JPS58105758A - Anti-thrombotic material having gas permeability - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] This invention relates to an antithrombotic gas permeable membrane.

Unlike ordinary polymers, which are single-phase, kraft copolymers are multi-phase polymers that have a microscopic multi-phase structure. Depending on the mechanical properties of the material, we can expect the development of multiphase materials with new multifaceted functions.

A graft copolymer in which two types of polymer chains of different nature (for example, hydrophilic and hydrophobic) are linked undergoes phase separation during the process of forming a film from a solution, resulting in a film having a non-uniform surface structure. It is thought that such a heterogeneous surface structure is involved in blood coagulation through selective adsorption and activation of blood proteins, and adhesion and deformation of platelets.

Furthermore, depending on the properties of the component polymers and the regularity of their higher-order structures, they can selectively permeate gases such as oxygen and carbon dioxide, promote the permeation of water and alcohols, and We have conducted extensive research to obtain a heterogeneous polymer that is expected to have selective plugging properties and selective permeability for solutes, and we have found that a graft copolymer consisting of a polydimethylsiloxane trunk and poly(α-amino acid) branches has excellent antithrombotic properties. The inventors have discovered that a membrane material that is transparent and oxygen permeable can be provided, and the present invention has been completed.

That is, an object of the present invention is to provide an antithrombotic material having excellent oxygen permeability, and the gist thereof is that α- The present invention is an oxygen-permeable antithrombotic material whose main component is a graft copolymer obtained by graft copolymerizing amino acid N-carboxylic anhydride.

The present invention will be explained in detail below.

(1) Synthesis of kraft copolymer consisting of polydimethylsiloxane@) and poly(α-amino acid)@0 Polydimethylsiloxane (hereinafter abbreviated as FDMS) is used as the backbone polymer, and poly(α-amino acid) The graft copolymer used as the branch polymer is produced and sold by α-Ami Co., Ltd. using PDMS in which some of the methyl groups are replaced with 3-aminopropyl groups, that is, amino side chain PDMEI as an initiator. There is a commercially available product which has a number average of 2 per polymer chain as determined by GPO.

Therefore, the structure of the amino side chain FDMS is as follows.

ffi In the above formula, X
It is thought that it is synthesized by reacting K-aminopropylmethyljethoxysilane in the presence of an alkali catalyst.

Next, α-amino acid N using amino side chain FDMS as an initiator
A graft copolymer with a microheterogeneous structure was produced by polymerizing OA.

Production Example 1 In this example, the above amine side dFDMS was used as the initiator polymer, α-amino acid 3- was added, and the internal solution was added (LYS (ZI NOA concentration is 0.3 M)) and carefully shaken. Mix.

Methylene chloride can also be used as a polymerization solvent. When this occurred, bubbles were immediately generated from the liquid surface, and decarboxylation residue was observed to be occurring. This was polymerized in a desiccator for several hours.

Thereafter, the solvent, tetrahydrofuran, was distilled off, concentrated, and added to ether to produce a white precipitate. This precipitate was extracted with ether and divided into a soluble fraction of 0.39 and an insoluble fraction of 2.377.

According to the engineering R spectrum, the ether soluble content is mostly F.
DMS and was found to contain a small amount of poly(α-amino acid).

On the other hand, although the ether-insoluble content consists of the desired graft copolymer, it cannot be excluded that it may contain a very small amount of poly(LYS(2)).

Yield: %.

Figure 1 shows the measurement results obtained by forming a film from a solution on a KBr plate.

The symbols A to F in the figure indicate the following.

D(tAtrscx-') Urethane0=0 Absorption part due to stretching vibration 'll1Ctt41ocrn-') Amide C=0 (amide■) Absorption part due to stretching vibration 'g(l
j da0ctn''''1) Amide 0 = 0 (amide ■) Absorption part due to stretching vibration The structure of this graft copolymer is as follows based on the signal intensity ratio by NMR measurement of a trifluoroacetic acid solution. Presumed.

/Tゝ←-7 In the above formula, X+7=4!4 Cholera FDMS -(LYE(Zl), expressed as 27.

