Note: Descriptions are shown in the official language in which they were submitted.
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DESCRIPTION
BIO-ABSORBABLE PLASTIC DEVICE FUR CLINICAL PRACTICE
Technical Field
The present invention relates to a bio-absorbable plastic
device of a bio-absorbable polymer for clinical practice, which
can be used for stems for tracts and tubes, biological cell
carriers, drug carriers, suture thread and the like.
Background of the Invention
Bio-absorbable polymers used for medical bio-absorbable
plastic devices such as stents for tracts and tubes , and suture
thread include for example polylactic acid, polyglycolic acid,
a copolymer of the two , namely polyglactin , polydioxanone , and
polyglyconate (the copolymer of trimethylene carbonate and
glycolide).
Such bio-absorbable polymers are decomposed and also
absorbed in biological organisms. Therefore, such
bio-absorbable polymers are widely used. Because the dynamic
propert ies thereof such as tensile strength and the decomposit ion
rate thereof for absorption are individually nearly definite,
the bio-absorbable polymers turn fragile when the dynamic
properties are enhanced, involving the reduction of the
decomposition rate. When the decomposition rate is increased,
the dynamic properties are deteriorated. Thus,
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disadvantageously, the bio-absorbable polymers have only
limited purposes for use and are applied to limited sites.
Disclosure of the Invention
The present invention relates to a bio-absorbable plastic
device such as suture thread, stems for tracts and tubes,
biological cell carriers and drug carriers for clinical practice ,
which is made of a bio-absorbable polymer of a copolymer with
a peptide unit as produced by copo.lymerizing a depsipeptide with
a bio-absorbable polymer to adjust the dynamic properties and
decomposition rate via the content of the depsipeptide, without
any occurrence of any problems such as inflammation.
The amount of the depsipeptide to be included is at about 2 to
60mo1 0. Below 2mol ~, the effect thereof cannot be exerted.
At a molar ratio of 60 0 or more, the resulting dynamic properties
are too much deteriorated. Many types of bio-absorbable
polymers can be utilized. Depending on the type oi= a
bio-absorbable polymer or the amount of a bio-absorbable
copolymer to be blended, the amount of the depsipeptide to be
included outside the limit range of the amount of the depsipeptide
to be included as described above may sometimes exert the effect .
Therefore, the ratio of the amount thereof to be added is not
a deffinite value.
Brief Description of the I>rawings
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Fig. 1 depicts the structure view of the depsipeptide;
Fig. 2 depicts the structure view of a copolymer with a
depsipeptide unit; Fig.3 depicts the decomposition properties
of copolymers with depsipeptide units; Fig. 4 depicts the
structure view of a copolymer with a depsipeptide unit; Fig.
shows the decomposition properties of copolymers with
depsipeptide units; Fig. 6 shows the relation between the amount
of the depsipeptide and the decomposition rate; Fig.7 - 13 are
an explanatory view of a structure example of a stmt for tracts
and tubes ; Fig . 14 is an explanatory view of a structure example
of a capsule ; Fig . 15 is an explanatory view of a carrier example ;
Fig . 16 shows the dynamic properties and thermal properties; of
copolymers with depsipeptide units; and Fig. Z7 is a relation
between the amount of a depsipeptide and the thermal properties .
Best Mode for Carrying out the Invention
So as to describe the invention in more detail, the
invention is now described with reference to the attached
drawings.
The structure of the depsipeptide is shown in Fig. 1.
As shown in the figure, the R group in a side chain is
an alkyl group such as methyl group, isopropyl group and isobutyl
group, while the R~ group in a side chain is an alkyl group such
as methyl group and ethyl group.
Concerning examples of the depsipeptide, depsipeptides are
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synthesized from an amino acid and a hydroxy acid derivative,
using chloroacetyl chloride, 2-bromopropionyl bromide and
2-bromo-n-butyryl bromide asthe hydroxy acid derivative, which
are L-MMO, L-DMO, and L-MEMO in the order of the above hydroxy
acid derivatives. All of them are applicable to the invention.
The enzymatic decomposition level of a copolymer from such
depsipeptide monomer and a bio-absorbable unit ~-caprolactone
( CL ) with proteinase K is in the order of L-MMO/CL > L-DMO/CL
> L-MEMO/CL.
As to the depsipeptide synthesized from amino acid and an hydroxy
acid, amino acids such as L-alanine, L-(or DL- or D-)valine,
and L-leucine are used, to prepare depsipeptides, which are DMO,
PMO and BMO in the order of the amino acids described above.
