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Description  |
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TECHNICAL FIELD
This invention relates to a flexible member for medical use having
biodegradability as well as excellent physical properties including
flexibility, impact resistance and workability.
BACKGROUND ART
Conventional flexible materials which have been used for medical purposes
include materials mainly comprising polyvinyl chloride having blended
therein a plasticizing agent selected from phthalic acid-based compounds
such as dioctyl phthalate and 2-ethylhexyl phthalate in an amount of from
10 to 100% by weight per 100% by weight of the polyvinyl chloride;
materials mainly comprising an elastomer resin such as a
styrene-butadiene-styrene-based resin, for example an ABA-type block
copolymer, an ethylene-propylene copolymer, a polyester elastomer or a
polyurethane elastomer; and flexible resins such as an ethylene-vinyl
acetate copolymer and an ethylene-ethylacrylate copolymer.
Most of the flexible medical members fabricated from such materials, for
example, blood bags, tubes, catheters and the like, are disposable
products, and after their use, they are abandoned as waste materials.
These materials, however, do not undergo environmental degradation and
retain their original shape for a prolonged period of time. It is well
known that such waste materials have induced various social problems
including the pollution.
In order to solve such problems, various investigations have been recently
carried forward to develop biodegradable materials, namely, high molecular
weight materials capable of being decomposed in ecosystem when placed or
abandoned in the environment, and these materials have attracted a
considerable public attention.
Of the conventionally known high molecular weight biodegradable materials,
those comprising polypropylene, polyethylene or the like having blended
therein corn starch for the purpose of their morphological collapse can
not be deemed essentially biodegradable, since these materials only
experience morphological change with the lapse of time, and the high
molecular weight backbone of the polypropylene or polyethylene do not
undergo any degradation.
Another group of biodegradable materials known in the art are
poly(3-hydroxybutyrate) and copolymers mainly comprising the
poly(3-hydroxybutyrate). Poly(3-hydroxybutyrate) is a material which has
been confirmed to undergo a considerable environmental degradation, and to
have an excellent biocompatibility. Therefore, this material was highly
expected to have various applications in medical and other fields.
Contrary to such expectations, the poly(3-hydroxybutyrate) failed to find a
large number of applications due to insufficiency in its impact resistance
and other physical properties because of its hardness and brittleness. The
poly(3-hydroxybutyrate) is also poor in its workability since it undergoes
decomposition in the vicinity of its melting point in spite of its useful
thermoplasticity.
In view of such conditions, various attempts have been made to modify the
physical properties of the poly(3-hydroxybutyrate). Japanese Patent
Application Kokai No. 63(1988)-269989 discloses a copolymer comprising
recurring structural units of D-(-)3-hydroxybutyrate and
D-(-)3-hydroxyvalerate. This material has attained considerable
improvements in reducing melting point and in increasing flexibility.
Synthesis of this material, however, could be effected only at a low
productivity, and also, required a special substrate for the fermentation.
As a consequence, this copolymeric material was rather expensive to
detract from its availability as a general-purpose material.
Other attempts of altering the physical properties of the
poly(3-hydroxybutyrate) include modification of the
poly(3-hydroxybutyrate) by mixing with such resin materials as
polyethylene oxide, ethylene propylene rubber, and polyvinyl acetate. None
of the attempts, however, have fully succeeded in providing the stability,
cost performance, workability, and the like with the resulting resin
compositions. Use of such resin compositions for medical applications
would be even more difficult since such applications would further require
high safety and hygienic properties.
SUMMARY OF THE INVENTION
An object of the present invention is to obviate the above-described
problems of the prior art by using a predetermined resin composition as a
material for fabricating the flexible medical member, and thereby provide
a highly biodegradable flexible member for medical use which is capable of
undergoing degradation in a relatively short period of time in natural
environment by burying in soil or abandoning in sea after its
sterilization so that no environmental pollution would be caused by its
disposal, and which additionally has excellent biocompatibility,
compatibility to ecosystem, workability as well as cost performance.
Such an object is achieved by the present invention as described below.
According to the present invention, there is provided a flexible member for
medical use which is characterized in that at least a portion of the
member is prepared from a material containing a resin composition
comprising a polyhydroxyalkanoate, a copolymer thereof, or a mixture
thereof as its main component, and 0.01 to 60% by weight of a lipid
compound.
The polyhydroxyalkanoate may preferably be at least a member selected from
poly(3-hydroxyalkanoate)s, poly(4-hydroxyalkanoate)s, and
poly(5-hydroxyalkanoate)s.
It is preferable that the flexible medical member has a tubular
configuration to constitute at least a part of a member, for example, an
infusion system, a blood transfusion system, a blood circulation circuit,
or a catheter.
