaurate, e%c. Of these,
tin octylate (II) is preferabl^'in view! of reactivity and safety
in the,polymerization reaction.~*i; .-/ ?•:•. •.::•?.''•
'. .- The used amount of the- metal> catalyst is-?;-about .100 to
about 1>000 pprn (about 29 to about 290^pm in^.term;s.,;of a metal),
and preferably about 200 to'about 700 pjpm (48 to 20%ppm in -terms
of a metal) relative, to the mixture weight consent.-X>i lactide-and
s-caprolactone. ?-t\ & " '•$**;
By using the metal ^catalyst in the range described
above,'a- copolymer that has;a itio 1 e cul a r—weight;'; strength, or "like
properties suitable for implant ^applications ..can beyproduced in a
shorter period of time. . When the amount of metal-catalyst to be
added is too small, a large'number of monomers remain unreacted,
or the reaction requires too much time, resulting-;-in a polymer
that is unsuitable for industrial manufacture. - Further, a polymer
having a large polymerization degree (a high molecular weight)
cannot be obtained, and it is thus not preferable.
The copolymer can be produced by subjecting lactide and
s-ca£rolac£"6rie tb^^a"publicly'''^riovin '"|jaiym&rlzatioft reaction such
as bulk polymerization, in the presence of a metal catalyst.
Specifically, the lactide and s-caprolactone are introduced in a
reaction vessel, and then the metal catalyst is added thereto
such that the metal catalyst is contained'in an amount of about
200 to about 700 ppm (48 to 203 ppm in £erms of a metal). Bulk
polymerization is then carried out under a nitrogen atmosphere,
or under reduced pressure according to a known method for 2 to 20
days at 110 to 180°C.
The weight average molecular "weight (Mw) of the
resulting lactic acid-s-caprolactone copolymer is about 50,000 to
about 800,000, and preferably about 100,000 to about 500,000.
At this stage, the content of the metal catalyst (in
terms of a metal)'-"'in the copolymer is Equivalent to the content
of the metal derived from • the metal catalyst used in the
polymerization reaction, i.e., 48 to 203 ppm.
(2) Washing of Copolymer <-i
The metal catalyst content (in terms - o&i.a metal) is .
r-reduced to" less "than 1 ppm by washing the copolymer obtained
-above-/.in step.-. (l)::-in a mixed solvent containing-.1 acetsic acid1 and
^isopropanol at- a volume ratio of 45/55 to 55/45 at lo~wer thagt40oC.
*:^ First, :'; it is preferable that the er)polyme£l be...
vpulve-mzed using a .grinder or the like into particle's having an
average particle .diameter of. about 0.3 to about 4 mm-.inorcter to
improve the. washing-efficiency of the. copolymer with:-.•-§. high rmetal
-, content. - The average particle diameter is measure^ using the
1 folloMng methods": ^Screening • the particles using ";sieves b.aving
various mesh ^sizes,/ and calculating the average particle diameter~
•based'on the- weight ratio of each of the screened;?portions; or
taking a certain •'• amount of the particles, and observing the
diameter of each of the particles by means of a microscope.
The washing solvent is a mixture comprising acetic acid
and isopropanol. /-The mixed solvent has a function of permeating
through the pulverized polymer to allow the acetic acid and metal
catalyst to produce a chelate complex, which is to be extracted
ihto""t:he ' "solution. v The volume ratio of" acetic acid and
isopropanol in the mixed solvent is in the range" of 45/55 to
55/45, and preferably in the range of 47/53 to 53/47. If
necessary, a small amount of ethyl a.cetate can be added in
addition to the isopropanol. .In this Case, the amount of ethyl
acetate is 20% or less by volume, and .preferably about 10% by
volume relative to the amount of isopropanol.
The .content (bath ratio) of the mixed solvent used in
the washing is, for example, not less than 1 L, preferably not
less than 3 L, and more preferably in the range of about 3 to
about 10 L per washing, relative to 1 kg of dry weight of the
polymer. The washing method employed is such that the polymer is
immersed in the mixed solvent having a temperature of less than
40°C, and preferably about 15 to about 30°C, and then stirred.
The mixed solvent is changed 4 times.?-;.or 'more, and preferably
about 5 to about 9 times. The washing -process takes a total of 30
hours or more, and-preferably about- 30 to about 72 hours.
