JPH05279416A - Hydrophilic biodegradable polymer - Google Patents

Abstract

PURPOSE:To obtain a hydrophilic biodegradable polymer comprising a specific polymer by subjecting a carboxyl group of side chain of polymer to amide bond with a specific crosslinking agent, having safety in organism, providing an excellent biodegradable hydrogel membrane. CONSTITUTION:A hydrophilic biodegradable polymer which is an acidic amino acid (preferably L-amino acid) polymer or (meth) acrylic acid polymer wherein a carboxyl group of side chain of polymer is subjected to amide bond with diketopiperazine (crosslinking agent) of L-lysine and optionally subjected to amide bond or ester bond with a hydrophilic group donor (e.g. hydroxyalkylamine). The hydrophilic biodegradable polymer is useful as a membraneous organism material or a biodegradable hydrogel membrane. For example, an ester of an acidic amino acid polymer or an acrylic acid polymer is formed into a membrane, the membrane is reacted with diketopiperazine of L-lysine in a proper reaction solvent and optionally a hydrophilic donor, then the swollen membrane is dried to give a membranaceous organism material. In use, the membranaceous organism material is immersed in water, etc., to give a hydrogel membrane.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a hydrophilic biodegradable polymer and a membranous biomaterial made of the same, and more specifically to a polymer of acidic amino acid, a polymer of acrylic acid or a polymer of methacrylic acid. A hydrophilic biodegradable polymer having a carboxyl group of a polymer side chain and an diketopiperazine (crosslinking agent) of L-lysine and an amide bond and, if desired, an amide bond or an ester bond with a hydrophilic group donor. The present invention relates to molecules and membranous biomaterials composed of such hydrophilic biodegradable polymers.

[0002]

2. Description of the Related Art Synthetic polyamino acids, whose skeletal chains are composed of peptide bonds like natural proteins and collagen, are digested and absorbed in vivo by enzymatic action if they are given appropriate hydrophilicity. It has a peculiarity. In addition, it has been clarified so far that many synthetic polyamino acids do not show antigenicity in vivo and their decomposition products are not toxic, and their usefulness as so-called biodegradable and absorbable medical polymer materials is expected. Has been done. For example, sutures that do not require thread removal, artificial skin dermis component materials for burns and wounds, diaphragm material for adhesion prevention after surgery, thread removal hole filling material for haemostasis in dentistry, sustained release pharmaceutical polymer carrier material, treatment It is considered to be used as a polymer for chemically modifying an enzyme for use or as a blood substitute.

Of these applications, synthetic polyamino acids are suitable for use as membrane biomaterials such as artificial skin materials and diaphragm materials for preventing adhesions after surgery, while having appropriate hydrophilicity. It is preferably crosslinked with a crosslinking agent. As such a cross-linking agent, various organic diamine cross-linking agents such as ethylenediamine and octamethylenediamine are used, but in many cases, there is a concern that adverse effects such as toxicity may occur in vivo.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel hydrophilic biodegradable polymer which can be an excellent membranous biomaterial without the above-mentioned concerns.

[0005]

As a result of earnest research to solve the above-mentioned problems, the present inventor has found that as a diamine cross-linking agent, L-
By adopting a diketo compound composed of a dimer of lysine (L-lysine diketopiperazine (DKP)), the obtained polymer is safe in vivo, and the crosslinking agent itself undergoes enzymatic decomposition, Therefore, for example, it was found that a hydrogel membrane prepared from such a polymer is a biodegradable hydrogel membrane that can be water-solubilized after a suitable time has passed. Based on this, the present invention has been completed.

That is, the present invention is a polymer of acidic amino acid, a polymer of acrylic acid or a polymer of methacrylic acid, wherein the carboxyl group of the polymer side chain is amide-bonded with diketopiperazine (crosslinking agent) of L-lysine, It also relates to a hydrophilic biodegradable polymer having an amide bond or an ester bond with a hydrophilic group donor, and a membranous biomaterial comprising such a hydrophilic biodegradable polymer.

The present invention will be described in detail below.

The hydrophilic biodegradable polymer of the present invention is a novel substance.

Examples of acidic amino acids include glutamic acid and aspartic acid. Such acidic amino acid polymers may be not only homopolymers of acidic amine acids, but also copolymers of such acidic amino acids with other amino acids such as alanine. The weight average molecular weight of these polymers is preferably in the range of 1,000 to 500,000 from the viewpoint of moldability of the hydrogel film. The polymers of acrylic acid and methacrylic acid may be not only homopolymers thereof, but also copolymers with other vinyl monomers such as acrylamide. The weight average molecular weights of these polymers are from the same viewpoint.
It is preferably in the range of 3,000 to 500,000. In the case of a copolymer, the ratio of the other amino acid and the other vinyl monomer is 99.9 mol% or less, preferably 50 mol% or less from the same viewpoint.

The amount of DKP of L-lysine as a cross-linking agent contained in the hydrophilic biodegradable polymer of the present invention is preferably 0.1 to 10 mol% of the carboxyl group of the polymer side chain.