It is also preferable that the flexible medical member is a member in the
form of a bag, for example, a blood bag, an infusion bag, a dialysis bag,
or a perintestinal nutrient bag.
Furthermore, it is preferable that the flexible medical member is a member
in the form of a thread, a woven fabric, or a nonwoven fabric, for
example, a suture, a mesh, a patch, a pledget, and a prosthesis.
Still further, it is preferable that the flexible medical member is a
member selected from a staple, a clip and a coalescence-preventing
membrane.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 a diagram showing number average molecular weight of the
poly(3-hydroxybutyrate) in relation to dose of the .gamma.-ray irradiated.
FIG. 2 a diagram showing number average molecular weight of the
poly(3-hydroxybutyrate) in relation to period of the heat treatment.
FIG. 3 is a schematic view of an example of a staple which is an embodiment
of the flexible medical member according to the present invention.
FIG. 4 is a schematic view of an example of an infusion system having
employed therein a flexible tube, which is an embodiment of the flexible
medical member according to the present invention.
FIG. 5 is a schematic view of an example of a flexible bag which is an
embodiment of the flexible medical member according to the present
invention.
BEST MODE FOR CARRYING OUT THE INVENTION
The flexible member for medical use according to the present invention is
hereinafter described in further detail.
The flexible member for medical use of the present invention is a member
wherein at least a part of the member comprises a resin composition
basically comprising a polyhydroxyalkanoate, a copolymer thereof, or a
mixture thereof, and further comprising from 0.01 to 60% by weight of a
lipid compound; a complex material comprising a mixture of such a resin
composition with another resin; or a processed material comprising such as
a resin composition and another resin material. Such a flexible member for
medical use of the present invention is suitable for various medical
members including those which have been conventionally fabricated from the
above-mentioned flexible material comprising polyvinyl chloride having
added thereto dioctyl phthalate, for example, a blood bag, an infusion
bag, a dialysis bag, a perintestinal nutrient bag, and the like, and
various tubings and manifolds to be connected to such bags, as well as
catheters, and the like; those fabricated from thread-like products, and
woven and nonwoven fabrics, for example, a suture, a mesh, a patch, a
pledget, a prosthesis, and the like; and those requiring non-brittleness
as well as flexibility, for example, a staple and a clip. Among these, the
flexible medical member of the present invention is particularly suitable
for a disposable medical member.
Such a flexible member for medical use of the present invention is
inexpensive, and has sufficient productivity, flexibility, corrosion
resistance, workability, cost performance, compatibility to ecosystem,
biocompatibility, as well as excellent biodegradability to cause no
environmental pollution after its disposal.
The flexible member for medical use of the present invention basically
comprises a highly biodegradable resin composition comprising a
polyhydroxyalkanoate, a copolymer thereof, or a mixture thereof as its
main component, and 0.01 to 60% by weight of a lipid compound.
The polyhydroxyalkanoates which may be used in the present invention
include those comprising recurring units of a hydroxyalkanoate having
about 3 to 12 carbon atoms. Preferable examples of the
polyhydroxyalkanoate include poly(3-hydroxyalkanoate)s such as
poly(3-hydroxypropionate), poly(3-hydroxybutyrate),
poly(3-hydroxyvalerate), poly(3-hydroxyoctanoate), etc;
poly(4-hydroxyalkanoate)s such as poly(4-hydroxybutyrate),
poly(4-hydroxyvalerate), etc; and poly(5-hydroxyalkanoate)s such as
poly(5-hydroxyvalerate), etc.
Among these, poly(3-hydroxybutyrate) may most preferably be used in the
present invention.
In the present invention, not only the use of homopolymers of the
hydroxyalkanoate, but also the use of copolymers of the hydroxyalkanoates
are preferable.
Exemplary copolymers of the hydroxyalkanoates include copolymers of
3-hydroxybutyrate with another hydroxyalkanoate having 3 to 12 carbon
atoms. Non-limiting preferable examples include
(3-hydroxybutyrate)-(3-hydroxypropionate) copolymer,
(3-hydroxybutyrate)-(3-hydroxypropionate)-(4-hydroxybutyrate) copolymer,
(3-hydroxybutyrate)-(3-hydroxyvalerate) copolymer,
(3-hydroxybutyrate)-(3-hydroxyvalerate)-(3-hydroxyhexanoate)-(3-hydroxyhep
tanoate)-copolymer,
(3-hydroxybutyrate)-(3-hydroxyvalerate)-(3-hydroxyhexanoate)-(3-hydroxyhep
tanoate)-(3-hydroxyoctanoate) copolymer,
(3-hydroxybutyrate)-(3-hydroxyhexanoate)-(3-hydroxyoctanoate) copolymer,
(3-hydroxyoctanoate)-(3-hydroxylaurate) copolymer,
(3-hydroxybutyrate)-(4-hydroxydibutyrate) copolymer,
(3-hydroxybutyrate)-(4-hydroxyvalerate) copolymer, and
(3-hydroxybutyrate)-(5-hydroxyvalerate) copolymer.
