JPH11319069A - Ultra-high molecular implantation material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To impart both of excellent dynamic characteristics and rapid biodegradability by introducing biodegradable groups degraded in an implanted region into both terminals of a water-soluble straight chain high polymer piercing the cavity of a cyclic molecule to provide a molecular structure wherein the cyclic molecule is not dissociated so far as the terminal groups are not degraded. SOLUTION: Polyethylene glycol being a straight chain high polymer or a block copolymer of polyethylene glycol and polypropylene glycol pierces the cavity parts of a plurality of cyclic molecules (cyclodextrin). Oligopeptide chains, oligosaccharides or ester groups are introduced into both terminals of the block copolymer as molecular chains (biodegradable groups) degraded in an implanted region in a time-specifical manner. By this constitution, dynamic characteristics necessary for tissue reconstruction can be developed by an ultra- high-molecular structure consisting of cyclic molecules and the straight chain high polymer. After reconstruction, an implantation material can disappears rapidly from the implanted region by the dissociation of ultra-high molecules based on the hydrolysis of the terminal groups.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel supramolecular implant material which can be widely used for implants in the field of orthopedics and the like.

[0002]

2. Description of the Related Art Conventionally, various biodegradable polymers have been used in orthopedic and oral surgery fields for the purpose of reconstructing hard and soft tissues. These biodegradable polymers are mainly polylactic acid and poly (lactic acid-
Glycolic acid) is an aliphatic polyester such as a copolymer. By controlling its excellent mechanical properties and non-enzymatic hydrolyzability, it achieves the strength to hold tissue for several months and the degradation and disappearance after reconstruction. I have.

However, in the case of these conventional implant materials, a polyester comprising a hydrophobic main chain is made highly crystalline by molding conditions in order to obtain strength as an implant device, and rather, after the tissue reconstruction, There is a problem with hydrolysis. In addition, biodegradation of polyester is usually performed by non-enzymatic hydrolysis, and is determined by the rate of water penetration into the material and the rate of hydrolysis of ester groups. Due to its high crystallinity, water intrusion into crystal sites is limited, and as a result, even if the material is no longer needed after tissue reconstruction, it does not easily disappear from the implant site, but remains in fine particles. This causes a local inflammatory response.

As described above, it is practically impossible with the prior art to design a material having both the mechanical properties necessary for tissue reconstruction and the rapid decomposition and disappearance after reconstruction. Therefore,
Against this background, there has been a strong demand for the realization of an ideal implant material having both excellent mechanical properties and rapid decomposition and disappearance.

[0005]

SUMMARY OF THE INVENTION In view of the above-mentioned problems of biodegradable polymers in the field of conventional orthopedic surgery and oral surgery, the invention of this application is necessary for holding and fixing during tissue reconstruction. An object of the present invention is to provide a new supramolecular implant material exhibiting mechanical properties and rapid degradation and disappearance after tissue reconstruction.

That is, the invention of this application firstly introduces a biodegradable group capable of decomposing at an implant site into both ends of a water-soluble linear polymer penetrating the cavity of a cyclic molecule. And a supramolecular implant material having a molecular structure in which a cyclic molecule is not eliminated unless this terminal group is decomposed. Secondly, the invention of this application relates to the implant material, wherein the biodegradable group at the implant site decomposes after a specific time,
Fourth, the specific time is the time after reconstitution of the biological tissue, and the fourth is the crystallinity, the rate of hydrolysis of end groups, the rate of desorption of cyclic molecules and the penetration per chain. Provided is a supramolecular implant having a controlled amount.

Further, the invention of this application relates to any one of the above-mentioned implanting materials. Fifth, the terminal group of the linear polymer is:
Sixth, a supramolecular embedding material that is an oligopeptide chain, an oligosaccharide chain, or an ester group is used. Seventh, the cyclic molecule is α-, β-, or γ-cyclodextrin, and the water-soluble linear polymer is polyethylene glycol or polyethylene glycol and polypropylene glycol. Block copolymer having a number average molecular weight of 20
Any supramolecular implant material that is between 0-5000 is provided.

