JPH01104270A - Antithrombogenic medical material - Google Patents

Abstract

PURPOSE:To provide a practical antithrombogenic medical material, by uniformly dispersing specific prostacyclines in a polymer material and exuding the same from the surface of the polymer material. CONSTITUTION:A prostacycline derivative represented by formula I (wherein R<1> is a hydrogen atom or a lower alkyl group, R<2> is a 3-12C alkyl group or a 3-12C alkenyl group and n is an integer of 1-5) and/or a physiologically acceptable salt thereof is uniformly dispersed in a polymer material. The mobility of the polymer material is 2X10<-9>g/cm<2>/sec<1/2> or more. Herein, the mobility shows [saturation solubility of prostacycline derivative represented by formula I in polymer material] X [diffusion constant of prostacycline derivative represented by formula I in polymer material]<1/2>. This prostacycline derivative exudes to the surface of the polymer material to develop an antithrombogenic property/.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] Thrombus formation can be broadly divided into extrinsic and intrinsic systems. The extrinsic system is a thrombus generated due to activation of tissue factors due to destruction of vascular endothelium, etc., while the intrinsic system is blood clots and thrombus formation that occur when foreign substances such as polymers come into contact with blood.

The present invention relates to an antithrombotic medical material that prevents the formation of blood clots by so-called medical materials in the endogenous system.

[Conventional technology]

Heparin (for example, 5science Vol. 142, p. 1297 (196
8th grade): Trans, Am, Soa, Art
if, Intern, Organs.

Vol. 17, p. 10 (1971) Vol. 24, p. 736 (1971)
(1978) and many others) and urokinase (e.g. Artificial Organs Vol. 7, No. 1, pp. 210 and 214 (197
8) and many others) are known, and medical materials such as catheters made of polymeric materials using these materials have already been put into practical use and are commercially available.

However, the endogenous thrombus formation is mainly divided into the coagulation factor system and the platelet system, and heparin suppresses the coagulation factor system but not the platelet system. That is, he/4' phosphorus cannot prevent the formation of platelet-based thrombi, and furthermore, when platelet-based thrombi are formed, anti-he/4' phosphorus factors are released, and as a result, the effect of hethumarin is reduced. It has disadvantages such as being attenuated.

Although it is possible to gradually alleviate the damage caused by the thrombus that has formed, it has drawbacks such as the inability to prevent the growth of the thrombus that is already forming.

That is, when heparin or urokinase is used as a drug that imparts anti-blood and orange properties to medical materials, there are essential drawbacks originating from the drugs themselves.

Prostaglandins may be used as drugs to overcome these essential drawbacks.

However, when prostaglandins such as PGE1 are used, there are known drawbacks such as a decrease in their activity (for example, Bamford C. et al. Po
lym, Pr5pr, (Am, Chem, So
e, * Dlv, Polym.

Chem, ) vol. 25, p. 27 (1984): H
, Jacobs et al.

Journal of Controlled Rel
@ase, Vol. 2, p. 313 (1985), etc.), but it has not yet been put to practical use.

Moreover, all conventional antithrombotic medical materials have been coated or chemically bonded with drugs that impart antithrombotic properties to the surface of polymeric materials.

[Problem to be solved by the invention]

As is clear from the above, Het! is a drug that imparts antithrombotic properties to medical materials. Zarin urokinase.

There is currently a desire for something that can solve the conventional problems that arise when prostaglandins are used and that can be put to practical use.

The object of the present invention is to provide an antithrombotic medical material that solves the above-mentioned problems and can be put to practical use by combining a certain kind of prostacyclin and a certain kind of polymeric material.

Moreover, whereas the conventional technology involved coating or chemically bonding a drug that imparts antithrombotic properties to the surface of a polymeric material, the present invention enables the prostacyclin to be uniformly dispersed within the polymeric material. It is based on the technology of causing the prostacyclin to ooze out from the surface of a polymeric material.

[Means to solve the problem]

The present invention is based on the formula (wherein R1 represents a hydrogen atom or a lower alkyl group,
R2 represents an alkyl group having 3 to 12 carbon atoms or an alkenyl group having 3 to 12 carbon atoms, and n
represents an integer from 1 to 5. ) and/or a pharmacologically acceptable salt thereof with a mobility of 2 x 10"9.li' 7cm2/8 @
(! ``Relating to an antithrombotic medical material comprising a polymeric material having the following properties.

In maximum (1) above, R1 is a hydrogen atom or, for example, methyl, ethyl, n-propyl, isopropyl, n-
Represents a linear or branched alkyl group having 1 to 5 carbon atoms, such as butyl, isobutyl, n-pentyl, impentyl, and R is, for example, n-propyl, isopropyl, n-butyl, isobutyl, n -pentyl, iso(methyl, 1-methylpentyl, 2-methylpentyl,
n-hexyl, n-heptyl, 1,1-dimethylpentyl, 2-ethylpentyl, n-octyl, 2-methyloctyl, n-nonyl, 2-methylnonyl, 2-ethyloctyl, n-decyl, 2- Straight-chain or branched alkyl groups having 3 to 12 carbon atoms such as methyldecyl, 2-ethyldecyl, and allyl, 2-butenyl, 3-pentenyl, 2-methyl-3-pentenyl,
4-hexenyl, 5-hebutenyl, 6-methyl-5-hebutenyl.

2.6-dimethyl-5-heptenyl, 1.1.6-drimethyl-5-hezotenyl, 6-methyl-5-octenyl, 2.6-dimethyl-5-octenyl, 6-ethyl-
It represents a linear or branched alkenyl group having 3 to 12 carbon atoms, such as 5-octenyl, 2-methyl-6-ethyl-5-octenyl, and 2,6-danityl-5-octenyl.