In the present invention, use of a mixture of the above-mentioned
polyhydroxyalkanoates, a mixture of the above-mentioned copolymers, as
well as a mixture of the above-mentioned polyhydroxyalkanoate and the
above-mentioned copolymer are also preferred.
As is well known in the art, the polyhydroxyalkanoates and their copolymers
are produced by various microorganisms. Those produced by any
microorganism may be employed in the present invention.
Chemically synthesized polyhydroxyalkanoates and copolymers thereof may
also be used in the present invention.
The microorganisms which produce a polyhydroxyalkanoate include, for
example, various species of bacteria belonging to Acinetobacter,
Actinomycetes, Alcaligenes, Aphanothese, Aquaspirillum, Azospirillum,
Azotobacter, Bacillus, Beggiatoa, Beijerinckia, Caulobacter,
Chlorofrexeus, Chlorogloea, Chromatium, Chromobacterium, Clostridium,
Derxia, Ectothiorhodospira, Echerichia, Ferrobacillus, Gamphosphaeria,
Haemophilus, Halobacterium, Hyphomicrobium, Lamprocystis, Lampropedia,
Leptothrix, Methylobacterium, Methylocystis, Micrococcus, Microcoleus,
Microcystis, Moraxella, Mycoplana, Nitrobacter, Nitrococcus, Nocardia,
Oceanospirillum, Paracoccus, Photobacterium, Pseudomonas, Rhizobium,
Rhodobacter, Rhodospirillum, Sphaerotilus, Spirillum, Spirulina,
Streptomyces, Syntrophomonas, Thiobacillus, Thiocapsa, Thiocystis,
Thiodictyon, Thiopedia, Thiosphaera, Vibrio, Xanthobacter, Zoogloea, and
the like.
The polyhydroxyalkanoate or its copolymer synthesized by fermentation
generally has a number average molecular weight, Mn of about 3,000 to
3,000,000. Use of a polyhydroxyalkanoate or its copolymer which has been
post-treated by heating or .gamma.-ray irradiation after its synthesis by
fermentation to reduce its molecular weight to, for example, about 3,000
to 10,000 is also preferable.
By using a 3-hydroxyalkanoate and/or 4-hydroxyalkanoate (.beta.- or
.gamma.-hydroxyalkanoate) polymer having a number average molecular weight
of 10,000 to 200,000, and preferably 30,000 to 100,000 for the main
component of the resin composition, the period of decrease in the
mechanical strength or degradation of the material itself through
hydrolysis in a living body may be adjusted within the range of from
several months to several years. Consequently, the resin composition can
be suitably employed for a flexible medical member to be buried in a
living body which should retain its action for a relatively prolonged
period of time, for example, a suture, a prosthesis, a
coalescence-preventing material, and the like.
When the resin composition is used for a member to be buried in a living
body, and the polyhydroxyalkanoate has a number average molecular weight
of more than 200,000, the period required for undergoing decrease in the
mechanical properties through in vivo hydrolysis would be excessively long
such that the buried material would not substantially undergo a sufficient
degradation while the material is in its use. On the other hand, when the
polyhydroxyalkanoate has a number average molecular weight of less than
10,000, the resin composition would not have a strength required for an
implanted member.
Adjustment of the molecular weight can be effected by a post-treatment, for
example, a heat treatment or a .gamma.-ray irradiation.
A polyhydroxyalkanoate would undergo a decrease in its molecular weight
when irradiated with an ionizing radiation, and in particular,
.gamma.-ray. In FIG. 1, number average molecular weight of
poly(3-hydroxybutyrate), which is a species of
poly(.beta.-hydroxyalkanoate)s, is plotted in relation to dose of the
.gamma.-ray emitted from cobalt 60. As apparent from the curve of FIG. 1,
the number average molecular weight, which is 275,000 before the
irradiation of the .gamma.-ray, would decrease in accordance with an
increase in the dose of the irradiation to 20,000, which is less than one
tenth of the initial molecular weight, by the irradiation of 10 Mrad or
the .gamma.-ray. It would be readily appreciated that the molecular weight
of the composition can be reduced to any desired degree by controlling the
dose of the .gamma.-ray irradiation regardless of the number average
molecular weight of the composition before the .gamma.-ray treatment.