Further, the invention of this application is, in an eighth aspect, that the terminal group of the linear polymer has a repeating unit of 1-5, and the constituent amino acids are alanine, valine, leucine, isoleucine, methionine, proline, Phenylalanine, tryptophan, aspartic acid, glutamic acid, glycine, serine, threonine, tyrosine, cysteine, lysine, arginine, oligopeptide chain consisting of one or more of any of histidine, repeating unit is 1-5, dextran as a constituent polysaccharide, The present invention also provides a supramolecular implant material having an oligosaccharide chain composed of hyaluronic acid, chitin, chitosan, alginic acid, chondroitin sulfate, starch, or an ester group.

According to the invention of this application, ninthly, a hydrolyzable decomposable group is introduced into both ends of a water-soluble linear polymer penetrating the cavity of a cyclic molecule, and this terminal group is degraded. There is also provided a supramolecular material characterized by having a molecular structure in which a cyclic molecule is not eliminated unless otherwise. In the invention of this application, unlike the conventional biodegradable polymer material,
It is characterized in that the structure exhibiting mechanical properties depends on the formation of supramolecular aggregates. That is, in the supramolecular embedding material of the present invention, the mechanical properties are not dependent on the crystallinity of the polymer composed of repeating hydrolyzable groups, but the water-soluble linear polymer penetrates a large number of cyclic molecules. Obtained by the supramolecular crystallinity. In conventional biodegradable polymers, it was necessary to hydrolyze all of the ester bonds, which are repeating units, so that high crystallinity made hydrolysis difficult on the contrary. In the molecular implant material, the bulky decomposable group introduced into the terminal of the linear polymer is hydrolyzed, so that the penetrating cyclic molecule or the cyclic molecule is quickly eliminated and dissolved, and disappears from the implant site.

[0010] In the supramolecular implant material of the present invention, the mechanical properties are secured by the formation of the supramolecules, and the elimination properties by rapid dissociation of the supramolecules based on the hydrolysis of the terminal group, and two different properties are independently obtained. It has the advantage that it can be controlled. According to the present invention, the design of various implantable devices conventionally used in the field of reconstruction of various tissues such as orthopedic surgery and oral surgery is fundamentally changed.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The supramolecular implantation material of the invention having the above-mentioned features will be further described. First, the cyclic molecule of the supramolecular implant material of the present invention is, for example, α
-, Β-, or γ-cyclodextrin or other compounds having a similar cyclic structure may be used, such as polyethers, polyesters, polyetheramines, and polyamines having a cyclic structure. The water-soluble linear polymer may be, for example, polyether, polyester, or the like, and is polyethylene glycol or a block copolymer of polyethylene glycol and polypropylene glycol, and has a number average molecular weight of 200 to 50.
00, preferably 400-2000 is illustrated as one of the suitable ones. As the polymer terminal group,
Oligopeptide chains, oligosaccharide chains, or ester groups are exemplified as appropriate ones. More specifically, for example, the repeating unit is 1-5, and the constituent amino acids are alanine, valine, leucine, isoleucine, methionine,
Proline, phenylalanine, tryptophan, aspartic acid, glutamic acid, glycine, serine, threonine, tyrosine, cysteine, lysine, arginine, an oligopeptide chain consisting of any one or a plurality of histidines, the repeating unit is 1-5, and as a constituent polysaccharide Oligosaccharide chains comprising dextran, hyaluronic acid, chitin, chitosan, alginic acid, chondroitin sulfate, starch, or those having an ester group can be mentioned.

The polymer end groups may be linked by a suitable reactive compound to increase the molecular weight. The following are exemplified as typical configurations. That is, polyethylene glycol, which is a linear polymer, or a block copolymer of polyethylene glycol and polypropylene glycol penetrates through the cavities of a plurality of cyclic molecules (cyclodextrins).
Alternatively, oligopeptide chains, oligosaccharides, or ester groups are introduced into both ends of a block copolymer of polyethylene glycol and polypropylene glycol as molecular chains (biodegradable groups) that are degraded in a time-specific manner at the site of implantation. It is a supramolecular implant material with a structure as a skeleton.