In the early stages of. washing-, since a large amount of
metal catalyst remains in the polymer; r£t is preferable that the
bath ratio of the '-solvent, be relatively increased (for example,
about 4 to about i8;-." L relative to . l--:;kg of dry . weight of the
polymer), and/or that the exchanges time of the washing solvent be
shortened each time*?,;' During, the latter-^half of the* washing, -it is
preferable that the--: bath ratio, of Jrhe solvent be-minimized (about
3 to about 6 L relative tf>. 1 kg of dry.- weight -of the polymer),
and/or that the;-washing time be prolonged. -_•
Further,;«±f~ necessary, it is.:.preferable that the acetic
acid be removed by. washing the, polymer with isopropanol to
prevent the molecular weight reduction*.after long storage.
The polymer after washing undergoes a drying process.
The drying is conducted at about 15 to about 60°C, and preferably
about 20 to about 50°C, for 6 hours ori-more, and preferably for
about 10 to 150 hours, to remove an.---organic solvent. It is
preferable that pre-drying be first performed at .about 20 to
about 35°C for about 10 to about 30~ hours to remove isopropanol,
and'then drying be performed at'about 35' to' about' 50°C" for'about
40 to about 100 hours. Both drying processes are conducted under
normal to reduced pressure (for example, about 0.01 to about 0.1
Pa), and are preferably conducted in vacuo at about 0.01 to about
0.05 Pa. The molecular weight reduction of the polymer can be
prevented as much as possible by emplqylng such drying conditions.
The biodegradable and bioahsorbable polymer of the
present invention is produced in the aforementioned process. The
metal catalyst content. (in terms of a m%tal) of the biodegradable
and bioabsorbable polymer is less than i ppm, preferably 0.1 to
0.95 ppm, more preferably 0.1 to 0.7 ppm, and further preferably
0.1 to 0.5 ppm.
The weight average molecular weight (Mw) of the
biodegradable and bioabsorbable polymer is about 50,000 to 'about
800,000/ preferably about' 100,000 to about 650,000, and*,more
•preferably about 210,000 to about 500-000. Particularly,.^: the
retention rate of the weight average ^molecular weight of-vthe
-copolymer after washing relative to tha^Joefore washing.-is T5.% or
-more,'land further 80% or more. According to the method of^the
present' invention, the molecular weight! reduction during,?-the
washing process can be suppressed as-Tnuc%:,;.as possible.
3. -Application -
•~- - .^' The biodegradable and bioabs©rbable^ polymer otethe
-pfesentvMnvention has an extremely low -foetal catalyst content- of
less '^han 1 ppm'(in terms of a metal), %^d is gafe when embedded
in thevbody. Another ~feature of the invention is-its easy general
-fabrication. Therefore, it is suitably^sed as~ a material -for a
-medical device (a medical implant, etc*:-) . Examples of medical
-implant's include sutures, ' bone-joimng materials, - fracture
fixation materials, tissue supplementation materials, tissue
reinforcing materials, tissue covering materials, tissue
regenerating base materials, tissue prosthetic materials, -antiadhesive
materials, artificial blood veSSels, artificial valves,
stents, clips, fiber cloths, hemostatic materials, adhesives,
coating agents,' etc.'," which can""be "i^ade" by known productionmethods.
EFFECTS OF THE INVENTION
According to the present inventions (First and Second
Embodiments), a biodegradable and bioabsprbable polymer having a
reduced content of metal derived from a metal catalyst used in a
polymerization . reaction, and a small reduction in molecular
weight can be obtained by washing the polymer obtained after a
lactide and s-caprolactone copolymerization reaction with a mixed
solvent containing acetic acid and isopropanol at a specified
ratio, and drying the polymer. The resulting biodegradable and
bioabsorbable polymer is comparable to known polymers in
physicochemical properties'^ and can be processed by a general
industrial method. Thus, it- is suitably used as a material for a
medical'.application (a-medical implant).
BRIEF DESCRIPTION OF-THE DRAWINGS
FigJ";l is -a; \graph> showing the relationship betweeri-„-the
dryingvtemperature and-v-the .-molecular weight retention rate of&£he
polymer, obtained in Test. Example 1-3... -
Fig.v-2 is-a" graph, showing the relationship between"i:the
dryings-temperature_ and the-rjnolecular weight retention rate of", the
polymer, obtained in Test Example II-3..
BEST MODE FOR CARRYING OUT^THE INVENTION
The ^invention .will be described in detail below, *;.with
reference to Production^Examples,- Examples, and Test Examples .>;>.