The poly(3-hydroxybutyrate) would also undergo a decrease in its molecular
weight when it is heated to a temperature in excess of about 160.degree.
C. although its melting point is 180.degree. C. In FIG. 2, number average
molecular weight of the poly(3-hydroxybutyrate) is plotted in relation to
the period of the heat treatment. According to the curves of FIG. 2, the
number average molecular weight would be reduced to about one fourth of
its initial value upon heat treating at 175.degree. C. for 20 minutes, and
to about one half of its initial value upon treating at 190.degree. C. for
1 minute.
Similar results were obtained for 3-hydroxybutyrate-3-hydroxyvalerate
copolymer and 3-hydroxybutyrate-4-hydroxybutyrate copolymer although the
results are not depicted.
The molecular weight of the composition can be adjusted to any desired
degree by a heat treatment as well as the irradiation with .gamma.-ray. It
should be noted, however, that the molecular weight can not be increased
by any of such methods. The poly(3- and the poly(4-hydroxyalkanoate) would
also undergo a decrease in their molecular weight when they are treated in
an acidic solution such as sulfuric acid, hydrochloric acid, hypochlorous
acid, or perchloric acid; or in an alkaline solution such as sodium
hydroxide or potassium hydroxide, and their number average molecular
weight can be similarly reduced to the desired value by adequately
selecting the conditions of the treatment to thereby adjust the period
required for their biodegradation.
Some experimental examples are hereinafter described.
EXPERIMENT 1
Poly(3-hydroxybutyrate) (number average molecular weight, Mn of 275,000)
purchased from Aldrich Corporation in an amount of 0.6 g was fully
dissolved in 30 ml of chloroform (guaranteed grade; manufactured by Wako
Pharmaceutical K.K.). The resulting solution was cast into a glass Petri
dish to obtain a film having a thickness of from 50 to 70 .mu.m after
evaporation of the chloroform. The thus obtained film was irradiated with
1 Mrad of .gamma.-ray emitted from cobalt 60. The number average molecular
weight was then reduced to 100,000. The number average molecular weight
was measured by liquid chromatography using LC-6A manufactured by Simadzu
Seisakusho Ltd. having secured thereto a column, Shodex GPC-80M
manufactured by Showa Denko K.K. using a differential refractometer for
the detector, solvent of chloroform, and a standard of polystyrene.
EXPERIMENT 2
Into 500 ml Sakaguchi flask (shaking flask) was poured a medium comprising
1 g of yeast extract (manufactured by DIFCO corporation), 1 g of
polypeptone (manufactured by Nippon Pharmaceutical K.K.), 0.5 g of meat
extract (Kyokuto Pharmaceutical Industries K.K.), and 0.5 g of ammonium
sulfate (manufactured by Wako Pharmaceutical K.K.) dissolved in 100 ml of
distilled water. The medium was inoculated with Alcaligenes eutrophus H16
(ATCC 17699), which is a hydrogen bacteria, closed with a cotton plug, and
then cultivated at 30.degree. C. for 2 days under shaking. The thus
propagated bacteria of 10 Sakaguchi flasks were collected by a
centrifugation at 6,000 rpm for 15 minutes. Another medium was prepared by
adding 1.0 ml of 20wt/vol % magnesium sulfate, 1.0 ml of the mineral
solution shown in Table 1, and 20 g of fructose (Kanto Chemical K.K.) to a
phosphate buffer solution, pH 7.5 containing 14.0 ml of 0.5M potassium
dihydrogenphosphate and 124.0 ml of 0.25M disodium hydrogenphosphate per
11 buffer solution. The thus prepared medium was poured into a 2.6 l jar
fermentor (manufactured by Marubishi Bioengeneering K.K.), and the
bacteria which had been collected by the centrifugation were transferred
into the jar fermenter. Cultivation was carried out at 30.degree. C. for
48 hours at a stirring blade-rotating rate of 500 rpm and a bubbling rate
of 1 ml/min. After completing the cultivation, the propagated bacteria
were collected by centrifugation at 6,000 rpm for 15 min. The thus
collected bacteria were washed with water and lyophilized. Into 2 l of
chloroform was added 11.2 g of the thus lyophilized bacteria, and the
suspension was stirred at room temperature for 24 hours to extract the
polymer product. The extract-containing solution was filtered to remove
insoluble bacteria components, and the filtrate was then dropped into
about 10 volumes of n-hexane (first grade; manufactured by Wako
Pharmaceutical K.K.) to precipitate the polymer. The thus precipitated
polymer was confirmed to be poly(3-hydroxybutyrate) by measuring with
.sup.1 H-NMR (nuclear magnetic resonance spectrometer, EX 90; manufactured
by JEOL Ltd.) The polymer product was also evaluated for its number
average molecular weight by gel chromatography to be 775,000. Upon
irradiation of the polymer product with 10 Mrad of .gamma.ray emitted from
cobalt 60, the number average molecular weight was reduced to 80,000.
