JPS63278924A - Urethane prepolymer absorbable on decomposition in vivo - Google Patents

Abstract

PURPOSE:To obtain a urethane prepolymer absorbable on decomposition in vivo, by introducing an ester bond into a polymer chain. CONSTITUTION:The title product is a urethane prepolymer having an ester bond in a polymer chain and being absorbable on decomposition in vivo. Introduction of an ester bond into the polymer chain can be attained by the use of a diisocyanate and a low-MW aliphatic polyester having hydroxyl groups at both ends of its molecule, such as polylactic acid polyglycolic acid poly-epsilon- caprolactone, lactic acid-glycolic acid copolymers, lactic acid-epsilon-caprolactone, lactic acid-glycolic acid copolymers and lactic acid-epsilon-caprolactone copolymers. The present polyhydroxyl compd. is a polymer absorbable on decomposition in vivo, which easily undergoes hydrolysis in the presence of a small amount of water in vivo. Products formed by the decomposition of this polymer are lactic acid glycolic acid and hydroxypropionic acid, which enter the normal metabolic pathway in vivo as harmless substances to become sources of energy for a living body.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention was developed for use in vivo or in the oral cavity. This invention relates to a biodegradable urethane prepolymer having an ester bond that undergoes hydrolysis in its polymer face, and a method for producing the same.

[Prior art] As a surgical adhesive currently used clinically, α-
There is cyanoacrylate and fibrin glue. Although α-cyanoacrylate is useful in that it hardens quickly with water in the living body, it has drawbacks such as hard and brittle cured products and strong reactivity with living tissues.

Fibrin glue has problems with storage stability because its main components are biological components fibrinogen and thrombin, and it also has drawbacks such as being time-consuming to prepare before use.

On the other hand, research efforts are underway to develop medical elastic adhesives (Proceedings of the 7th Japan Society for Biomaterials, P. 5).
3. 1985) reported on liquid reactive urethane prepolymers of polyols and diisocyanates. However, since this urethane prepolymer uses polyethylene glycol, polypropylene glycol, etc. as a polyol, it is not subject to hydrolysis.

[Problems to be Solved by the Invention] An object of the present invention is that, unlike conventionally known liquid reactive urethane prepolymers, it undergoes hydrolysis at an arbitrary rate in the presence of water in living organisms, and is capable of absorbing biological tissue. The object of the present invention is to provide a biodegradable and absorbable urethane prepolymer that is completely decomposed and absorbed after healing.

[Means for Solving the Problems] The above-mentioned object of the present invention is to combine conventionally known diisocyanates with low molecular weight polylactic acid, polyglycolic acid, poly-ε- Caprolactone, lactic acid-glycolic acid copolymer, lactic acid-ε
- This can be achieved as a result of introducing ester bonds into the polymer chain by using an aliphatic polyester such as a caprolactone copolymer.

The present inventors have arrived at the present invention as a result of extensive studies aimed at synthesizing a biodegradable and absorbable polyhydroxyl compound based on two or more of the above backgrounds.

Originally, in the healing of living tissues and the repair of damaged parts, connective tissue proliferates due to the living body's own repair power, and m-healing is completed. Therefore, it is expected that adhesives used for biological tissues, especially biological soft tissues, will support and fix the joint for about one week to 10 days until wound healing is completed, and then disappear as soon as possible once it has served its purpose. Ru. That is, since the surgical adhesive has a recovery function in the living tissue itself, it must not inhibit that function.

To do this, it must be a temporary adhesive until the body heals, and then it must be absorbed and excreted without being harmful or toxic to the body.

The polyhydroxyl compound of the present invention is synthesized using lactic acid, glycolic acid, and E-caprolactone, which are widely distributed not only in living organisms but also in nature, as starting monomers, and is easily synthesized in the presence of trace amounts of water in living organisms. It is a biodegradable bioabsorbable polymer that undergoes hydrolysis. (Polymer processing, P, 2
08.1981), and the decomposition products of this polymer are lactic acid, glycolic acid, and hydroxypropionic acid, which enter the normal metabolic pathway in the body. !
! It is a substance that is poisonous and serves as an energy source for living organisms.