Preparation Example In this example, the above amino side chain FD was used as the initiator polymer.
Using MS, γ-benzy-L-glutamate NOA [hereinafter referred to as Glu(0m1)N] was used as α-amino acid NOA.
[abbreviated as OA] was used for graft copolymerization.

The above amino side chains FDMS/, 0 Zl and Glu (0
Tetrahydrofuran can also be used to dissolve M1) and Δ0AjII in the polymerization solvent methylene chloride).
After adding the inner solution (the concentration θ of Glu (OBZI)NCA was 3M) and stirring carefully, the mixture was left in a desiccator for 1 hour to polymerize.

The product was separated by the same operation as described in Production Example 1, and the ether soluble components o, z g and the insoluble components '1. A Ji'
I got it. Although the ether-insoluble portion consists of a graft copolymer, the possibility that it contains a very small amount of poIJ (G'1u(OBZI)) cannot be excluded.

Yield t 9.7%.

The IR spectrum of the ether fraction (1111 constant) obtained by forming a film on a KBr plate from a methylene chloride solution is shown in FIG.

The symbols A to F in the figure indicate the following.

DCt't2ocm-') Absorption part due to ester O=O stretching vibration BCtb4toctn-1) Amide C=
0 (amide I) Absorption part y (isyoo
r”) Amide 0=Q (7mid II) The structure of this graft copolymer, which is an absorption part due to stretching vibration, is as follows based on the intensity ratio of the jig length by NMR measurement of a trifluoroacetic acid solution. It is estimated that there is.

H /+\ Q=Q H 16 In the above formula, x+y=4I4 This is F D M S - (Glu(OBZI))74
It is expressed as

Production Example 3 Amino side chain FDMS/, 9 and sarcosine 10A (hereinafter B
abbreviated as arNOA)i,! Dissolve each rfl in methylene chloride (tetrahydrofuran can also be used) as a polymerization solvent (the concentration of BarNOA is 0.1M), carefully shake it, and then dissolve it in a desiccator for 7 hours.
It was left to stand for 1 hour to polymerize.

The product was separated by the same operation as described in Production Example 1 to obtain an ether soluble fraction of 0.079 and an insoluble fraction t, ti.

Although the ether-insoluble portion consists of a kraft copolymer, it cannot be ruled out that it may contain a very small amount of poly(Sa). Yield: 9t%.

The IR spectrum of the ether-insoluble component (measured by forming a film on a KBr plate from a methylene chloride solution) is shown in FIG.

The symbols A to D in the figure indicate the following.

B (/θ00-110000-1l00-0-8i-stretching vibration K yo7) absorption part, ``/O (gooan-'') -st -OH, absorption part by bending vibration ζ D (/group jjclL-') The structure of this graft copolymer is calculated from the molar concentration ratio of 13ar N OA used in the polymerization and the amino side chain PDMB, and is as follows. Presumed.

N.H. 7+\ C=0 H2 ■ -Ms \ten +, 1 In the above formula, X+7=i This is expressed as PDM5-(ear)g3.

The degree of polymerization of the branched poly(α-amino acid) is the amino side chain FDM
S α-゛・1. relative to the amine concentration of the initiator. Manufacturing example 1
．． ．． When the grafted electrolyte two-layer body obtained in 2.3 was formed into a film from a dimethylpolamide solution, a transparent, flexible and strong film was obtained.

PDMS and poly('LY5(Z)) and poly(G
The graft copolymer film of '1u (OBzl)] is stable even when immersed in water, but the graft copolymer film of PDMS and poly(ear) is water absorbent and swells significantly when immersed in water. However, the original shape is damaged.

Examples of α-amino acids that can be used in producing the graft copolymer include alanine, glutamic acid γ-alkyl ester, aspartic acid β-alkyl ester, glycine, leucine, isoleucine, norleucine, ε-carbobenzoxy II sine, γ -carbobenzoxyornithine, phenylalanine, 0-benzylserine, valine,
Norvaline, proline, sarcosine, etc. can be mentioned.

Moreover, both optically active forms and racemic forms thereof can be used for one-time use.

After the simultaneous addition of one kind of α-amino acid NOA, the first α-abanoic acid IOA is added. 2. One type of α-amino acid arranged in a block is obtained.

Next, an example of manufacturing such a graft coelectric composite will be described.