First Embodiment
Production Example 1-1
Lactide and e-caprolactone (50:50, molar ratio) was
introduced into a reaction glass tube, and 300 ppm of tin
octylate (87 ppm in terms of a tin metal) was added thereto.
Polymerization was performed under a nitrogen atmosphere using a
'known method to thereby obtain 'a polymer 'having a "weiglit average
molecular weight of 400,000. The polymer was pulverized using a
grinder into a granulated polymer having a mean particle diameter
of 3.0 mm. The amount of tin remaining in the polymer was 80 ppm.
The average particle diameter was determined from the
weight ratio using sieves having different mesh sizes.
Test Example 1-1
The polymer obtained in Production Example 1-1 was
immersed inr per 1 kg by weight of the polymer, 5 L of the mixed
solution shown in Table 1', and stirred at 20°C for 4 hours using a
stirring device. The solution was replaced and stirred for 4
hours. Further, the solution was replaced, and stirred again for
16 hours. This series of procedures was repeated three times.
Specifically, the polymer was washed with a solution having the
same components nine times, for 72 hours in total;-*; Subsequently,
the polymer was immersed in '-5~ L of isopropanol,-and stirred at
20°C for one hour. Further, the solution was-'replaced, and washed
under stirring with isopropanol:' for one frour.:;-
"The resulting polymer was -.-vacuum-dried->'at- 30°C for 24
hours- (0.01 Pa), and then- vacuum-drfed at 4;0°C :for 48 hours- to
remove a solvent.
The resulting polymer was measured ^for the - metal
catalyst content (residual tin content) arid -molecular weight
retention rate. The results are shows?-in Table 1-t:- The measuring
methods are as follows.
(1) Measurement of Metal Catalyst Content
The resulting polymer was added to a sulfuric "acid/nitric acid
mixture (1:1, volume ratio),: and gradually heated--to degrade an
organic component. A commercially available tin standard solution
(tin chloride dihydrate, produced £>y Wako • -.--Pure Chemical
Industries, Ltd.) was used as a standard, and quantified using a
plasma emission spectrometry machine (a CID-AP model, produced by
Nippon Jarrell-Ash Co. Ltd.).
(2) Measurement of Molecular Weight -
! The' polymer "was' dissolved in" chloroform/' 'and "the" weight' average
molecular weight (Mw) was measured by gel permeation
chromatography (GPC) using polystyrene standards. The molecular
weight retention rate (%) was obtained by the following formula.
The molecular weight retention rate {%) = (the weight
•average molecular weight of the polymer after washing) / (the
weight average molecular weight of the polymer before washing) x
100
Table 1
Comparative
Example 1-1"
Comparative
Example 1-2
Example 1-1
. Example 1-2
Comparative
Example 1-3
Example 1-3
Volume Ratio of Washing Solvent
Acetic
Acid
10%
20%
30%
40.%.
50%
30%
Isopropanol
90% -
80%
70%
60%
50%
65%
Ethyl
Acetate
-
-
-
-
-
5%
Status '
Of
Polymer
Swelling
Swelling
Swelling
Swelling
Dissolution
Swelling
Residual
Tin
Content
C
B
A
A
^ - ^
"'A
Weight
Retention
Rate
A
A
A
A
" ^ ^ ^
A
Residual Tin Content:-
A: l&ss than V ppm, "B": 1 to less than 6 ppm, C: 6 ppm or :frtore' -:
Molecular Weight Retention Rate
A: 76--to 100%-,-'B: 60 to less than-75%, C: less than 60% :r
V~ Table-1- reveals- that the polymers of Examples -£-1 to I-
3 tiad a reduced-residual tin content, which was derived f£om the-*
met-al catalyst,- 'of less than 1 ppm, kept a high moTl ecul a a? -'weight
retention rate after washing, and had no appearand© problem.
Further, there was little'change in physical properties "before
and after washing. _ ***'*
l-~ • Contrarily, in Comparative Examples I-jL"and 1-2, themolecular
"weiglifc- retention rate was excellent, but-the residualtin
content beca'me larger. The polymer in Comparative Example 1-3
was dissolved because acetic- acid was contained in a large amount.