[Example] The polyhydroxyl compound used in the present invention is.

These are low molecular weight polylactic acids, polycaprolactones, polyglycolic acids, lactic acid-glycolic acid copolymers, lactic acid-caprolactone copolymers, etc. that have hydroxyl groups at both ends, and have ester bonds in their polymer chains, making them difficult to hydrolyze. It is a biodegradable and absorbable polyester. These polymers use glycerin, ethylene glycol,
Lactide monomer, caprolactone monomer in the presence of propylene glycol, polyethylene glycol, etc.

It was synthesized by ring-opening polymerization of glycolide monomers, etc. Synthesizing the polymer by ring-opening polymerization made it possible to introduce hydroxyl groups at both ends, and it was also easy to control the molecular weight of the polymer.

Furthermore, when polyethylene glycol or polypropylene glycol was used as an initiator, it became possible to introduce a hydrophilic moiety into the polymer electrolyte. The isocyanate compounds used in the present invention include hexamethylene diisocyanate (I-IMDI), tolyl diisocyanate (TD
I), diphenylmethalin isocyanate (MDI),
Alternatively, it is a diisocyanate compound such as hydrogenated diphenylmethalin isocyanate (hydrogenated MDI). Using these polyhydroxyl compounds and diisocyanates, we synthesized a urethane prepolymer composition that foams and hardens in the presence of water in vivo, and then undergoes decomposition and absorption.

(Production of urethane prepolymer) What is the molecular weight of the polyhydroxyl compound used?

It can be arbitrarily controlled by the amount of initiator added during synthesis.

As shown in Figure 1, glycerin, ethylene glycol, polyethylene glycol moleculesff1400°1000
In either case, the molecular weight can be controlled. The polyhydroxyl compounds shown in Table 1 were obtained and used to prepare prepolymers.

Preparation of urethane prepolymer was carried out under nitrogen flow6.
The reaction temperature varies depending on the type of polymer used, but 50
The reaction time was 4 to 24 hours at a temperature range of ~80°C. If the reaction rate is too high, thermal polymerization will occur and the reaction will not remain in the prepolymer state, so it is preferable to carry out the reaction at a temperature of 80° C. or lower. The stirring speed is controlled to keep the reaction temperature constant. Also.

In order to reduce the amount of residual isocyanate, it is desirable to carry out the second reaction for a longer time.

The properties of the prepared prepolymer vary greatly depending on the type and amount of the polymer and incyanate. Preparation NGOlo
) When the I ratio is less than 1, the prepolymer will not be formed and will be cured.Also, even if the charged NGOloH is greater than 1, the stability of the produced prepolymer will be poor and it will harden, so the charged NGO10H will be 2. The degree is preferable, and
Regarding the polyhydroxyl compound, the molecular weight of the polymer used is preferably about 500 to 4,000, since if the molecular weight becomes too high, the prepolymer produced will be in a solid state at room temperature, although it depends on the type of polymer.

(Prepolymer curing speed and properties after curing) As an example of prepolymer curing speed, Figure 2 shows a caprolactone-lactic acid (1:1) copolymer with a molecular weight of 1300 using ethylene glycol as an initiator. Prepolymer ■ synthesized from and HMDI, prepolymer ■ synthesized from caprolactone-lactic acid (1:1) copolymer with a molecular weight of 2000 using polyethylene glycol (molecular fi 400) as an initiator, and HMDI, and prepolymer ■ synthesized from HMDI as an initiator. Molecular weight 2000 using polyethylene glycol (molecular weight 400)
The curing speed of prepolymer (1) synthesized from the caprolactone-lactic acid copolymer and MDI was measured using the change in adhesive force to a steel plate as an indicator over time. 3, which was synthesized from HMDI and a polymer that does not contain a hydrophilic moiety in the main chain of the prepolymer, had a very slow curing time of about 1 day.
In case (2) in which a hydrophilic block was introduced into the main face, the curing time was significantly shortened to about 2 hours. In addition, in case (2), in which a hydrophilic block was introduced into the main face and MDI, which has a higher reactivity as a diisocyanate, was used, the curing time was about 30 minutes, resulting in a prepolymer with a higher curing speed.