Production Example In this example, the above amino side chain P' was used as the initiator polymer.
Using DMS, 5ar as α-amino acid IOA
Graft polymerization is performed using NO and A, followed by G.
Grafting was performed by adding lu(OBzl) N OA.

Amino side chain PDMB/, 0/i and Sar N OA/
,,! ig was dissolved in methylene chloride (tetrahydrofuran can also be used) as a polymerization solvent, and the sub-solution was added (the concentration of SarNOA was set to (17, ? M)), carefully shaken, and left in a desiccator for about 72 hours. It was left to polymerize.

After that, add a methylene chloride solution of a1u(oBzl)t,o g so that the concentration of Glu(oBzl)NOA is about 0, /j M. After stirring carefully,
−・.

・) Produced by the same operation as described in Production Example/14
- Separate the substances, ether soluble part 0.317 and insoluble part λ
I got it. The ether-insoluble content consists of a graft copolymer, and the results were measured by forming a film on a KBr plate from a main solution containing very small amounts of α-amino acid homopolymers and copolymers.

The symbols A to G in the figure indicate the following.

C(za θ0 (jn-') -8i -0H3 Absorption part D (172θcIn-1) ester 0-
0 Absorption part K due to stretching vibration (#+0c1n-')
Glu (OBzl) residue amide a=o (7 mid ■)
Absorption part due to stretching vibration 1Ctsyo'cm-' ) Amide c=o of Glu (OBzl) residue (7 mid ■) Absorption part G due to stretching vibration (/A5jcIn-') Amide 0 of Sar residue
The structure of this graft copolymer has an ash-like structure, calculated from the molar concentration ratio of Glu(OBzl)NOA, BarNOA, and amino side chain PDMS used in the polymerization. It is estimated that

H / dimension h C=O H2 -Me In the above formula, x y = /I4 This is expressed as p D M s - (sa, r%t-(olu
oBZl))/,? It is expressed as

When the above graft copolymer is formed into a film from a dimethylformamide solution, it swells to some extent when immersed in clear, flexible, and strong water, but it swells violently like the graft copolymer of FDMS and polysarcosine described in Production Example 3. It will not lose its shape.

By grafting -yuzu poly(α-amino acid) in this manner, a membrane having appropriate hydrophilicity can be produced.

(1i) Graft copolymer poly(α-amino acid)
The graft copolymer synthesized in modified production example 1 of
In addition, the kraft copolymer synthesized in Production Example 2 and G contains Glu
(OBzl) polymers can be induced into structures.

The reaction equation for this process is as follows.

15- Glu(OBzl) Glu can be synthesized.

Examples of such reactions are described below.

Reaction example! 21i! ! Graft copolymer pDMB-(Lys(Zl)2DO) synthesized according to the method of Preparation Example 1
，! Dissolve r i in 16-dimethylformamide/Omj and dilute with 23% HBr/AOO.
10 ml of H was added and stirred at room temperature for 2 hours.

After concentrating the solution, the resulting oil was well-tented with ether, and the volatile components were distilled off again.
Addition of H gave a white material.

This was washed with methanol and dried.

The pressure spectrum (KBr tablet method) of the reaction product is shown in Figure S.

Compared to the engineering R spectrum before the reaction (Figure 81), the absorption is weaker based on the urethane bond of /Aza, td' and the benzene ring of 70θcTn-', and Lys (
It can be seen that the Zi residue was converted to the L78 residue.

The structure of the reaction product is considered to be as follows: 0 1 0H-(OH,), -NHl ■ φ 0 In the above formula, Polymer FDMS-(Glu-(OBzl))/? (The IR spectrum is the first time or the upper part of Figure 6) o, q g is 11
Dissolve in 0ml dimethylformamide / N N
a OHII ml was added and stirred at room temperature for 5 minutes.

The precipitated white substance was separated, washed with methanol, bottled, and dried. R spectrum of reaction product 1 (KBr
Tablet method) is shown in the middle row of Figure 6.

Compared to the engineering R spectrum before reaction / 7.20cm-
Based on the ester group of '(absorption) and based on the benzene ring of ?00 cm-''(absorption disappears and instead of
Absorption based on the symmetrical stretching vibration of the carboxylade group appeared near l. In the above formula of the reaction product in this state,
The 10y-group is expressed as FDMS-(Glu(ONa))/q.