All of them are applicable to the invention. The enzymatic
decomposition level of a copolymer from such depsipeptidemonomer
and a bio-absorbable monomer-caprolactone(CL)with proteinase
K is in the order of DMO/CL > PMO/CL >_ BMO/CL . The enzymatic
decomposition level thereof with cholesterol esterase is ire the
order of PMO/CL > BMO/CL ~ DMO/CL.
Examples of the bio-absorbable copolymer with an added
cyclic depsipeptide as applicable in accordance with the
invention include those described below.
A first example is a tercopolymer produced by ring-opening
copolymerization of depsipeptide, L-lactide, and
f~-caprolactone . Fig . 2 depicts the structure view of a copolymer
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with a depsipeptide unit. U expresses depsipeptide unit.
A specific example of the tE:rcopolymer was produced by
copolymerizing together f-caprolactone, L-lactide, and L-3,
DL-6-dimethyl-2,5-morpholine-dione (L-DMO) prepared from
alanine and 2-bromopropionyl bromide.
It was shown by NMR data and the results of the measured thermal
properties that the resulting copolymer was a random copolymer.
Fig. 16 shows the dynamic properties and thermal properties of
the copolymers with the depsipeptide units.
This indicates that the softness is provided by a caprolactone
unit.
Further, Fig.3 depicts the decomposition properties of the
copolymers with the depsipeptide units.
This indicates that the addition of the depsipeptides can elevate
remarkably the decomposition rate without any loss of the
mechanical strength and softness.
In the above description, L-lactide was used as the lactide.
Additionally, L-lactide and the enantiomer D-lactide are
combinedtogetherfor copolymerization,toform astereo complex,
to thereby improve the thermal properties such as melting point .
Further, the change of t:he glass transition temperature can
impart free formation potency.
Therefore, a bicopolymer produced by copolymerizing a
depsipeptide with L-lactide may be satisfactory, other than the
terpolymer. Additionally,a depsipeptide iscopolymerized with
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a combination of L-lactide and the enantiomer D-lactide to
prepare a stereo complex of a copolymer.
As a second embodiment, Fig. 4 depicts the structure view of
a copolymer comprised of a depsipeptide and f~-caprolactone,
namely f-caprolactone and a depsipeptide are copolymerized
together via the ring-opening polymerization. U expresses
depsipeptide unit.
This also imparts the increase of the decomposition rate.
So as to elucidate the influence of the depsipeptide unit in
the copolymer with the peptide unit, further, the R group in
the side chain of the depsipeptide was modif ied into methyl group ,
isopropyl group and isobutyl group, to examine the influence.
Fig. 5 depicts the decomposition properties of a copolymer of
a depsipeptide and ~-caprolactone.
This indicates that the decomposition level is in the order of
methyl group » isopropyl group > isobutyl group, indicating
that the increase of the bulkiness of the side chain involves
the decrease of the decomposition level.
A third embodiment was a copolymer produced by ring-opening
polymerization of ~-caprolactone and a depsipeptide, using
3-isopropyl-6-methyl-2, 5-morpholine-dione(PMO) as the
depsipeptide.
Then, the change of the thermal properties and decompos5_tion
rate was examined when the amount of the depsipeptide was changed.
Fig . 17 shows the results of the thermal properties , while Fig . 6
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shows the results of the decomposition rate.
This indicates that the glass transition temperature ( T~) was
elevated as the depsipeptide amount increased. At the amount
of ~-caprolactone at 20mo1 ~ or less, the melting point (Tm)
and the heat of fusion(~Hm) were observed, indicating that the
resulting copolymer was c:rystallizable.
The decomposition rate was elevated as the amount of the
depsipeptide increased.
Herein , the description in the individual embodiments has been
done , exemplifying poly e-caprolactone and polylactic acid as
the bio-absorbable polymers. However, the bio-absorbable
polymers are not limited to them. Any bio-absorbable polymer
may be satisfactory, including for example polydioxanone,
trimethylene carbonate and copolymers of two or more of all such
bio-absorbable polymers.
Embodiments using bio-absorbable polymers of copolymers
produced via ring-opening polymerization of the depsipeptide
are described below.
First Embodiment
Fig. 7 is an explanatory view of a structure example of a stmt
for tracts and tubes. Herein, tracts and tubes mean digestive
tract, airway tract and vascular tube.