Test Example 1-2
Relationship Between the Washing Temperature and the Residual Tin
Content and Molecular freight Retention Kate
The polymer obtained in Production Example 1-1 was
immersed -in, per 1 kg by weight of the polymer, 5 L of the mixed
solution of Example 1-1 shown in Table 1. Each solution was
stirred at 20°C, 30°C, and 40°C for 4 hours using a stirring
device. The solution v/as replaced- ^rtd stirred for 4 hours.
Further, the solution was replaced, and stirred again for 16
hours. This series of procedures was repeated three times.
Specifically, the mixture v/as washed with a solution having the
same components nine times for 72 hours in total.
Twenty grams of the polymer was sampled during the
washing process, specifically, after completion of each of the 3rd,
5th, 6th, 8th, and 9th washing steps. The polymer sampled was
immersed in 100 mL of isopropanol, ahd stirred at 20°C for one
hour using a stirring device. The Solution was replaced and
stirred for one hour. Specifically,—the solution was washed v/ith
isopropanol alone for two hours'" in total. The resulting polymer
was vacuum-dried-:at 30°C for 2'4" hours" (0.01 Pa), and vacuum-dried
again at 40°C fo'r'48 hadrs (O.Qi"Pa) -to remove a solvent.
The metal catalyst content"(the residual tin content)
and the molecular^ weight'.retentibn rate of the-resulting polymer
v/ere measured. The results are shown-in Table 2". The measuring
method used was-'.-;'the same':"as that, described in Test Example 1-1.
Table':~2 shows>temporal changes of the washing
temperature 'and:-residua-iil-tin content'; •--, Table 3. shows temporal
changes of the washing temperature and molecular weight retention
rate.
Table 2
""'Residual Tin Cdntent:(ppm)
Diagonal Parts: less than the detection limits (0.5- ppm).
Table 3
Molecular Weight Retention Rate(%)
Time (h)
0
24
32
48
56 -
72
20°C
100
92
87
83
81
82
30°C
100
89
86
81
82
75
40°C
100
71
67
57
51
49
/*• Table 2 reveals that the residual tin content Iwas
reduced at any temperature to less than 1 ppm by the washing
method of the present invention. The time required for reducing
the^--residual tin content to less tharbl ppm was the shortest when
washing was conducted at 40°C; however/ Table 3 reveals that the
molecular weight was greatly reduced.1 with time at 40?C. .'-?)
"••s-r • On the other hand,' Table l^hows that there was* no-
're'm'arkable difference in the time- -required t^'-achieve' a .residual
tin-content" of less than 1 ppm between, the washing-temperature of
20?G- and 30°CV Table 3 shows that-thetmolecular weight retention
rat"4 at 20°C was likely higher than at'30°C.
Test- Example 1-3
Relationship Between the Drying Temperature and the 'Molecular
Weight Retention Rate
The polymer obtained in Production-"-Example- I-1Vun'derwent
steps before the drying step in accordance" wit-ftrfehe
washing method of Example 1-1 of Test" Example 1-1. The polymer
obtained after washing was dried at 30°C for 24 hours, ancf then
vacuum-dried (0.01 Pa) at 40°C for 48 hours or at 70°C for' 12
hours to remove a solvent.
Figure 1 reveals that the "molecular weight retention
rate of the polymer obtained by drying at 40°C (Example 1-1) is
82.2%; however, the molecular weight retention rate of the
polymer obtained by drying at 70°C was greatly reduced to 61.0%.
Second Embodiment
Production Example II-l
Lactide and e-caprolactone (75:25, molar ratio) was
introduced into a reaction glass tube, and 300 ppm of tin
octylate (87 ppm in terms of a tin m^tal) was added thereto.
Polymerization was performed under a nitrogen atmosphere using"a
known method to thereby obtain a polymer having a weight average
molecular weight of 700,000. The polymer was pulverized using a
grinder into a granulated polymer having a mean particle diameter
of 3.0 mm. The amount of-tin remaining ih the polymer was 80 ppm.
The average ^particle diameter w a s determined from the
weight ratio using-sieves having different mesh sizes.
Test-^Example II-l
: .'-"-: The polymer .^obtained in Production Example II-l was.-'"
-Immersed in* per l^.lcg by weight of-the bolymer, 5 L of the\ mixedh:
'•'solUfeLon shown in Tabled, and stirred at 20°C for 4 hoursV^sing a^-
. stirring device." - The-^solution was replaced and stirredv-for Air
-"-hour's-. Further, the solution was • replaced, and stirred again for"^-
16 -hours. -^This series;" of procedures was repeated .two-times. '£*
.Specifically, the polymer was washed with a solution havi%g thel£*
:same>"*components six times for 48 hours in total. Subsequently, -.;.