Thus, by changing the type of polymer and the type of isocyanate, it was possible to control the curing rate of the prepolymer.

The physical properties of the prepolymer after curing vary depending on the type of polymer, molecular weight, and type of isocyanate.

Figure 3 shows a caprolact-lactic acid copolymer synthesized using ethylene glycol as an initiator, with a molecular weight of 1000.200.
0,4000. The physical properties of a prepolymer synthesized from MDI and MDI after curing were investigated using the shear force during adhesion to a steel plate as an indicator.

The prepolymers NGOloH used here are all 2
It is. As the molecular weight of the main chain increases.

A tendency for the shear force to decrease was obtained. As a result of observing the fracture surfaces, it was found that all of the fractures were cohesive fractures, which indicates that the density of crosslinking points contained in a unit area decreased and the shear force decreased.

By controlling the molecular weight of the polymer, the properties after curing could also be controlled.

A curing test was conducted by reacting a prepolymer prepared from the above polyhydroxyl compound and diisocyanate with water. In the test, an equal amount of water was added to 100 parts of the prepolymer at room temperature, stirred, and the curing time was measured.

Example 1゜■) Ethylene glycol initiated polylactic acid molecule M 500 (
EG-PLA500) ■EG-PLA500 100 copies HM D
T 72 parts preparation NGO10
H = 2 Reaction temperature: 0℃ 12 hours
``Low'' L property - Curing time: Approximately 1 day Properties after curing JJj: Brittle and hard foam EG-PLA500 100 parts TDI
72 parts preparation NCO10H=
2 Reaction = 70°C 6 hours, Soda −° □ Curing time: Approximately 3 hours Properties after curing: Brittle and hard foam ■EG-PLA500 100 parts MDI
108 copies prepared NGO10R=
2 Reaction at 60°C for 6 hours-Reaction temperature
/ Go! -::=-≦=j≧-1-Warmichi hardening time: Approx. 3
Properties after time curing: brittle and hard foam 2) Glycerin-initiated polylactic acid molecular weight 600 (G-pr,
AeOO) ■G-PLA600 100 copies 'TDI
60 parts prepared NCO10
H=2 Reaction 260℃ 12 hours, t −゛・
゛ □ Curing time: Approximately 3 hours Properties after curing: Brittle and hard foam ■G-PLA600 100 parts MDI
90 copies prepared NGO10H=
2. Reaction at 60°C for 6 hours - Wow! Smile °□ Curing time: Approximately 3 hours Properties after curing: Brittle and hard foam 3) Ethylene glycol starting polylactic acid molecular weight 1200 100 parts HMDI
30 copies prepared NGO10H=
2 Reaction: 60°C 24 hours - 1l +
' ・1-1 Curing time: Approximately 1 day Properties after curing: Hard foam 4) Glycerin-initiated polylactic acid molecular weight 1200 (G-PL
A1200) ■G-PLA1200 100 copies TDI
30 parts preparation NCO10H=
2 Reaction near 0℃ 6 hours - NI -〇 □ Curing time: Approximately 2 hours Properties after curing gt: Hard foam ■G-PLA1200 100 parts MDI
45 parts preparation NGO/OH
= 2 Reaction near 0°C 6 hours' - ILL upper tray λ upper tray - 1 curing time: Approximately 2 hours Properties after curing: Hard foam Example 2゜1) Polycaprolactone molecular weight 800 (Daicel Plaxel 208 ) ■Plaxel 208 100 copies HMDI
84 parts preparation NCO10H=
2 Reaction = 60℃ 24 hours
': 'Curing time: Approximately 12 hours Properties after curing: Soft foam ■Plaxel 208 100 parts TDI
87 parts preparation NGO10H=
2 Reaction = 60°C 6 hours, "--Curing time approximately 4 hours Properties after curing: Soft foam 2) Polycaprolactone molecule ff12000 (Daicel Plaxel 22ON-1) ■ Plaxel 22ON-
1100 parts HMDI 34 parts Preparation NCO
10H=2 Reaction near 0℃ 12 hours lever Cmer
, U” ・Peichi Curing time: Approximately 15 hours Properties after curing: Soft foam ■Plaxel 22ON-1100 parts TDI 35 parts Preparation NCO
/ OH = 2 Reaction at 60°C for 6 hours
:P Curing time: Approximately 4 hours Properties after curing: Soft foam Example 3゜1) Ethylene glycol initiation lactic acid-glycolic acid (1:
1) Copolymer 2 molecular weight 1600 (EG-P (LA-
Go-GA) 1600) EC-1) (LA-Co-GA
)1600 100 copies HMDI
42 parts preparation NGO10I+=2
Reaction: 80°C 6 hours - Imer LLL f' Curing time: Approximately 1 day Properties after curing: Hard foam 2) Glycerin-initiated lactic acid-glycolic acid (1:1) copolymer Molecular weight [800 (G-P (LA-Go-OA)1800) to -P(L
A-Co-A) 1800 100 copies HM
DI 37 part preparation NGO
/ OH = 2 reaction = 80 ° C. 6 hours J -- Official
L'-1111-m- Curing time: Approximately 1 day Properties after curing: Hard foam Example 4゜1) Polyethylene glycol molecular weight 400 starting lactic acid-prolactone (1:1) copolymer 2 molecular weight 200
J PEG400-P (CL-Go-LA) 200
0 ■ PEG40O-P (CL-Co-1, A) 2000
100 copies HMDI
34 parts charged NGO10H = 2 Reaction: 60°C 2
4 hours - two hours.