[0013] The supramolecular structure of polyethylene glycol, which is a linear polymer penetrating through cyclodextrin, which is a cyclic molecule, or a block copolymer of polyethylene glycol and polypropylene glycol, exerts excellent mechanical properties and exhibits excellent mechanical properties. Tissue reconstruction, and the hydrolysis of oligopeptide chains, oligosaccharide chains or ester groups, which are biodegradable groups introduced at the ends of the linear polymer, after tissue reconstruction (timed) As a result, cyclodextrin is once eliminated from polyethylene glycol or a block copolymer of polyethylene glycol and polypropylene glycol and disappears. This realization makes it possible to construct an ideal implantable device having excellent mechanical properties over a long period of time and quick disappearance after a certain period of time.

Controlling the crystallinity by the supramolecule, the rate of hydrolysis of the terminal groups, the rate of desorption of the cyclic molecule and the amount of penetration per chain, the time during which the therapeutically effective mechanical properties are exhibited and the time at which the degradation disappears , And its speed can be controlled. A supramolecular structure composed of a cyclic molecule and a linear polymer can exert the mechanical properties required for tissue reconstruction. After reconstruction, it can be quickly cleared from the implantation site by dissociation of the supramolecule based on hydrolysis of the terminal groups. This is expected to enable treatment with high efficacy (mechanical properties) and safety (dissociation of supramolecules) for use every several months in tissue reconstruction in the field of orthopedic surgery and oral surgery.

The present invention will be described in more detail with reference to the following examples.

[0016]

EXAMPLES (Example 1) Synthesis of polyrotaxane According to the following formula, polyrotaxane was synthesized by the following procedure.

[0017]

Embedded image

(1) Introduction of an ester bond to the end of PEG PEG (molecular weight: 3300, 33 g, 10 mmol) was dissolved in 220 ml of toluene, and succinic anhydride (20 g, 2 g
(00 mmol) and refluxed at 150 ° C. for 5 hours. The solution was concentrated and poured into ether to obtain a precipitate. It was dissolved in methylene chloride, and insolubles were removed by centrifugation. The supernatant was concentrated and poured into ether to obtain a white precipitate. Yield 2
7.5 g. (2) Succinimidation of PEG terminal Carboxyl-functionalized PEG (20 g, 5.7 mmol) was mixed with methylene chloride / dioxane (1: 1) mixed solvent 350 m
was dissolved in 1 under ice-cooling, and N-hydroxysuccinimide (17.1 g, 148.2 mmol) was added. Here, N, N'-dicyclohexylcarbodiimide (23.5 g, 114 mmol) dissolved in 50 ml of the same mixed solvent
Was added and stirred at room temperature for 24 hours. After the reaction, urea was removed by filtration, and the filtrate was allowed to stand in a cool place overnight. The solution was filtered again, concentrated, and poured into ether to obtain a white precipitate.
Yield 18.25g. (3) Introduction of amino group to PEG terminal Succinimidated PEG (10 g, 2.7 mmol) was dissolved in 50 ml of methylene chloride, and 75 ml of methylene chloride was dissolved.
Ethylenediamine dissolved in water (0.4ml, 6mmo
1) was added dropwise over 30 minutes and stirred at room temperature for 1 hour. After the reaction, the mixture was poured into ether to obtain a precipitate. Yield 9.44 g. (4) Preparation of pseudopolyrotaxane α-CD (23.95 g, 24.6 mmol) was added to water 15
It was dissolved in 5 ml to prepare a saturated aqueous solution. Here 10m of water
Then, 2 g of aminated PEG dissolved in 1 l was dropped and stirred for 10 minutes. Further, ultrasonic waves were irradiated for 10 minutes, and the mixture was allowed to stand at room temperature overnight. The resulting precipitate was collected by centrifugation, washed with water, and dried under reduced pressure. Yield 9.75g. (5) Synthesis of polyrotaxane ZL-Phe-OSu (3.97 g, 10 mmol)
Was dissolved in DMSO (6 ml), pseudopolyrotaxane (average CD penetration number: 35) (3.76 g, 0.1 mmol) was added, and the mixture was stirred at room temperature. After 24 hours, 1 ml of DMSO was added to keep the reaction solution in a heterogeneous state uniform.
One hour later, 1 ml of DMSO was added, and the reaction was carried out for a total of 96 hours. After the reaction, the mixture was poured into ether to obtain a white crude product. The crude product was purified by washing with acetone and water.
Yield 0.933 g. Thermogravimetry (TGA) and differential scanning of polyrotaxanes
Calorimetry (DSC) TGA of the polyrotaxane obtained in the above synthesis,
DSC measurements were taken in the range 20 ° C to 320 ° C. The test was performed at a temperature of 2 ° C./min with a sample of 2 mg. The DSC measurement was performed under a nitrogen stream.