Subsequently, water was added to the reaction mixture, and then washed with /N hydrochloric acid and dried. Technique R spectrum of reaction product
7. The power is strong.

Q=Q NHO '+' The above formula represents C: x +y = DMS - (Glu(OH))/?

A thin hydrophilic layer can be applied to the surface.

An example of surface modification by a heterogeneous reaction of a membrane is described below.

Reaction Example 3 A graft copolymer FDMS-(Glu(OBZI)) synthesized according to the method of Production Example- was immersed in a mixed solution of dimethyl and methanol/jOmj.
The membrane was removed at regular intervals and the attenuated total reflectance (ATR) spectrum was measured to track the reaction.

FIG. 7 shows the ATR-R spectrum. The middle diagram shows the ATR-■R spectrum after immersion in the above alkaline bath for 0 minutes, but compared to the spectrum of the reaction book in the upper diagram, there is a symmetrical stretching vibration of the carboxylate group near the varnish of 1720 ctn''1. Based on (absorption appeared. The surface structure of the film in this state is F D M S -(Glu(ONa)
]J is considered to be a t-tracing.

Next, apply a 10% citric acid aqueous solution to the membrane! It was immersed in a mixed solution of r Orni and butanol isomi and left for -0 minutes. The ATR-IR spectrum of the film thus obtained is shown in the lower part of FIG. 300cm
Broad absorption based on the stretching vibration of the carboxylic acid hydroxyl group appears in the vicinity of 41 o o tri-1 and 41 o o tri-1. Therefore, the surface structure of the membrane in this state is F D
It is thought to be M S -(Glu(OH))J4'.

匝) Polydimethylsiloxane
When a graft copolymer consisting of -amino acid)@ is formed from a solution onto a glass plate, non-uniformity in the longitudinal distribution of A blocks and hydrophilic blocks may occur in the completed film. That is, the membrane is an asymmetric membrane.

Measurement Example 1 Graft copolymer PDM prepared by the method of Production Example
El-(Glu(oBzl)) cog was dissolved in dimethylformamide and cast onto a glass plate, and the solvent was slowly evaporated to form a film. The film was peeled off from the glass plate, and the compositions of the air side surface and the glass side surface (7) were measured by the A'l'R-■R method.

As the characteristic absorption of the FDMS segment, the absorption intensity of g 00 catl of the bending vibration of the 51-Mθ bond is calculated using poly[G
lu(OBzl)] as the characteristic absorption of the segment / 4
The absorption intensity of the absorption band of amide (2) of j Oart-' was taken as 1, and the ratio of both components was evaluated using the ratio of 2. Z on the air side of the membrane is 33, and Z on the glass side of the membrane is 2.67, indicating that when a kraft copolymer is formed into a membrane, more FDMS segments gather on the glass side than on the air side. That is, an asymmetric membrane can be prepared from a graft copolymer synthesized by the method shown in Production Example 2 by forming a membrane from a dimethylformamide solution.

□ Hydrophobic PDMEI ((b) and hydrophilic poly(α)
In a graft copolymer consisting of (amino acid)@, the compatibility of both segments is low, so when forming a film by distilling off the solvent from the solution, intramolecular micelles are first formed as the sample concentration increases, Subsequently, intermolecular micelles are formed, and the micelle structure, that is, the phase-separated structure is maintained in the solid phase even after film formation. Therefore, the formed film may have a heterogeneous surface structure (domain structure), which can be seen in transmission electron micrographs (TxM).
can be researched.

Measurement Example - Graft copolymer P synthesized by the method of Production Example 1
M 8-(Lye(Z) Difference 7 and FDMS-(Ly
A z% dimethylformamide solution of s (Z) .

In the photograph, the FDMS segment with high electron density appears black, and the poly(α-amino acid) segment appears white. Both graft copolymers exhibited a clear seabird structure, and the development of a domain structure accompanied by microphase separation was observed.

F D M S -(Lys(Z)) In J7, poly(L
7i1(Zl)-1! Since the craft is short, there are many black parts, whereas P D M B - (Lys (21
)j/TIIM, the ratio of black and white parts is y
They were equal.