The structure example illustrated is composed of a bio-absorbable
polymer of a copolymer with depsipeptide unit. If necessary,
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an agent never transmitting X ray may be mixed therein. Via
such mixing, the stent inserted in the vascular tube can be
confirmed by X ray.
An example of the stem in the form of surface structure such
as cylindrical body and tubular body (referred to as cylindrical
body hereinaf ter ) is expressed as "a" . The mo lding method thereof
may be any method satisfactorily. The surface structure i:~ for
example cylindrical body integrally molded or a structure
produced by rounding up a plate body and bonding together the
side end parts thereof to prepare cylindrical body 1.
A structure with plural air holes 2 , opened in the surface
structure of the cylindrical body 1 is expressed as "b", where
the air holes 2 may be positioned at a constant interval or at
inconstant intervals.
A structure with plural protrusions 3,forrned on the exterior
surface of the surface structure of the cylindrical body 1 is
expressed as "c." , where the protrusions 3 may be positioned at
a constant interval or at inconstant intervals.
A structure of the cylindrical body 1 formed of a net structure
is expressed as "d" . For the composition of the net structure
4 , any formation approach may be satisfactory, such as knitting
one thread of yarn to form the net structure, or weaving one
thread of yarn and forming the structure or melt adhesion of
the bonded parts to form the net structure.
A structure of the cylindrical body 1 with advantages of both
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of tube coil and coil stent is expressed as "e" , which is formed
of coil structure 5.
Fig.8 is also an explanatory view of a structure example of a
stmt for tracts and tubes .
Forming one or more windows 6 at intervals along the peripheral
direction of the peripheral surface of the cylindrical body,
bending the connection part 7 inward to form a plastic deformed
part, mounting the cylindrical body and subsequently enlarging
the plastic deformed part as shown in the figure, the structure
at the mounted state is retained.
Fig. 9 is also an explanatory view of a structure example of
a stent~ for tracts and tubes.
Forming link 8 in the character form "N" or "S" on the peripheral
surface of the cylindrical body to make the cylindrical body
plastically deform, mounting the cylindrical body and
subsequently enlarging the cylindrical body as shown in the
figure, the structure at the mounted state is retained.
Fig. 10 is an explanatory view of a structure example of a stmt
for tracts and tubes.
Forming thick fastening protrusion groove 10 on both the. side
ends of rectangle sheet 9 along the longitudinal direction
thereof, groove 11 is formed on the exterior surface in the
proximity of one of the side ends to fasten the fastening
protrusion groove 10.
Rounding up the sheet 9 thus formed in a cylindrical shape,
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fastening to the groove 11 the fastening protrusion groove 10
on the opposite side thereof to form a cylindrical body, mounting
the resulting cylindric:al body, and subsequently enlarging the
c:ylindr.ical diameter as shown in the figure, the fastening
protrus ion groove 10 is detached from the groove 11 so that the
thick end faces of the fastening protrusion groove 10 are put
in contact to each other to prepare a cylindrical body of a larger
diameter, to allow the resulting structure to retain the mounted
state thereof.
fig. 11 is an explanatory view of a structure example of a stmt
for tracts and tubes.
The structure is at a state with a smaller diameter resu7.ting
from the folding up of a cylindrical body of a larger diameter.
After mounting the cylindrical body, the cylindrical diameter
is enlarged to a desired diameter so that the cylindrical body
can be of a structure permitting the retention of the mounted
state.
fig. 12 is also an explanatory view of a structure example of
a stent for tracts and tubes.
The stmt is of a structure with groove 12 formed at a given
interval in the form of lattice along the circumference direction
and longitudinal direction on the peripheral surface of a
cylindrical body. After mounting the cylindrical body, the
cylindrical diameter can be enlarged via the groove 12 , so that
the stmt is of a structure to retain the mounted state by enlarging
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the cylindrical body to a desired diameter. Herein, the
direction of the groove formed is not limited to the direction
as in the case of the orthogonal grooves described above . The
groove may be formed along a diagonal direction along the
circumference direction.
Fig. 13 is an explanatory view of a structure example of a st~ent
for tracts and tubes.
