CA2427601A1 - Bio-absorbable plastic device for clinical practice - Google Patents
Bio-absorbable plastic device for clinical practice Download PDFInfo
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- CA2427601A1 CA2427601A1 CA002427601A CA2427601A CA2427601A1 CA 2427601 A1 CA2427601 A1 CA 2427601A1 CA 002427601 A CA002427601 A CA 002427601A CA 2427601 A CA2427601 A CA 2427601A CA 2427601 A1 CA2427601 A1 CA 2427601A1
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- clinical practice
- plastic device
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- absorbable plastic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
- A61L17/06—At least partially resorbable materials
- A61L17/10—At least partially resorbable materials containing macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
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- Animal Behavior & Ethology (AREA)
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- Chemical & Material Sciences (AREA)
- Transplantation (AREA)
- Surgery (AREA)
- Dermatology (AREA)
- Medicinal Chemistry (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Vascular Medicine (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Materials For Medical Uses (AREA)
Abstract
Bio-absorbable polymers for use as medical materials for vascular stent and suture thread have almost defined dynamic properties such as tensile strength and almost defined decomposition rate for absorption. When the dynamic properties thereof are elevated, therefore, the bio-absorbable polymers turn fragile, involving slower decomposition rate. When the decomposition rate is elevated, further, the dynamic properties are deteriorated. Disadvantageously, such bio-absorbable polymers have limited purposes for use and limited sites for use.
Thus, copolymerization of a bio-absorbable monomer as lactide with a cyclic depsipeptide can allow the adjustment of the dynamic properties and decomposition rate of the resulting copolymer via the content of the depsipeptide.
Thus, copolymerization of a bio-absorbable monomer as lactide with a cyclic depsipeptide can allow the adjustment of the dynamic properties and decomposition rate of the resulting copolymer via the content of the depsipeptide.
Description
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, 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 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 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 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 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 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, 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 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, 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 IZ
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 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 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 , 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 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.
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
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, 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 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 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 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 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 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, 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 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, 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 IZ
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 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 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 , 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 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.
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
Claims (25)
1. A bio-absorbable plastic device for clinical practice, which is composed of a copolymer produced by copolymerizing a bio-absorbable monomer such as lactide and a cyclic depsipeptide.
2. A bio-absorbable plastic device for clinical practice according to claim 1, which has free molding potency.
3. A bio-absorbable plastic device for clinical practice according to claim 1 or 2, which is prepared as a stent for tracts and tubes.
4. A bio-absorbable plastic device for clinical practice according to claim 3, which is mixed with an agent never transmitting X ray.
5. A bio-absorbable plastic device for clinical practice according to claim 3 or 4, where the stent for tracts and tubes is constituted in a net structure.
6. A bio-absorbable plastic device for clinical practice according to claim 3 or 4, where the stent for tracts and tubes is constituted in a cylindrical surface structure.
7. A bio-absorbable plastic device for clinical practice according to claim 3 or 4, where the stent for tracts and tubes is in a cylindrical surface structure and plural air holes are formed on the surface thereof.
8. A bio-absorbable plastic device for clinical practice according to claim 3 or 4, where the stent for tracts and tubes is in a cylindrical surface structure and the surface thereof is folded to have a small diameter.
9. A bio-absorbable plastic device for clinical practice according to claim 3 or 4, where the stent for tracts and tubes is in a cylindrical surface structure and plural protrusions are formed on the surface thereof.
10. A bio-absorbable plastic device for clinical practice according to claim 3 or 4, where the stent for tracts and tubes is in a cylindrical surface structure and grooves are formed on the surface thereof.
11. A bio-absorbable plastic device for clinical practice according to claim 1 or 2, which is a carrier of biological cells.
12. A bio-absorbable plastic device for clinical practice according to claim 11, which is mixed with an agent never transmitting X ray.
13. A bio-absorbable plastic device for clinical practice according to claim 11 or 12, which is a capsule for placing biological cells therein.
14. A bio-absorbable plastic device for clinical practice according to claim 11 or 12, which is a carrier in a shape for example particle shape, plate shape, linear shape, band shape, and spiral shape, capable of immobilizing biological cells thereon.
15. A bio-absorbable plastic device for clinical practice according to claim 1 or 2, which is a carrier of drugs such as therapeutic agents, examination agents, and imaging agents.
16. A bio-absorbable plastic device for clinical practice according to claim 15, which is mixed with an agent never transmitting X ray.
17. A bio-absorbable plastic device for clinical practice according to claim 15 or 16, which is a capsule for placing drugs such as therapeutic agents, examination agents and imaging agents therein.