When a hydrophilic group donor is used to impart hydrophilicity to a polymer, the hydrophilic group donor has an amino group or a hydroxyl group capable of forming an amide bond or an ester bond with a carboxyl group of a polymer side chain. It is a saturated aliphatic substance having a hydrophilic group such as an amino group, a carboxyl group, and a mercapto group, which should have hydrophilicity. Needless to say, these substances must be safe when the hydrophilic polymer obtained when introduced into a polymer is used as a membranous biomaterial in humans and other animals.

In order to introduce DKP of L-lysine as a cross-linking agent and a hydrophilic group donor, for example, each ester of an acidic amino acid polymer, an acrylic acid polymer and a methacrylic acid polymer is used as a mother sample polymer, and a usual exchange reaction is carried out. It can be easily done by attaching.

As such a hydrophilic group donor, 2-
Mention may be made of hydroxyalkylamines such as amino-1-ethanol. Next, the present invention will be described by taking this as an example.

The DKP (crosslinking agent) and the hydroxyalkylamine (hydrophilic group donor) of L-lysine are amide-bonded to the carboxyl group of the polymer side chain. From a perspective 0.1: 99.9-1
It is preferably in the range of 0:90 (molar ratio). As will be described later, the ratio of the biodegradable polymer of the present invention can be controlled, for example, by adding poly (L-glutamic acid-γ-benzyl ester) to 2-amino-1-ethanol and L.
Since both lysine DKP and DKP are co-reacted, it can be performed by controlling the ratio of both during such synthesis.

The hydrophilic biodegradable polymer of the present invention is decomposed by an in vivo enzyme by cleavage of the diketopiperazine ring at the DKP portion of L-lysine which is a cross-linking agent. In addition, when the polymer is a polymer of amino acids, if this amino acid is an L-amino acid, its peptide bond is also hydrolyzed by an in vivo enzyme, so that biodegradability is increased.

The membranous biomaterial made of the hydrophilic biodegradable polymer of the present invention is decomposed and absorbed in vivo when it is used as an artificial skin or a diaphragm for preventing adhesion after surgery. Therefore, it will be understood that it is an extremely excellent biomaterial.

The hydrophilic biodegradable polymer of the present invention, the membranous biomaterial made of the same, and the biodegradable haloid gel membrane made of the same can be synthesized and prepared, for example, as follows. .. That is, in the case of an exchange reaction, an ester is used as the mother sample polymer, and its membrane is
In a suitable reaction solvent, DKP of L-lysine or DKP of L-lysine and a hydrophilic group donor are reacted. Then, the swollen membrane is dried to obtain a membranous biomaterial. When this is used as a biomaterial, it is immersed in water or an appropriate aqueous solution in advance to form a hydrogel film.

[0018]

EXAMPLES The present invention will be further described below with reference to examples.

Example 1 (Amino acid polymer) 300 mg of a dry film prepared by a casting method from a 3% by weight methylene chloride solution of poly (L-glutamic acid-γ-benzyl ester) (molecular weight 220,000) (50 × 50 × 0.
1-mm) 2-amino-1-ethanol 12.22 g (200 mM)
50% of L-lysine and DKP 0.512 g (4 mM)
It was immersed in an ethanol solution and reacted at 60 ° C. for 16 hours under gentle stirring.

The swollen membrane was immersed in ethanol, washed, and then dried under reduced pressure at room temperature to obtain a hydrophilic biodegradable polymer membrane. The side-chain complete substitution reaction was assayed by measuring the FT-IR spectrum and completely eliminating the peak due to the ester bond (1730 cm ^-1 ).

The dried film was immersed in a simulated body fluid (pH 7.4) to form a hydrogel film, which was stored as it was at 4 ° C. The equilibrium swelling degree q of the film was 11.0. For the simulated body fluid and the equilibrium swelling degree, see Example 2.

Example 2 (Amino Acid Polymer) According to the method of Example 1, poly (L-glutamic acid-γ-benzyl ester) (PBL was used as a mother sample polymer.
G) or poly (D-glutamic acid-γ-benzyl ester) (PBDG) is used, and this dry film (50 × 50
X 0.1 mm) was reacted with 2-amino-1-ethanol (E) and L-lysine DKP (invention) as a cross-linking agent or octamethylene diamine (OMDA) for comparison at a ratio shown in Table 1 to give 9 Two kinds of hydrophilic biodegradable polymer membranes were prepared. The amounts of 2-amino-1-ethanol and the cross-linking agent used were a large excess with respect to the mother sample polymer, and they were used as a 50% ethanol solution. The complete substitution reaction of the side chain of 2-amino-1-ethanol and L-lysine with DKP is
The infrared absorption spectrum of the reaction product was measured and confirmed by the complete disappearance of the peak (1730 cm ⁻¹ ) of the ester bond, as in Example 1.

[0023]

[Table 1]

Table 1 also shows the swelling degree q of each hydrophilic biodegradable polymer film.