TABLE 1
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Composition of the mineral solution (in 1 l of 0.1N HCl)
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CoCl.sub.2
119.0 mg NiCl.sub.2.6H.sub.2 O
118.0 mg
FeCl.sub.3
9.7 g CrCl.sub.3
62.2 mg
CaCl.sub.2
7.8 g CuSO.sub.4.5H.sub.2 O
156.4 mg
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EXPERIMENT 3
The poly(3-hydroxybutyrate) synthesized in Experiment 2 was heat treated by
placing it in an oven at 190.degree. C. for 10 minutes. The resulting
polymer had a number average molecular weight of 120,000.
EXPERIMENT 4
The procedure of Example 2 was repeated except that the fructose was
replaced with sodium 4-hydroxybutyrate (manufactured by Aldrich
Corporation) to produce 1.2 g of 3-hydroxybutyrate-4-hydroxybutyrate
copolymer (comprising 20% by mole of 4-hydroxybutyrate unit) having a
number average molecular weight of 467,000. The thus produced copolymer
product was added to a 100 ml solution comprising 1 volume of aqueous
solution of sodium hypochroride (manufactured by Wako Pharmaceutical K.K.)
and 1 volume of distilled water, and the suspension was heated to
50.degree. C. for 2 hours. The resulting product had a number average
molecular weight of 182,000.
EXPERIMENT 5
The procedure of Example 2 was repeated except that the fructose was
replaced with valeric acid (first grade; manufactured by Wako
Pharmaceutical K.K.) to produce 3.8 g of
3-hydroxybutyrate-3-hydroxyvalerate copolymer (comprising 63% by mole of
3-hydroxyvalerate unit) having a number average molecular weight of
225,000. The thus produced copolymer product was irradiated with 3 Mrad of
.gamma.-ray emitted from cobalt 60. The resulting product had a number
average molecular weight of 50,000.
The results of the Experiments are summarized in Table 2.
TABLE 2
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MW MW
Exp. Polymer before Type of after
No. structure treatment
treatment treatment
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1 poly(3-hydroxy
275,000 1 Mrad .gamma.-ray
100,000
butyrate)
2 poly(3-hydroxy
775,000 10 Mrad .gamma.-ray
80,000
butyrate)
3 poly(3-hydroxy
775,000 190.degree. C., 10 min.
120,000
butyrate)
4 3-hydroxybutyrate-
467,000 sodium 182,000
4-hydroxybutyrate hypochloride,
copolymer 50.degree. C., 2 h.
5 3-hydroxybutyrate-
225,000 3 Mrad .gamma.-ray
50,000
3-hydroxyvalerate
copolymer
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EXPERIMENT 6
Film pieces of about 50 .mu.m thick with a size of 1.times.1 cm were
prepared from the polymers produced in Experiments 1 to 5 by solvent
casting. The film pieces were buried in the back of a rat under its skin.
After one year of the burial, the film pieces were retrieved and
inspected.
Upon burial for one year, no substantial decrease in mechanical strength of
the each film was recognized. Each film, however, had undergone a
considerable decrease in its number average molecular weight. The time
that would be required for undergoing a substantial decrease in the
mechanical strength was estimated from the data of the decrease in the
number average molecular weight of the each film. The results are shown in
Table 3.
COMPARATIVE EXPERIMENT 7
The poly(3-hydroxybutyrate) synthesized in Experiment 2 which had not been
subjected to the .gamma.-ray irradiation was subcutaneously buried in the
back of a rat as in the case of Experiment 6. The molecular weight after 1
year burial as well as the estimated time required for undergoing
substantial decrease in the mechanical strength are shown in Table 3. The
results indicate that, although the material had undergone some decrease
in its molecular weight, the time that would be required for deterioration
of the mechanical strength is as long as 20 years, and estimated period
for complete disappearance (solubilization in water) of the material is as
long as about 50 years. The material, therefore, can not be deemed as
essentially in vivo biodegradable.
COMPARATIVE EXPERIMENT 8
A polylactic acid film (number average molecular weight, Mn of 100,000;
purchased from Polyscience K.K.) was subcutaneously buried in the back of
a rat as in the case of Experiment 6. Upon inspection after 1 year burial,
the film had undergone a complete degradation to leave no traces. It is
estimated that the film had experienced a substantial decrease in its
mechanical strength in several days. Degradation of this material is too
fast.