Curing time: Approximately 2 hours Properties after curing Rainbow-yellow and strong elastic foam ■40% PE
0-P (CL-Co-LA) 2000 100 parts TD1 35 parts Preparation NGO
10II=2 Reaction=60℃ 4 hours-j Upper JL
IY2J-゛.

Curing time: Approximately 30 minutes Properties after curing: Flexible and strong foamed elastic body PEG40
O-P (CL-Co-Otsu A) 2000
100 parts MDI
50 parts charged NCO10H=2 Reaction=60℃
4 hours・"-".

Curing time: Approximately 30 minutes Properties after curing: Flexible and strong foamed elastic body 2) Ethylene glycol initiated lactic acid-caprolactone (1:1) copolymer 9 Molecular weight 1300 EC-P (LA-Co-CL) 1
300 i 00 part HMDI
52 parts preparation NGO10H = 2
Reaction = 60°C 24 hours Example 5 Polyethylene glycol molecule JitlOOOO starting Polylactic acid 2 molecules test 2400 (PEG100O-PLA) 2400 ■ (PE(1,1000-PLA) 2400
100 parts TDI
29 parts preparation NGO10H=
2 Reaction: 60℃ 24 hours jut! J Uni 11 Engineering 1
L-"11 Lid L--Curing time: Approximately 30 minutes Properties after curing: Flexible foam (PEC1000-PLA) 2400 1
00 parts MDI 42 parts Charge NCO10H = 2 Reaction = 60°C 5 hours -1'' MBO I -L'jlULl ''' -
Curing time: Approximately 30 minutes Properties after curing: Flexible foam ■ (PEG100O-PLA) 2400
100 parts Hydrogenated MDI (manufactured by Sumitomo Bayer) 43 parts NCO10H = 2 Reaction = 60°C 8 hours IR: Soft foam The prepolymers of Examples 1) to 5) and amino groups at both ends were used to increase the curing speed of the prepolymer, and to further increase the diffusion of water into the polymer after curing and promote hydrolysis. Polyethylene glycol (PEG-ami
nc PEO-am
As inine, it has a molecular weight of 200.40 which is liquid at room temperature.
0. I used one from Boo. No matter which prepolymer is used, when stirring and mixing of the prepolymer and PEGam1ns is started, the viscosity increases instantly and changes to a gel-like elastic body within several tens of seconds. If you add PF: Gamine in an amount equal to or less than the isocyanate in the prepolymer, stir it, and then leave it in water, PEGam will initially form.
The viscosity increases due to the reaction between 1ns and incyanate, and the reaction with water causes foaming and hardening, resulting in a cured product with high elasticity.