"the-'^olymerT was immersed- in 5 L of isopropanol, and1 stirred at*v'
20°C':'%or one hour. '-Further, the solution w a s replaced, ahdvrwashed
under stirring with isopropanol for one hour.
The resultineFpolymer was vac;Uum-dried at 30°C'.':for 24
hours (0.01 Pa), and then vacuum-dried at 40°C for 48 hours to
remove a solvent.
The resulting polymer was measured for the metal
catalyst content (residual tin content) a.nd molecular-1 weight." The
results are shown in Table 4. The measuring methods are as
follows.
(1) Measurement of Metal Catalyst Content
The resulting polymer was added to a sulfuric acid/nitric acid
mixture (1:1, volume ratio), and gradually, heated to degrade an
organic component. A commercially available tin standard solution
(tin chloride dihydrate, produced. by Wako Pure Chemical
Industries, Ltd.) was used as a standard, and quantified using a
plasma emission spectrometry machine (a CID-AP model, produced by
Nippon Jarre11-Ash Co. Ltd.).
(2) Measurement of Molecular Weight
The polymer was dissolved in chloroform, and the weight average
molecular weight (Mw) was measured by gel permeation
chromatography (GPC) using a polystyrene standard as a standard.
The molecular weight retention rate (%): .was obtained by the
following formula. :-p^
The molecular. weight retention rate (%) = (the weight
average molecular weight- of the polymer -after washing) /(the
weight average molecular^ weight of the polymer before washing) x
100
Table 4
-
Comparative
Example II-l
Comparative
Example 11-2
Comparative
Example II~3
Comparative
Example II-4
Conparative
Example I1-5
Example II-l
Comparative
Example II-6
Volume Ratio of Washing SolVent(%) ... ;';t:
Acetic
Acid
50%
50%
10%
10%
30%
50%
70%.
Isopropanol-
80% • ['
90%
70%
50%
30%
Ethylene
'Glycol
'-:>
:'-~25%
'•% ^
---
-: -t
' - •
Acetone
•%o%
**.
v->
f^
Ethyl
Acetate :
- ** L . •;
.25%
' '10% ,T]
-. " ''
" - •
-
•:"
- Status
*•• of
_ _: Polymer
-. Dissolution
: 'Swelling
'vSwelling
'"•"* Swelling
Swelling
"' Swelling
"Dissolution
.Residual
Tin
• Content
^ \ ^
B
B
C
B
h
^ Molecular
'Weight
Retention
Rate
^ \ ^
C
A
A
A - -
A
" - - - ^
Residual Tin Content
A: less than 1 ppm, B: 1 to less than 6 ppm, C: 6 ppm or more
Molecular Weight Retention Rate
A: 75 to 100%, B: 60 to less than 75%, C: less than 60%
Table 4 reveals that the polymer of Examples II-l had a
reduced residual tin content, which was derived from the metal
catalyst, of less than 1 ppm, kept a high molecular weight
retention rate after washing, and had no appearance problem.
Further, there was little change in physical properties before
and after washing.
Contrarily, in Comparative Examples II-2 to II-5, the
residual tin content exceeded 1 ppm', and further the molecular
weigh retention rate was greatly reduced in Comparative Example
II-2. The polymer in Comparative Examples II-l and II-6 was
dissolved.
Test Example; 11-2
Relationship' Between the Washing Temperature and the Residual- Tin v
• Content and ^Molecular Weight Retention Rate ;--. --
:--T-he polymer obtained in Production Example II-L' wasf'--'
immersed in/'; per 1 kg by weight of the polymer, 5 L/~of the-mixed
:-.: solution of Example .11-1 shown in Table•• 4.y^t Each solution-; was-,
^stirred; at 20°C or 40°C for 4 hours using: a stirring ^device.:-;-' The..
^solution was replaced " and stirred for .4 h©urs. .farther, ;V-the:;y
Vr solution was-again replaced, and stirred again>for 16;/hours. * This.--
^-series^-of i procedures was repeated two times!.:-1. Specifically^ i the7
^•mixture was- washed with a solution having the^same components^ six"
-i,times for ,48. hours ih total.
.TWenty grams of the polymer was= sampled during the*:.