COMPARATIVE EXAMPLE 9
The poly(3-hydroxybutyrate) synthesized in Experiment 1 which had not been
subjected to the .gamma.-ray irradiation having a number average molecular
weight of 275,000 was subcutaneously buried in the back of a rat as in the
case of Experiment 6. The molecular weight after 1 year burial as well as
the estimated time required for undergoing substantial decrease in the
mechanical strength are shown in Table 3. This material would require 5
years for substantial decrease in its mechanical strength, and this period
is rather too long in practical point of view. Furthermore, this material
would require a period of as long as from fifteen or sixteen years to
several decades for its complete disappearance (solubilization in water)
to leave no debris, to render the material unusable.
TABLE 3
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Molecular weight
Estimated time
before after burial
required for reduction
burial for 1 year in mechanical strength
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(Exp. 1) 100,000 70,000 1.5 years
(Exp. 2) 80,000 68,000 1.5 years
(Exp. 3) 120,000 97,000 3 years
(Exp. 4) 182,000 100,000 2 years
(Exp. 5) 50,000 48,000 3 years
Comparative
775,000 563,000 20 years
Exp. 7
Comparative
100,000 not determined
several days
Exp. 8
Comparative
275,000 221,000 5 years
Exp. 9
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EXPERIMENT 10
In 300 ml of chloroform (first grade; manufactured by Wako Pharmaceutical.
K.K.) were dissolved 30 g of the .gamma.-ray irradiated poly
(3-hydroxybutyrate) (number average molecular weight 100,000) and 9 g of
glycerol tributyrate (manufactured by Tokyo Chemical K.K.), and stirred.
The solvent was distilled to produce a mixture of the
poly(3-hydroxybutyrate) and the glycerol tributyrate. The mixture was cut
into pellets using scissors.
The thus produced pellets were charged in a small-sized, small-amount
extruder (manufactured by Ohba Works K.K.) to extrude a string-like
extrudate from a nozzle having an inner diameter of 0.5 mm at a cylinder
temperature of 178.degree. C. and a die temperature of 176.degree. C. The
string-shaped extrudate was quenched immediately after the extrusion by
using liquid nitrogen. The quenched product was gradually (manually)
stretched in a stretching machine at room temperature (about 29.degree.
C.) to more than ten folds of its original length until it was almost at
break. The resulting product was heat-treated in an oven at a temperature
of 60.degree. C. for 3 hours to produce a flexible thread-like product
(suture) having an outer diameter of 0.10 mm. The thus produced
thread-like product was sterilized with ethylene oxide gas, and attached
to Bear stitching needle (round needle, strongly curved, #0) manufactured
by Kyowa Clock Industries K.K., to stitch an incision in the back of a
rat. The suture was removed after two weeks. No specific problem was noted
during its use.
EXPERIMENT 11
The procedure of Experiment 6 was repeated except that the
poly(3-hydroxybutyrate) which had not under gone the the .gamma.-ray
irradiation (number average molecular weight, 275,000) was used to obtain
a thread having an outer diameter of 0.10 mm. The thread was then exposed
to 1 Mrad of .gamma.-ray irradiation. The resulting suture was used for
stitching an incision at the back of a rat as in the case of Experiment
10. The suture was removed after two weeks. No specific problem was noted
during its use. The number average molecular weight after the
sterilization was 100,000.
EXPERIMENT 12
A suture having an outer diameter of 0.08 mm was obtained by repeating the
procedure of Experiment 6 except that the orientation conditions were
somewhat altered. The resulting suture was attached to Bear stitching
needle (round needle, strongly curved, #0) to stitch an incision in
intestine of an adult crossbred dog (weight, approx. 12 kg). Upon
inspection after about one year by incising the abdomen, the incision had
been successfully sutured, and the suture was located at its original
place.
EXPERIMENT 13
The procedure of Experiment 6 was repeated except that the .gamma.-ray
irradiated 3-hydroxybutyrate-3-hydroxyvalerate copolymer prepared in
Experiment 5 (number average molecular weight, 50,000) was used to produce
a suture. The thus produced suture was attached to a stitching needle to
stitch the skin in the back of a rat. No specific problem was noted in the
use of the suture.
EXPERIMENT 14
The 3-hydroxybutyrate-4-hydroxybutyrate copolymer after its
treatment(number average molecular weight, 182,000) was fabricated into a
film of 0.3 mm thick by solvent casting using chloroform. A film piece of
30 mm.times.30 mm was cut out of the film, and inserted in abdominal
cavity of a rat between the incision in the skin and the intestine for the
purpose of coalescence prevention. Upon inspection after one month, the
incision had substantially healed, and no coalescence between the incision
and the internal organs was recognized. It was also noted that the film
had substantially retained its original shape.