Example 6゜100 parts of the prepolymer of Example 4-1)
,ni---IL-''IL Ln (L---m---
No ff1l Curing time: Increased viscosity with stirring Properties after curing Nigel-like viscoelastic body Example 7゜ Prepolymer of Example 6 100 parts - R''L
``Shi'', ``L''-5-LIJ-ilL good storage
- Curing time of L part: Viscosity increases at the same time as stirring.

Hardens in about 20 to 30 minutes Properties after hardening: Flexible elastic foam Table 1 [Effects of the invention] The biodegradable and absorbable urethane prepolymer of the present invention is
Since various curing speeds and flexibility can be imparted depending on the type of polymer and isocyanate combination used, it can be used not only for the conventional surgical adhesives α-cyanoacrylate and fibrin glue, but also for a wide range of other applications. It can be used for various purposes.

Furthermore, since it hardens in the presence of a trace amount of water, it is useful not only for the above-mentioned surgical applications but also for general industrial and household applications.

Patent Applicant Biomaterial Universe Co., Ltd. Representative Genjo Biodegradable and absorbable urethane prepolymer 3, relationship with the amended person case Patent applicant address: 43-15, Kurimachi, Higashikujo Minamimatsu, Minami-ku, Kyoto City, Specification subject to amendment 1, Specification, page 22 Add and correct "4. Brief explanation of the drawings" on line 12 as follows.

[Brief explanation of the drawing]

FIG. 1 is a graph showing the relationship between the type and amount of initiator added and the number average molecular weight of the produced polyhydroxy compound. FIG. 2 is a graph showing the relationship between the curing rate of the prepolymer and the incyanate and initiator (EG: PEG) used. FIG. 3 is a graph showing the relationship between the molecular weight of the polyhydroxy compound and the physical properties of the prepolymer after curing. ”

Claims (1)

[Claims] 1) A biodegradable and absorbable urethane prepolymer having an ester bond in the polymer chain. 2) The method according to claim 1, which is obtained by foaming and curing a low molecular weight polyhydroxyl compound having an ester bond in a polymer chain and a diisocyanate compound by reacting with moisture in a living body. Biodegradable and absorbable urethane prepolymer. 3) low molecular weight polylactic acid as a polyhydroxy compound,
Polyglycolic acid, poly-ε-caprolactone, lactic acid-
It is an aliphatic polyester of glycolic acid copolymer or lactic acid-ε-caprolacto copolymer, and the diisocyanate compound is hexamethylene diisocyanate, tolylene diisocyanate, diphenylmethalin isocyanate, or hydrogenated diphenyl diisocyanate. A biodegradable and absorbable urethane prepolymer according to claim 2. 4) Polyhydroxyl compounds with hydroxyl groups at both ends are
In the presence of glycerin, ethylene glycol, propylene glycol, polyethylene glycol, etc., using these polyhydric alcohols as initiators, lactide, glycolide, ε
- The biodegradable and absorbable urethane prepolymer according to claim 3, characterized in that a homopolymer or copolymer of caprolactone is synthesized. 5) A two-component fast-curing material produced by a reaction between the biodegradable and absorbable urethane prepolymer described in claims 1 to 4 and polyethylene glycol having amino groups at both ends.