As shown by TEM, the hydrophobic 24-PDM8@) and the hydrophilic poly(Lys(Z)
)(e) (D/5) By synthesizing a 5-ft copolymer, it is possible to prepare a superficially heterogeneous membrane with a developed domain structure due to microphase separation.Also, by changing the composition of the graft copolymer, By this, the domain structure of the membrane can be adjusted.

(■ Antithrombotic properties of the graft copolymer of polydimethylsiloxane (Co., Ltd.) and poly(α-amino acid) @) Antithrombotic properties of the graft copolymer of the present invention and FDMS and α-amino acid pomopolymer for comparison therewith The results of measuring gender are shown below.

In this test, FDMS is applied as it is to the surface of the watch, and the others are first dissolved in dimethylformamide solvent (each sample 3θoroy is dissolved in dimethylformamide solvent to prepare a test sample, and the above members). Reaction Example 3 The samples whose surfaces were modified after film formation as shown in 2 were subjected to the antithrombotic test as they were.

Furthermore, for comparison, weight/! without any treatment.
30 ml of blood was taken from the femoral artery of r Kp ).
! mJ of AOD solution (liquid consisting of citric acid, sodium citrate, and glucose) was added, and this was O6-
mt was poured onto each sample prepared on the watch glass as described above, and 0. /M calcium chloride aqueous solution 0
．． 0; trU is added to initiate clotting. set,
At each time point, distilled water is added to stop the clot, and the formed thrombus is fixed in formalin and replaced with distilled water. Remove the wet clot with a spatula, place it between tissue paper to absorb excess water, and weigh.

100% clot weight after <r minutes when using glass
The thrombus formation rate was compared based on the relative weight %.

Homopolymers such as FDMS and poly[Glu(oBzl)] exhibit better antithrombotic properties than glass.

However, their graft copolymers, i.e. (Al
, fB) and (0) are found to have even more severe antithrombotic properties than the homopolymer.

Among graft copolymers with different compositions, the one in which the chain length of the poly[Glu(OBzl)] branch polymer is neither too long nor too short compared to the chain length of the FDMS trunk polymer has the best antithrombotic properties. It can be seen that it shows gender.

Test Example In this example, a graft copolymer of PDMS and poly(Lys(Z)) was tested for antithrombotic properties.

It exhibits better antithrombotic properties than dimethylsiloxane or L7θ(Z) homopolymer glass.

However, their kraft copolymers (Dl
, (lii) and f'E'l have even better antithrombotic properties than the homopolymer.
Among the 1g of kraft copolymers, those whose chain length of the poly[LysfZl] branched polymer is neither too long nor too short relative to the chain length of the PDM B backbone polymer have the best antithrombotic properties. I understand what is shown.

Test Example 3 In this example, a graft copolymer of FDMS and poly(Bar), and a graft copolymer of FDMS, poly(Sar), and poly(Gl) were used.
A tertiary graft copolymer of u(OBzl) was tested for antithrombotic properties.

The graft copolymer of FDMS and poly(8ar) showed better antithrombotic properties than the homopolymer FDMS, and F D
It is comparable to the M5-(Glu(OBzl))n graft copolymer. A ternary graft copolymer in which a block copolymer of poly(Sar) and poly(Glu(OBZI)) is bonded to a PDM8 backbone polymer as a branch polymer has better antithrombotic properties than a Yu-based graft copolymer. I understand what is shown.

Test Example In this example, F D M S @ whose surface was modified according to the method of Reaction Example 3 of (IL) and poly(Glu(oBgl)
))(N-graft copolymers were tested for antithrombotic properties.

Although graft copolymers have been shown to exhibit better antithrombotic properties than their respective homopolymers, poly(
It was shown that when the side chain of the Glu (OBZl) segment was hydrolyzed, the antithrombotic properties were further improved.

(71) Oxygen permeability of a graft copolymer consisting of polydimethylsiloxane (Co., Ltd.) and poly(α-amino acid Co., Ltd.) Polydimethylsiloxane is porous, and its general gas permeability, especially oxygen permeability, is extremely low. It is used as a material for artificial lungs.