The stmt is of a structure of the cylindrical body at the state
with a smaller diameter, by folding the cylindrical body into
a cross sectional form of a star shape along the longitudinal
direction. If necessary, one or more windows may satisfactorily
be formed at an interval as in the case of f in Fig. 8. Via
such structure, the cylindrical diameter can be enlarged by
elongating the mountaintop or valley of the star shape after
the arrangement of the cylindrical body, so that the stmt is
of a structure capable of retaining the mounted state by enlarging
the cylindrical body to a desired diameter.
Those described above are structure examples. Additionally,
any structure deformable along the diameter direction may be
satisfactory. Such structures can be used for stems of all
of the related art structures.
By structuring the stmt in such manner, the stent can prevent
restenosis of tracts and tubes, which is the essential stent
effect. Additionally, the stent can select desired softness
and decomposition rate . A stent adjusted to various conditions
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such as symptoms and sites for use can be constituted.
Furthermore, the mixing of an agent never transmitting X ray
can establish the confirmation of the state of the resulting
stent during surgery or post-surgery.
Second embodiment
Fig. 14 is an explanatory view of a capsule.
The figure shows a structure example, which is composed of a
bio-absorbable copolymer with depsipeptide unit. If necessary,
an agent never transmitting X .ray may be mixed therein. Via
the mixing, the capsule in bodies can be verified by X ray.
The figure shows the state of body 131 detached from lid 132.
Integrally, they compose capsule 13.
Inside the capsule 13, a therapeutic agent, drugs such as
examination agents and imaging agents and biological cells in
some case may be placed for use.
By structuring the capsule 13 in such manner, the capsule can
be adjusted to a desired decomposition rate, depending on the
substance placed therein and the site where the substance is
intended to be reached, to thereby determine the dissolution
rate thereof.
Third embodiment
Fig.lS is an explanatory view of a carrier.
The figure shows a shape example in a disc form. The carrier
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14 is composed of a bio-absorbable copolymer with depsipeptide
unit and may be mixed with an agent never transmitting X ray
if necessary. Via the mixing, the carrier in bodies can be
verified by X ray .
The carrier 14 shown in the figure is of a disc shape but may
satisfactorily be of other appropriate shapes such as particle
shape, plate shape, thin plate shape, wave plate shape, band
shape, linear shape, spiral shape and container shape.
Furthermore, the carrier may satisfactorily be of such a shape
as shown in the first embodiment.
Drugs such as therapeutic agents, examination agent and imaging
agents and biological cells may be embedded in the carrier 14
or may be at a state integrally mixed therein or may be impregnated
therein or may be attached on the surface thereof. Further,
these procedures may be done in a complex manner for use.
By constituting the carrier 14 in such manner, the carrier can
be adjusted to a desired decomposition rate, depending on the
material. immobilized on the carrier or on the site where the
material immobilized thereon is intended to be reached, to
thereby determine the dissolution speed.
Fourth embodiment
Not shown in the figure , the entirety or a part of a medical
device such as treatment device, for example catheter or a part
thereof and guide wire to be used for catheter or a part thereof ,
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is constituted with a bio-absorbable copolymer with depsipeptide
unit, so that the device never causes any disorder even when
the device is left in bodies intentionally or by accident.
Fifth embodiment
Not shown in the figure, a suture thread composed of a
bio-absorbable copolymer with depsipeptide unit never causes
any disorder even when the suture thread is left in bodies
intentionally or by accident.
Sixth embodiment
Not shown in the figure, a coil shape for vascular occlusion
in aneurysm composed of a bio-absorbable copolymer with
depsipeptide unit can occlude aneurysm and additionally,, the
coil shape of itself can be decomposed and absorbed to keep the
occluded state.
Industrial applicability
In accordance with the invention described in detail above , a
copolymer with a depsipeptide unit , as produced by copolymerizing
a depsipeptide with a bio-absorbable monomer unit such as lactide
and the like , can advantageously be prepared as a bio-absorbable
plastic device for clinical practice, where the dynamic
properties and decomposition properties are adjusted. The
resulting copolymer can advantageously be used for example for
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stmt , medical. capsule , carriers of drugs and biological cells ,
and suture thread.
Further, advantageously, the modification of the peptide unit
with alkyl groups can adjust the dynamic properties and the
decomposition properties.
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1 1% 1 1
Description of the reference characters
J. cylindrical laody
'? air hale
3 torot.r union
4 net structure
5 coil structure
G windov~~
connection part
8 link
~ sheet
1 0 fastening protrusion groove
1 1 grootre
1 2 groove
1 3 capsule
1 4 carrier