The results are shown in Table 1 below.

[0020]

[Table 1]

As a result of TGA and DSC, neither pseudo-polyrotaxane nor polyrotaxane had a melting point,
Only close decomposition temperatures were observed.

[0022]

According to the supramolecular structure of the present invention comprising a cyclic molecule and a linear polymer, it is possible to exhibit the mechanical properties required for tissue reconstruction. After reconstruction, it can be rapidly eliminated from the implant site by dissociation of the supramolecule based on hydrolysis of the terminal groups. This is expected to enable treatment with high efficacy (mechanical properties) and safety (dissociation of supramolecules) for use every several months in tissue reconstruction in the field of orthopedic surgery and oral surgery.

Claims (9)

[Claims] 1. A biodegradable group capable of decomposing at an implantation site is introduced into both ends of a water-soluble linear polymer penetrating a cavity of a cyclic molecule. A supramolecular implantable material having a molecular structure from which molecules are not eliminated. 2. The supramolecular implantable material according to claim 1, wherein the biodegradable group at the implant site is decomposed after a specific time. 3. The supramolecular implantation material according to claim 2, wherein the specific time is a time after reconstitution of the living tissue. 4. The supramolecular implantation material according to claim 1, wherein the crystallinity, the rate of hydrolysis of the terminal group, the rate of desorption of the cyclic molecule, and the amount of penetration per chain are controlled. 5. The terminal group of the linear polymer is an oligopeptide chain, an oligosaccharide chain, or an ester group.
Or 4 supramolecular implant materials. 6. The linear polymer has a terminal group linked by an appropriate reactive compound to have a high molecular weight.
5. The supramolecular implant material according to any one of the above-mentioned items 5 to 5. 7. The cyclic molecule may be α-, β-, or γ-
Cyclodextrin, a water-soluble linear polymer,
7. A block copolymer of polyethylene glycol or polyethylene glycol and polypropylene glycol having a number average molecular weight of 200-5000.
Any of the supramolecular implanted materials. 8. The terminal group of the linear polymer has a repeating unit of 1-5, and the constituent amino acids are alanine, valine, leucine, isoleucine, methionine, proline,
Phenylalanine, tryptophan, aspartic acid,
Glutamic acid, glycine, serine, threonine, tyrosine, cysteine, lysine, arginine, an oligopeptide chain consisting of any one or a plurality of histidines, the repeating unit is 1-5, and dextran, hyaluronic acid, chitin, chitosan as a constituent polysaccharide, The supramolecular implantation material according to any one of claims 1 to 7, which has an oligosaccharide chain composed of alginic acid, chondroitin sulfate, and starch, or an ester group. 9. A hydrolyzable decomposable group is introduced into both ends of a water-soluble linear polymer penetrating the cavity of a cyclic molecule, and the cyclic molecule is not desorbed unless this terminal group is decomposed. A supramolecular material characterized by having a molecular structure.