EXPERIMENT 15
The procedure of the Experiment 6 was repeated except that the die of the
extruder was replaced with a multi-hole die having 6 holes each having a
diameter of 0.3 mm to produce a thread-like product having an outer
diameter in the range of from 0.01 to 0.03 mm. A 1 g portion of the
thread-like product was placed in a test tube having an inner diameter of
0.8 cm, and compressed with a glass rod inserted into the test tube to
fabricate a felt. The thus produced felt was placed inside the abdominal
cavity of a rat in contact with various organs. No specific problem was
noted for one month.
Although Experiments 10 to 15 were carried out under in vivo conditions
using animals, for example, rats, no degradation of the material was
recognized in the period of up to 1 year. It is, however, conceived that,
with the lapse of time, the materials would undergo a decrease in their
mechanical strength, and eventually, a complete deterioration to leave no
trace.
The resin composition used for the flexible member for medical use of the
present invention contains 0.10 to 60% by weight of a lipid compound in
addition to the above-described polyhydroxyalkanoate or a copolymer
thereof, which is the main component.
Exemplary lipid compounds which may be blended with the
polyhydroxyalkanoate in the resin composition of the present invention
include monoglycerides, diglycerides, triglycerides, monocarboxylic acid
esters, dicarboxylic acid monoesters, dicarboxylic acid diesters,
dialcohol monoesters, dialcobol diesters, tricarboxylic acid monoesters,
tricarboxylic acid diesters, tricarboxylic acid triesters.
More illustratively, exemplary monoglycerides include glycerol monoacetate,
glycerol monopropionate, glycerol monobutyrate, glycerol monocaproate,
glycerol monolaurate, glycerol monomyristate, glycerol monopalmitate,
glycerol monostearate, etc.;
diglycerides include glycerol diacetate, glycerol dipropionate, glycerol
dibutyrate, glycerol dicaproate, glycerol dilaurate, glycerol dimyristate,
glycerol dipalmitate, glycerol distearate, etc.; and
triglycerides include glycerol triacetate, glycerol tripropionate, glycerol
tributyrate, glycerol tricaproate, glycerol trilaurate, glycerol
tripalmitate, glycerol trimyristate, glycerol tristearate, etc.
Other carboxylic acid esters include an ester of a carboxylic acid having 2
to 30 carbon atoms with an alkylalcohol having 2 to 30 carbon atoms. More
illustratively, exemplary preferred saturated or unsaturated
monocarboxylic acid esters include n-amyl acetate, ethyl propionate,
methyl caproate, ethyl crotoate, n-butyl oleate, etc;
saturated or unsaturated dicarboxylic acid monoesters include monomethyl
cebaciate, mono-n-butyl maleate, monoethyl terephthalate, etc.;
saturated or unsaturated dicarboxylic acid diesters include dimethyl
cebaciate, dimethyl terephthalate, di(2-ethylhexyl) phthalate, di-n-octyl
phthalate, etc.;
tricarboxylic acid monoesters include monomethyl trimellitate, mono-n-butyl
trimellitate, etc.;
tricarboxylic acid diesters include dimethyl trimellitate, dibutyl
trimellitate, etc.;
tricarboxylic acid triesters include trimethyl trimellitate, tributyl
trimellitate, etc.;
dialcohol monoesters include ethylene glycol monostearate, propylene glycol
monostearate, etc; and
dialcohol diesters include ethylene glycol distearate, propylene glycol
distearate, etc.
The lipid compounds as mentioned above may be either liquid or solid at
normal temperatures.
In the resin composition used for the flexible medical member of the
present invention, the lipid compound as described above functions as a
plasticizing agent or a flexibility-imparting agent for the
polyhydroxyalkanoate. The lipid compound, when mixed with the
polyhydroxyalkanoate, may also reduce the melting point of the
polyhydroxyalkanoate to enable the resin composition to be worked at a
lower temperature and prevent unnecessary decomposition of the
composition. The workability of the resin composition is thereby improved.
In addition, such an inclusion of the lipid composition, which is
generally inexpensive, is advantageous in economic point of view.
In the resin composition, the lipid compound may comprise from 0.01 to 60%
by weight, and preferably, from 1 to 40% by weight of the composition. The
lipid compound of a content of less than 0.01% by weight is insufficient
for improving the physical properties of the polyhydroxyalkanoate. The
lipid compound of a content in excess of 60% by weight may induce phase
separation of the lipid compound to detract from the physical properties
of the resulting flexible medical member.
