JPH01283228A - Biodegradable sustained release material - Google Patents

Abstract

PURPOSE:To obtain the title material containing an amino acid polymer containing aspartic acid as a constituent amino acid and capable of arbitrarily controlling a rate of decomposition by a biological enzyme. CONSTITUTION:A biodegradable sustained release material containing a water soluble amino acid polymer containing aspartic acid as a constituent amino acid and having preferably 1,000-1000,000, especially 3,000-300,000 molecular weight. The decomposition rate can be arbitrarily controlled (since increase of aspartic acid content retards the decomposition) by changing the composition of aspartic acid acid in a constituent amino acid for the above-mentioned polymer. In the above-mentioned polymer, uses as a carrier for sustained release of medical enzyme preparation, modifier for preventing side effects and antigen, artificial skin, raw material for wound covering agent and carrier for cell culture are expected.

Description

Detailed Description of the Invention (Field of Industrial Application) The present BA relates to novel biodegradable sustained release materials, such as assemblies for sustained release of pharmaceutical enzyme preparations, modified materials for preventing side effects of medicines and antigens, artificial skin, etc. It is expected to provide materials for wound dressings and cell culture carriers.

(Prior Art) Amino acids are constituents of tannins, which are the constituents of living organisms, and are substances that are highly compatible with living organisms and are highly safe. Therefore, progress is being made to make it into a polymer and use it as a biomaterial.

Among amino acids, glutamic acid is 1) inexpensive, 2) easily polymerized, and easily made to have a high molecular weight. In addition, the obtained polyglutamic acid is 1) water-soluble; 2) the polymer structure (
(from α-helical structure to β-zigzag random coil structure) changes reversibly. ■Advantages such as the ability of the γ-position of the side chain to chemically support various active substances on the xyl group), (References G, F, Rowland, 5ta)
l, Naturs+ (London), 255,4
87 (1975)) Awarded the award.

Water-soluble polyamino acids containing glutamic acid are decomposed extremely rapidly by enzymes, and it is difficult to provide them with sustained decomposition and release properties that suit the purpose and application (such as medical applications that require relatively slow degradability). As a method of slowing down the enzymatic decomposition of polyglutamic acid, there is a method of esterifying or amidating the carboxyl group at the γ-position of the side chain. however,
As a result, water solubility is lost or the original function is diminished, making it unsuitable as a biodegradable sustained release water-soluble polyamino acid (Reference T, Hayashl atal, So
n-IGakkml-ski, 44.59 (1988
) ).

(Problems to be Solved by the Invention) It is desired to develop a practical water-soluble amino acid polymer that can be used as a biomaterial and whose decomposition rate by enzymes can be arbitrarily controlled in the living body.

(Means for Solving the Problems) The present inventors have made extensive studies to solve the above problems, and have found that polyamino acids containing aspartic acid as constituent amino acids have a slow decomposition rate due to the substrate specificity of enzymes in living organisms. Furthermore, the inventors have discovered that the decomposition rate of water-soluble polyamino acids can be arbitrarily controlled by changing the composition of aspartic acid among the constituent amino acids, and have completed the present invention based on this discovery.

The polyamino acid used in the present invention may be any one as long as it is water-soluble and contains aspartic acid as a constituent amino acid.

The molecular weight is not particularly limited, but is 3.000 to io, o, ooo in terms of decomposition rate V and in vivo stability.

Good condition. The constituent amino acids are preferably L-units because they occur naturally.

Constituent amino acids include acidic amino acids such as glutamic acid, neutral amino acids such as alanine, basic amino acids such as lysine and arginine, synthetic amino acids such as methionine and cysteine, aromatic amino acids such as phenylalanine, and cyclic amino acids such as zoroline. Can be adopted. The polyamino acid used in the present invention has an ether or an ether in its main chain.
Ingredients with ester, urethane bonds, etc.! It also includes those obtained by lock copolymerization or the like.

When polyamino acids are used as the sustained release material of the present invention, they can be used, for example, in the form of powder, aqueous solution, or hydrogel obtained by treating the aqueous solution with a suitable crosslinking agent such as diamine. However, the state and shape can be arbitrarily selected depending on the purpose of use.

(Example) Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 14! Preparation of poly-L-asnocragic acid Preparation of L-7 sunocragic acid β-benzyl ester Recrystallized MA-NCA 5 # was mixed with triethylamine (IAO equivalent) as a polymerization initiator and dioxane as a solvent. Poly-β-benzyl-L-aspartate (hereinafter abbreviated as "pnLAJ") 4I was obtained by carrying out a polymerization reaction at room temperature using 50 ml of a 1:1 mixed solution of 1:1 and acetonitrile.

By the trifluoromethanesulfonic acid method (method of treating with a mixed solution of 1.31 d of trifluoromethanesulfonic acid and 1.gmJ of thioanisole, 0.2N of m-cresol, and 121111 of trifluoroacetic acid), the nine PBLA obtained above was heated to 0°C. Poly L-
Asuno's mother Ugin! ! (hereinafter abbreviated as "PLAA") was obtained at 1.99. Molecular weight: 16,600 (for ultracentrifugation, I
Preparation of poly L-glutamic acid with a weight average molecular weight determined from the sedimentation equilibrium method using L-glutamic acid-γ-benzyl ester 20I as a starting material. BoIJ-L-glutamine M2.1N was obtained in the same manner as in the above ①. . Weight average molecule ji: 48,8
00 θCobo lJ, -L-asnoglagine l#/-Production of L-glutamic acid L-aspartic acid-β-benzyl ester NCA 2
．． Oli, BA-NCA and glutamic acid-γ-benzyl ester NCA O,, 6-2.4 N tof
A polymerization reaction was carried out in the same manner as in (1) above to produce the desired copolymer.

CC-AC-50> has a molar ratio of 1/1, and 2. Got O.J.

(c-80-75) was 1.99 at 75 moles for Asuno and Ragin Kai.

Example 2 Enzymatic Decomposition 50m9 of the polyamino acid produced in Example 1 was dissolved in 10ml of phosphate buffer (0.1M). As enzymes, ficin 2m9 or Noyanoyain 2In9 (cysteine and EDTA in 1 mJ phosphoric acid solution were 0 and 04, respectively).
Contains mmol. ) was added and slowly stirred at 370°C to determine the viscosity over time and track the decrease in molecular weight.The time until the molecular weight decreased to -2 was measured, and the reciprocal of that time was defined as the decomposition rate (V).

Table 1 and FIG. 1 show the experimental results for ficin, and Table 2 and FIG. 2 show the experimental results for papain.

As is clear from this result, polyamino acids with a high content of aspartic acid are degraded slowly by enzymes.

(Effects of the Invention) As is clear from the above, the present invention allows the decomposition rate of a water-soluble amino acid polymer obtained by using aspartic acid as a part of its constituent amino acids to be arbitrarily controlled by living enzymes. The present invention is extremely useful in this regard.

[Brief explanation of the drawing]

The results of the decomposition experiment using ficin in Example 2 were
The results of a decomposition experiment using /'P/4'in are shown in Figure 2.

Claims (5)

[Claims] (1) A biodegradable sustained-release material characterized by containing an amino acid polymer containing aspartic acid as a constituent amino acid. (2) The material according to claim 1, wherein the amino acid polymer is water-soluble. (3) The molecular weight of the amino acid polymer is 1,000 to 1,0
2. The material of claim 1, wherein the material is 0.00,000. (4) The material according to claim 1, wherein the constituent amino acids are L-form. (5) The material according to claim 1, wherein the amino acid polymer contains aspartic acid and glutamic acid as constituent amino acids.