However, selectivity depending on the type of gas is low. Even when poly(α-amino acid) is used as hydrophobic FDMS, it is desirable to maintain oxygen permeability at a certain level.

Here, FDM synthesized by the method of Production Example 1 or -
S and poly(LygFl, l or poly((nu(OB
The oxygen permeability of the graft copolymer of zl)) was measured and compared with the oxygen permeability of various synthetic polymer membranes. An ethylcellulose film in which erythrosine, a dye that excites oxygen with light of an appropriate wavelength, and dimethylanthracene, an acceptor that reacts with excited doublet oxygen, was sandwiched between sample films to be measured and examined.

Membrane oxygen permeability coefficient at (8T P ), am x
toio/cd, sea-crnHy (J
? °C) Segmented polyaminoether urethane l Urea'1. ．． 20 (Bz1tl quaternization) FDMS
604. 'IPDMS-(Lys(Z)
), 7.7? ! r, t C29℃) Poly(Lys(Z)) o, θt
.

FDMS-(Glu(oBzl))/? / t it,
7FDMS-(elu(oBzl)), u,
? t,, sFDMS-(Glu(OBzl))jf
f 2 A, /FDMS-(Glu(OBzl
)97:1.9035-FDMS-(Glu(OBZ'l))/llA
O, the3FDMS-(Glu(OBzl))l
O,7A poly(elu(onzl))
o,s,iPDMS has a high oxygen permeability at extreme pressures, and poly(α-amino acid) has a very low oxygen permeability.

FDM8 (trunk) with poly(Lys(Z)) and poly(G)
It was revealed that when lu(onzl)) was grafted as a branched polymer, the oxygen permeability decreased, and that the oxygen permeability could be controlled by adjusting the composition of the graft copolymer.

The oxygen permeability of graft copolymers with short poly(α-amino acid) branches is considerably greater.

The reason why the graft copolymer of the present invention exhibits excellent antithrombotic properties as described above is due to the crystallinity of the poly(α-amino acid) block.
Hydrophilicity, rigidity and FDMS block quality, hydrophobicity,
This is thought to be due to the development of a domain structure that produces a microphase-separated structure based on flexibility, and these structures activate and organize blood platelets through selective interaction with blood proteins. It is thought that it controls the promotion of Furthermore, the antithrombotic properties are increased by modifying the side chains of poly(α-amino acid) blocks because the modification increases the hydrophilicity of the membrane surface and lowers the interfacial free energy with blood. Conceivable.

Based on the above-mentioned excellent performance, the antithrombotic material of the present invention can be used in various medical instruments and materials that require antithrombotic properties, such as blood vessels and extracorporeal blood transport circuits. In addition, due to its excellent oxygen permeability, it is used in various medical devices and materials that require both antithrombotic properties and oxygen permeability, such as gas exchange membranes for oxygenators, membranes for artificial skin, and isobaric contact lenses. It is possible.

What has been explained above and shown in the specific examples of implementation is related to illustrations to help the understanding of the present invention, and the present invention is not limited to these illustrations, but is limited only by the scope of the claims. Other changes and modifications may be made within this scope.

[Brief explanation of the drawing]