Mixing of the polyhydroxyalkanoate and the lipid compound may be effected
by such means as dissolution of the compounds in a suitable solvent such
as chloroform, methylene chloride, 1,2-dichloroethane, and dioxane,
followed by stirring and evaporation of the solvent; and addition the
lipid compound to the polyhydroxyalkanoate using a mixing roll or an
extruder under heating.
Such a resin composition which is utilized in the flexible medical member
of the present invention is described in detail in Japanese Patent
Application No. 2-76585 filed by the applicant of the present invention.
Use of a complex material comprising the above-described resin composition
in admixture with another resin is also adequate for fabricating the
flexible medical member of the invention.
The resin which may be used for such a mixing is not limited to any
particular species, and various conventional resins may be used in
accordance with the desired properties. Exemplary preferable resins
include polyethylene, polypropylene, polyvinyl chloride, polyvinyl
acetate, ionomer, polyacrylic acid, polyacrylate, polymethacrylic acid,
polymethacrylate, polyvinyl alcohol, polystyrene, polyvinylidene chloride,
polyethylene terephthalate, polybutyrene terephthalate, nylon,
polycarbonate, polyethylene glycol, polypropylene glycol, fluororesin, and
copolymers thereof.
As mentioned above, such a resin which is mixed with the above-described
resin composition may be adequately selected in accordance with the
desired properties. For example, the resin composition may be imparted
with mechanical durability by an addition of polyethylene terephthalate;
and with a surface water repellency by an addition of a fluororesin.
When a complex material comprising the above-described resin composition
mixed with such a resin is utilized for the flexible medical member of the
invention, the material may generally contain from about 1 to 70% by
weight of such a resin, although the content of the resin may not
necessary fall within such a range.
In addition to such a resin, the resin composition may optionally include a
filler, a die, a pigment, a lubricant, an antioxidant, a stabilizer, and
the like.
Preparation of the complex material by the mixing of such a resin with the
above-described resin composition may be effected by such means as
dissolution of the resins in a suitable solvent such as chloroform,
methylene chloride, 1,2-dichloroethane, and dioxane, followed by stirring
and evaporation of the solvent; and mixing of the resins using a mixing
roll or an extruder under heating.
At least a part of the flexible member for medical use of the present
invention is fabricated from the above-described biodegradable resin
composition or a complex material comprising a mixture of such a
biodegradable resin composition with various resins (which are hereinafter
referred to as the biodegradable materials).
The medical member which is fabricated from such a biodegradable material
is not limited to any particular type, and the biodegradable material may
be used for fabricating any flexible medical member which has been
fabricated from a flexible material such as a polyvinyl chloride having
added thereto a phthalic acid-based compound as a plasticizing agent, an
elastomer, a rubber, or the like.
Furthermore, the configuration of the member fabricated from the
biodegradable material is not limited at all, and the medical member may
be a cylindrical member including a tube, a bag, a box, a columnar member,
a cone-shaped member, a film, a sheet, a thread, a woven or nonwoven
fabric, or a molded article of other irregular configurations.
Examples of the medical member which may be fabricated from the
above-described biodegradable material include:
blood transfusion system, infusion system, tubings for blood circuits and
the like, connecting tubing, connector, manifold, drop cylinder, branched
tube, stopcock, and the like;
blood bag, infusion bag, urinary bag, dialysis bag, perintestinal nutrient
bag, and other liquid bags;
catheter to be introduced into urinary tract, digestive tract or other body
cavities, and balloon catheter;
suture, mesh, patch, pledget, coalescence-preventing film, prosthesis, and
other thread, fabric, or sheet-form products; and
staple, clip, and other molded articles.
The flexible member for medical use of the present invention has an
excellent biodegradability, and therefore, such members are particularly
suitable for disposable medical members.
It should be noted that the flexible member for medical use of the present
invention does not have to be fabricated solely from the above-described
biodegradable material. It is also possible to fabricate some parts of the
flexible medical member from such a biodegradable material, and other
parts from a conventional resin material. In the case of a balloon
catheter, for example, the biodegradable material may be used for
fabricating the balloon or the shaft, and other parts may be fabricated
from a conventional resin. In the case of a liquid-accommodating bag, the
biodegradable material may be used for the body of the bag while other
parts including the connecting portions may be fabricated from a
conventional resin.
The flexible medical member may also comprise a laminate of the
above-described biodegradable material with another conventional resin.
The biodegradable material used for fabricating the flexible medical member
of the present invention has thermoplastic properties. Therefore, the
flexible medical member of the invention having a tubular, bag, or other
configuration can be fabricated from the bio | | |