18. A bio-absorbable plastic device for clinical practice according to claim 15 or 16, which is a carrier in a shape for example particle shape, plate shape, linear shape, band shape, and spiral shape, capable of immobilizing drugs such as therapeutic agents, examination agents and imaging agents thereon.
19. A bio-absorbable plastic device for clinical practice according to claim 1 or 2, which is a suture thread.
20. A bio-absorbable plastic device for clinical practice according to claim 19, which is mixed with an agent never transmitting X ray.
21. A bio-absorbable plastic device for clinical practice according to claim 1 or 2, which constitutes at least a part of a medical device.
22. A bio-absorbable plastic device for clinical practice according to claim 21, which is mixed with an agent never transmitting X ray.
23. A bio-absorbable plastic device for clinical practice according to claim 21 or 22, which constitutes at least a part of catheter.
24. A bio-absorbable plastic device for clinical practice according to claim 21 or 22, which constitutes at least a part of guide wire for use for catheter.
25. A bio-absorbable plastic device for clinical practice according to claim 1 or 2, which constitutes at least a part of coil shape for vascular occlusion in aneurysm.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/JP2002/006331 WO2004000377A1 (en) | 2002-06-25 | 2002-06-25 | Bioabsorbable plastic instruments for medical use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2427601A1 true CA2427601A1 (en) | 2003-12-25 |
Family
ID=29808143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002427601A Abandoned CA2427601A1 (en) | 2002-06-25 | 2002-06-25 | Bio-absorbable plastic device for clinical practice |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPWO2004000377A1 (en) |
| KR (1) | KR20050013049A (en) |
| CA (1) | CA2427601A1 (en) |
| WO (1) | WO2004000377A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006175153A (en) * | 2004-12-24 | 2006-07-06 | Goodman Co Ltd | Biodegradable bio-absorbable material for clinical practice |
| CN1321705C (en) * | 2004-07-02 | 2007-06-20 | 清华大学 | Method for preparing multilayer medicine composite degradable biliary tract rack visible under X-ray |
| EP1830902A2 (en) * | 2004-12-30 | 2007-09-12 | Cinvention Ag | Combination comprising an agent providing a signal, an implant material and a drug |
| JP4828268B2 (en) * | 2006-03-16 | 2011-11-30 | テルモ株式会社 | Stent |
| US7862830B2 (en) * | 2006-07-13 | 2011-01-04 | Abbott Cardiovascular Systems Inc. | Stereocomplex-forming composition and implantable medical device comprising same |
| US8298466B1 (en) | 2008-06-27 | 2012-10-30 | Abbott Cardiovascular Systems Inc. | Method for fabricating medical devices with porous polymeric structures |
| CN102408389B (en) * | 2011-09-15 | 2013-07-31 | 南开大学 | Lactic acid-glutamic acid morpholine dione and synthetic process method thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4441496A (en) * | 1982-02-08 | 1984-04-10 | Ethicon, Inc. | Copolymers of p-dioxanone and 2,5-morpholinediones and surgical devices formed therefrom having accelerated absorption characteristics |
| US4916209A (en) * | 1987-12-23 | 1990-04-10 | Pfizer Inc. | Bioabsorbable polydepsipeptide, preparation and use thereof |
| RU2086209C1 (en) * | 1991-03-08 | 1997-08-10 | Игаки Кейдзи | Vascular shunt, carrier and device for shunt fastening |
| JPH10127754A (en) * | 1996-11-06 | 1998-05-19 | Koken Co Ltd | Occlusion material composed of collagen |
| JP3816603B2 (en) * | 1996-11-29 | 2006-08-30 | オリンパス株式会社 | Stent |
| EP1659142B1 (en) * | 1997-12-22 | 2010-03-24 | Metabolix, Inc. | Polyhydroxyalkanoate compositions having controlled degradation rates |
| US6338739B1 (en) * | 1999-12-22 | 2002-01-15 | Ethicon, Inc. | Biodegradable stent |
-
2002
- 2002-06-25 JP JP2004515462A patent/JPWO2004000377A1/en active Pending
- 2002-06-25 KR KR10-2003-7007427A patent/KR20050013049A/en not_active Application Discontinuation
- 2002-06-25 WO PCT/JP2002/006331 patent/WO2004000377A1/en not_active Application Discontinuation
- 2002-06-25 CA CA002427601A patent/CA2427601A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| KR20050013049A (en) | 2005-02-02 |
| JPWO2004000377A1 (en) | 2005-10-20 |
| WO2004000377A1 (en) | 2003-12-31 |
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