FIG. 1 shows the kraft coelectric compound obtained in Production Example 1, that is, pDM8-(Lys(Z))27 in the main text.
Figure 2 of the Noko R spectrum diagram is the graft copolymer obtained in Production Example 1, namely FDMS-(Glu(
OBzl))74, Figure 3 shows the graft copolymer obtained in Production Example 3, that is, F
The engineering R spectrum of DMS (Sar)4I5, Figure 1, is shown in the text as a graft copolymer produced by Seisakusetei, that is, F DMS -(sar)u-(Glu
(oBzl) In the main text, the changes in the engineering R spectrum due to chemical modification of the graft copolymer in Reaction Example- are shown, and the upper row shows FDMS-(Glu(OBz'l):)/? ,
Moan middle stage Fip D M S -
(Glu(oNa))/ri, bottom row is F DMS-[:'
Gtu(.H))/91c just 8 Rx <ri, ya diagram,
The seventh tooth is a spectral diagram showing changes in the ATR-R spectrum due to Table m1 modification of the graft copolymer film in Reaction Example 3 in the main text, and the upper row is the one before surface modification treatment. That is, F DMS −(Glu(OBZI))J
, the middle row is the one treated with alkali, that is, FDM S
-(Glu(ONa))/? , and the lower row is the one further treated with acid, that is, p D M S -(Glu(OH))/V. In the charts of FIGS. 1 to 7, the vertical axis represents the wave number (cIn-1), and the horizontal axis represents the transmittance. No. 6 Nagio 7 Written amendment to figure procedures (voluntary) February 12, 1932, Director of the Japan Patent Office Haruki Shimada / Indication of the case Patent application No. 39, 1982-2θ3 Name: Yuki Konishi Ogu agent S Amendment Column B of "Detailed Description of the Invention" and Brief Description of 1 Drawing of the subject specification Contents of amendment <11 r
x+y=Hirootsu” and corrector 1. ．． Ru. (2) "ε-Garbobenzoxy" on the last line of the same page is replaced with "ε-Garbobenzoxy"
-Carbobenzoquine”, corrected. (3) ``Correct LYsJ to rLysJ'' in line S, line C (insert sentence) and line 3 of the same page. Tetra...concentrate," is corrected to "1. Then, the solvent is distilled off and concentrated. If tetrahydrofuran is used, dimethylformamide is added and then concentrated." (5) Change “CH2Cl2” on the 6th page/line to [0H2C
Correct it to 12J. (6) In the structural formula in the bottom row of the 4th page, the text at the end of the top row is corrected. (Power same page 7/line 1' (L Y S (Z)
,l,l? Correct J to rcLy日(Z):),□. (8) Correct "(OBzl month) in lines 6 and 3 of page 7 to 1 (0BZI) J." (9) Change "1 trifluoroacetic acid" in lines 3 to 2 from the bottom of No. (]0) J-[Glu(OB
zl))7J to [-(Glu(OBzl))7. Correct it with J. (11) Delete "(Tetrahydrofuran can also be used)" from the 3rd to 2nd lines from the bottom of the 9th page 0 (12) 1-(Sar%5
B as [-(Sar)lI! Correct it as d. (13) Same page 1/page bottom or λth line [LYS(Z))
Correct J to r(Lys(Z)) J. (14) Delete "(tetrahydrofuran can also be used)" from line 70 to line 1 on page 73. (15) “Insoluble portion” in the 1st & 6th line of the same page is “Insoluble portion”
I am corrected. (16) [PDMS-(
ear) IIy [Glu (OBzl)] 7.7". (Correct the structural formula of Lys(Z) on the left side of page 77/line % of the same. A certain “H2/pd” is respectively [H2
/PJ Correct. (Kon) Change [-CLys(Z)CO] at the end of page 77 to 1
−[:Lys(Z))λθ”. (@[HBr/Ac0H4 on page 7g, line 1]
Corrected to HBr/Ac0H4. (c) r - (0BZI) on page 79, 3rd line from the bottom
:]/qJ-3= is corrected to r-(OBzl)), J. (to) "/720cm'" on the last line of page 79 [/q;
1ocyn”J. (Correct [7oocm’J on the first 10th page/line to