Here, the degree of swelling is determined in consideration of in vivo conditions.
0.03M NaHCO ₃ , 0.002MK ₂ HPO ₄ , 0.12M
It was measured and calculated using a simulated body fluid (PECF) having a composition of an aqueous solution of NaCl and 0.003 M KCl. That is, the weight (Ww and Wd) of the polymer membrane at the time of absorbing water and drying at 37 ° C. was measured, and PECF was calculated from the following equation.
The equilibrium swelling degree q was calculated.

[0026]

[Equation 1]

Example 3 (amino acid polymer) The hydrophilic biodegradable polymer membrane (B) obtained in Example 2,
(C), (G) and (H) were examined for in vitro enzymatic degradability.

That is, 0.01 M L-cystine and 0.
PECF containing 02M EDTA, under biological conditions (37 ℃,
Each test piece was immersed in pH 7.4 and papain 0.5 mg / ml), and the enzymatic degradation state by papain was measured by the weight decrease of the hydrogel film and the time change of the swelling degree.

More specifically, DF Williams conducted research on various proteases produced at the wound site, and among the proteases produced at the inflammatory site, as a protease that strongly decomposes polyamino acids, endopeptidase It is pointed out that there are cathepsin B as an example, carboxypeptidase as an exopeptidase, and leucine aminopeptidase.
(J. Bioeng., 1, 279 (1977), in this test, papain, which is a plant-derived thiol-type endopeptidase, was selected as an enzyme exhibiting a polyamino acid hydrolysis behavior similar to cathepsin B. In the in vitro enzymatic degradation experiment, the dry weight of the sample membrane (test piece) for which the q value was determined in advance was weighed (initial dry weight Wo), and 0.5 m under in vivo conditions.
Immersing in PECF containing papain at a concentration of g / ml, taking out the sample membrane after each predetermined time while gently stirring at a constant speed, weighing the membrane after washing and drying (remaining solid content dry weight Wr), and remaining The film weight ratio s was calculated from the following equation.

[0030]

[Equation 2]

The q value (swelling degree) after each predetermined time was also measured by a separate parallel experiment.

Table 2 shows the measured values of the degree of swelling and the weight of the remaining sample film after the elapse of a predetermined time for various film samples.

[0033]

[Table 2]

From Table 2, the dependency of the swelling degree (q) of the membrane and the residual film weight ratio (s) on the decomposition time in the papain decomposition process can be seen. When this is described in detail, as can be seen from the data on the test pieces (B) and (C), in the poly-L-amino acid hydrogel, the polymer main chain is also hydrolyzed by papain, so that the decomposition also occurs in the OMDA crosslinked film. Although progressing, the increase in the swelling degree of the membrane due to the decomposition is slower than that of the L-lysine DKP crosslinked membrane. In contrast, as can be seen from the data for (G) and (H), poly-D-amino acid hydrogels, as expected, because the polymer backbone is not hydrolyzed by papain,
The OMDA cross-linked membrane showed no change, but L-lysine D
In the KP cross-linked membrane, the degree of swelling of the membrane first increases with the passage of time, and when the decomposition progresses to some extent, the polymer chains are detached and water-solubilization occurs, and the weight of the membrane decreases. It is considered that this is because the portion of DKP is hydrolyzed by the action of papain.

Example 4 (Acrylic acid polymer) Adhesive film (50 × 50 × 0.2 mm) (580 m) cast from an acetone solution of polymethyl acrylate (molecular weight 100,000)
g) is immersed in a mixed solution of 2-amino-1-ethanol 24.5 g (400 mM) and DKP 0.512 g (4 mM), and 60
The reaction was carried out at ℃ for 24 hours.

The swollen film thus obtained was washed with ethanol and dried, and then the sample was put into a simulated body fluid (PECF) to prepare a papain.
Treated at 0.5% by weight. After 24 hours, the hydrogel film became completely water-soluble.

As described above, when the biodegradable and absorbable hydrogel membrane was molecularly designed, it was clarified that the required degree of swelling was obtained and the rate of enzymatic degradation could be controlled by selecting the degree of crosslinking. ..

[0038]

EFFECTS OF THE INVENTION According to the present invention, a novel excellent raw material which is safe in vivo and can be used as a material for a hydrogel film which is hydrolyzed after a suitable time has elapsed due to enzymatic decomposition of the crosslinking agent itself. A degradable polymeric material has been provided.

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Claims (5)

[Claims] 1. A hydrophilic amino acid polymer, acrylic acid polymer or methacrylic acid polymer, wherein the carboxyl group of the polymer side chain forms an amide bond with diketopiperazine (crosslinking agent) of L-lysine. Biodegradable polymer. 2. The hydrophilic biodegradable polymer according to claim 1, wherein a part of the carboxyl group of the side chain of the polymer is amide- or ester-bonded with the hydrophilic group donor. 3. The amino acid is an L-amino acid.
Or the hydrophilic biodegradable polymer described in 2. 4. A membranous biomaterial comprising the hydrophilic biodegradable polymer according to claim 1. 5. A biodegradable hydrogel film made of the membranous biomaterial according to claim 4.