- washing, process, specifically, after completion of each of the 2Iidj-
"••-3rd, 54*1/ and-!6th washing steps. The polymer sampled was immersed ;-:-•
in 100-mL pfi-isopropanol, and stirred at 20°Crfor one hour using ay-;-
stirring device. The solution was replaced and stirred for one
hour. Specifically, the solution was washed with isopropanol
alone for two hours in total. The resulting polymer was vacuumdried
at 30°C for 24 hours (0.01 Pa), and vacuum-dried again at
40°C for 48 hours (0.01 Pa) to remove a' solvent.
Table 5 shows temporal changes of the washing
temperature and residual tin content. Table 6 shows temporal
changes of the washing temperature and molecular weight retention
rate.
Table 5
Residual Tin Content(ppm)
Time (h)
0
8
24
32
48
20°C
73
3 .6
1.0
0 .5
0 .5
40°C
73
1.6
0 .4
~~~~~~~-~~-~~~~^__
^ ~~~~~--~~^_
Table 6
Molecular Weight Retention Rat^(%)
Time (h)
0
8
24 _
32 " ::
48 "••' :-
20°C
100
9 2 ,
90"
91: ;:
- SS'f
, 40?C .
100
79
- ^ ?1/:
'~-'' 53 ' '
•'" 46^'
- Table 5 reveals that the -residual tin content was
reduced at any temperature to less than 1 ppm by the washing
method of the' preserit" invention.; The time-i-required for reducing
the residual-"tin content to--less'^'than 1 ppm was shorter when the
washing was conducted at 40°"C; -however, Table 6 reveals that the
molecular weight was.- reduced*wi ttrtime at 40°C. On the other hand,'
the molecular weight-retention rate was kept at a high rate (90%
or more) at & washing temperaturev::of 20°C.
Test Example I1-3
Relationship Between the Drying ^Temperature and the Molecular
Weight Retention Rate
The polymer obtained in Production Example II-l
underwent steps before the drying step in accordance .with the
washing method of Example II-l of Test Example II-l. The polymer
obtained after washing was dried at 30°C for -24 hours, and then
vacuum-dried (0.01 Pa) at 40°C for 48 hours-or at 70°C for 12
hours to remove a solvent.
Figure 2 reveals that the molecular weight retention
rate of the polymer obtained by drying at 40°C (Example II-l) is
78.7%; however, the molecular weight retention rate of the
polymer obtained by drying at 70°C is greatly reduced to 54.6%.
Wc Claim:
1. A method for producing a biodegradable and bioabsorbable copolymer
having a weight average molecular weight of 50,000 to 800,000 and a metal catalyst content
of 0.1 ppm to less than 1 ppm in terms of a metal, comprising the steps of:
(1) copolymerizing lactide and e-caprolactone at a molar ratio ranging from
65/35 to 85/15 in the presence of the metal catalyst to produce a copolymer; and
(2) washing the copolymer with a mixed solvent comprising acetic acid and
isopropanol at a volume ratio ranging from 45/55 to 55/45 at less than 40°C, and drying the
copolymer.
2. The method as claimed in Claim I, wherein a lactic acid forming the lactide
in Step (1) is L-form, D-form, or DL-form.
3. The method as claimed in Claim 1 or 2, wherein the temperature of the
mixed solvent during washing in Step (2) is 15°C to 30°C.
4. The method as claimed in any one of Claims 1 to 3, wherein the mixed
solvent is exchanged four times or more, and the washing time is a total of 30 hours or more
in Step (2).
5. The method as claimed in any one of Claims 1 to 4, wherein the metal
catalyst is at least one member selected from the group consisting of tin octylate (II), tin 2-
ethylhexanoate, triphenyltin acetate, tin oxide, dibutyltin oxide, tin oxalate, tin chloride, and
dibutyltin dilaurate.
6. The method as claimed in any one of Claims 1 to 5, wherein the copolymer
after washing is vacuum-dried at 20°C to 35°C for 10 to 30 hours, and then vacuum-dried at
35°C to 50°C for 40 to 100 hours.
7. The method as claimed in any one of Claims 1 to 6, wherein the produced
copolymer is used for a medical implant selected from the group consisting of sutures, bonejoining
materials, fracture fixation materials, tissue supplementation materials, tissue
reinforcing materials, tissue covering materials, tissue regenerating base materials, tissue
prosthetic materials, anti-adhesive materials, artificial blood vessels, artificial valves, stents,
clips, fiber cloths, hemostatic materials, adhesives, and coating agents.