Correct it to m −1. (24) Correct [11100cm IJ in line C of page 20 to ``/lioocm J.'' (25) In the structural formula in line 6 of page 20, the side chain 1 NHNH 2 \ that extends downward 10＼ C=Q c=. 1 Corrected as 4- ((6) g-(Glu(O
Correct Na))/9J to 1-(Glu(ONa))7y'. (4) 7-[Glu(OH
)]191 is corrected as r-(Glu(OH)), J. (2B) J-Glu (OB
zl)) Correct 2Q as toplu(OBzl), l,, J. (29) Same No., page 22, line 3, "J(ATR) Engineering R" [
Correct it as (A'fR)=lRJ. (1) In the third line from the bottom of No. 22, ``Jin 1u (ONa)) review'' is corrected to ``Jin 1u (ONa))'', J. 01) Correct "butanol" in line S from the bottom of page 22 to read "1 methanol." ) g-(()1u(OH)C+ on page λ3, line λ)
Correct J to g-[Glu(OH)]. r-(Glu(oBzl
)) s as J [G1 u (OBZ 1 ) ), 2.
Correct it as lIJ. ``goo-1'' on the 1st line of page lq in [EO
Ocrn-'J and correction-3'-le. 2) Correct ``(Lys (Z)) 27'' in the 6th line of page 2S to r(Lys (Z) J, 27J). (Z))5/
Correct J to r(Lys (z) ] syi. (e) On page 25, line S from the bottom,
Correct it to r-(Lye (Z)), 7J. (G) Same No. 2! Correct ``1 short'' on the gth line from the bottom of page r to ``short''. (39) 3rd line from the bottom of page u5 I) “-[:L
7S(Z))5/ is corrected as r-(Lys(Z)), J. (In the sample column at the bottom of the table on page 2g of the same page)
BI PDMS-(Glu(OBZI))-7A, [
(B) PDMS (olu(oBzl,)]qt, J
I am corrected. (b) Sample column 1 in the lower row of the table on page 23 of the same
-(cl FDMS-(Glu(OBzl))-dil"
"(c) PDMs-[Glu(OBZI))-, J
I am corrected. (Kan ``1 homophory'' on page 29, line 7 of the same book)
Correct "shorten" to "shorten by one". (471) Correct the column (Il) of the sample at the bottom of the table on page 3 of the same page. (B) Correct the column (J) of the sample at the bottom of the table on page 32 of the same page. ) Sample at the bottom of the table on page 3.2 (corrected as in the Kl column. (47) 1-[Glu (OBzl) on page 33, line 3)
]n” to [-(Gllll(OBZI)]J) (
To) "1-amino acid" on page 35, line 7 is corrected to "-amino acid)". (49) “lOθ” on page 36/line θ is “10”
I am corrected. (@ Line B from the bottom of page 3A (7) r-(Lys(
Correct Z)) JJJ to r (LyS(z)'), 7.74. ) on page 36, line G from the bottom [-(Glu(0BZI
))/! Correct 1 to ``-(Glu(OBZI)), J.''
)) JJt;, - "-Glu(OBzl)], ?xJ."
)) sgJ as “-(Glu(oBzl)],, J
I am corrected. g) l”'-(Glu(OBZI)) on the last line of page 36
g7J to J (Glu (o B Z 1)] g 7
Correct it with J. ) p. 37/line r-(Glu(0BZI))
/FA, woto(Glu(oBzl))71I, J
I am corrected. ), page 37, line 2, 1-(Glu(oBzl), l
Correct zg/J to 1 (olu(oBzl))7x7'. (e) r (Lys(z)27J, page 39, line 3)
Correct it to r-(L7B(Z))27J. g-olu(oBzl))7' in line 6 on page 39 of the same page as r(Glu(OBz 1))? b J
I am corrected. (59) IPDMs(sar)pr on page 39, line 1
Correct J as "pDMs(sar), J. (e) 1-(sar)<z, t on page 39, line o.
Correct J as 8-t(S a r ) ys J. Bait) “-[Glu(OBzl)]” on page 39/line 1 of the same page.
/3'' to r-(Glu(OBZI)), J correction. -Page 39, line 73, 1FDMS (Lys)
” is corrected as [PDMS (Ly s ) ao J. g-CGILI (OBZ) on page 39, bottom line 9
1-[Glu(OBzl)]7. ” he corrected. ) g-(Glu(ONa) on page 39, bottom 3rd line)
) /ri” (G 1 u (ON a) )
/ q Correct it as J. g-(Glu(OH)) in the second line at the bottom of page 39
/9 Correct J to g-(Glu(C)H), J. ) On page 90, line 9, correct [(OBzl):12+ J to r (oBZ 1 ))ati J. □□□) [=(Glu(ONa)
) /9 J r (G1 u (ONa )) i
q Correct J (e) same yo negative 6th line J-(Gl
u(OH))/? J is 1-(olu(oH) 〕1q
Correct it with J. Lying down

Claims (1)

[Claims] Polydimethylsiloxane with amino groups in the side chain allows
Anti-thrombotic material with gas permeability, consisting mainly of a graft copolymer obtained by polymerizing α-amino acid N-carboxylic anhydride