Further particularly preferred compounds include R representing a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-progyl, isopropyl;
For example, n-butyl, isobutyl, n-pentyl, impentyl, 1-methylpentyl, 2-methylpentyl,
4 to 10 carbon atoms such as n-hexyl, n-heptyl% 1.1-dimethylinthyl, 2-ethyl 4-entyl% n-octyl, 2-methyloctyl, 2-ethyloctyl
for example 3-1'-intenyl, 2-methyl-3-intenyl, 4-hexenyl, 5-
Heftynyl, 6-methyl-5-heptenyl, 2.6-
dimethyl-5-heptenyl, 1.1.6-) dimethyl-5-heptenyl, 6-methyl-5-octenyl, 2
, 6-dimethyl-5-octenyl, 6-ethyl-5-octenyl, 2-methyl-6-nityl-5-octenyl%
Examples include compounds representing an alkenyl group having 5 to 12 carbon atoms, such as 2,6-dinityl-5-octenyl, where n is an integer of 3.

Among the compounds of the present invention having -maximum (I), R1
Compounds in which is a hydrogen atom can be made into a pharmacologically acceptable salt form, if necessary. Examples of pharmacologically acceptable salts include sodium, potassium, magnesium,
Salts of alkali metals such as calcium and alkaline earth metals; ammonium salts; tetramethylammonium;
Tetraethylammonium, benzyltrimethylammonium.

Quaternary ammonium salts such as phenyltriethylammonium; methylamine, ethylamine.

dimethylamine, diethylamine, trimethylamine,
Triethylamine, N-methylhexylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-phenylethylamine,
Salts of lower aliphatic, lower cycloaliphatic and lower araliphatic amines such as ethylenediamine; heterocyclic amines such as piperidine, morpholine, pyrrolidine, piperazine, pyridine, 1-methyl bicytodine, 4-ethylmorpholine and Salts of their lower alkyl derivatives; monoethanolamine, ethyljetanolamine, 2-amino-1
- salts of amines containing hydrophilic groups such as butanol;
-threo-2-amino-3-paranitrophenyl-1,
3-Frono J? Examples include salts of diol.

In addition, in the compound having the above-mentioned maximum (1), the coordination of the cyclointane ring and the hydroxyl group of its side chain.

There are also stereoisomers based on the coordination of the side chain bonded to the cyclopentane ring, the double bond bonded to the cyclopentane ring, and the double bond when R2 is an alkenyl group. Therefore, when a compound having the above-mentioned maximum (I) is obtained as a mixture of these stereoisomers, the respective isomers can be obtained by separation and resolution by conventional methods.The above-mentioned maximum (1) Although these stereoisomers and mixtures of stereoisomers are all represented by a single formula in K, the scope of the present invention is not limited thereto.

Among the compounds having the general formula (I), preferred are compounds having H (wherein R1, R2 and n have the same meanings as described above).

The compound having the general formula (1) is disclosed in Japanese Patent Publication No. 61-212
It is a known compound described in No. 16, and its production method is described in the publication. Furthermore, all of the useful compounds specifically described in the publication can be particularly suitably used in the present invention, that is, the compounds described below.

1) 6,9α-methylene-11α,15α-dihydroxypros)-5(Z),13(E)-dienoic acid and its sodium and potassium salts and its methyl and ethyl.

. -propyl, isopropyl ester 2) 6.9α-methylene-11α, 15β-dihydroxypros) -5(Z), 13(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl Ester 3) 6.9α-methylene-11α, 15α-dihydroxygloss)-5(E), 13(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-7'lopyl and isozorovir Esther 4)
6.9α-methylene-11α,15β-dihydroxypros)-5(E),13(E)-dienoic acid and its sodium and potassium salts and its methyl and ethyl.

n-propyl, isozolobyl ester 5) 5.8α-methylene-1oα, 14α-dihydroxynorprost-4(Z), 12(E)-dienoic acid and its sodium, potassium salts and its methyl, ethyl, n -propyl, isopropyl ester6) 5.8ot-methylene-10α,14β-dihydroxynorpros)-4(Z),12(E)-dienoic acid and its sodium, lithium, potassium salts and their methyl, ethyl, n- 7'lopyl, isozolobyl ester 7) 5,8α-methylene-10α, 14α-dihydroxynorprost-4(E), 12(E)-dienoic acid and its sodium and potassium salts and its methyl and ethyl.

n-70 lopyl, isopropyl ester 8) 5.8
α-methylene-10α, 14β-dihydroxynorprost-4(E), 12(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters9) 4,7α-methylene- 9α,13α-dihydroxybisnorpros)-3(Z),11(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-7'lopyl and isopropyl esters 1
0) 4.7α-methylene-9α, 13β-dihydroxybisnorzolost-3(Z), 11(E)-dienoic acid, its sodium and potassium salts and its methyl.

Ethyl, -propyl, isopropyl ester.

11) 4.7α-methylene-9α,13α-dihydroxybisnorzolost-a(E),o(E)-dienoic acid and its sodium and potassium salts and its methyl.

Ethyl, n-, Is lobil, isopropyl ester 12
) 4,7α-methylene-9α, 13β-dihydroxybisnorprost-3(E), 11(E)-dienoic acid and its sodium and potassium salts and its methyl.

Ethyl, n-propyl, isozorobyl ester 13)
6,9α-methylene-11α, 15α-dihydroxy-
ω-norprost-5(Z), 13(E)-dienoic acid and its sodium and potassium salts and its methyl.

Ethyl, -, 110 biru, isozorobyl ester 14
) 6.9α-methylene-11α, 15β-dihydroxy-ω-norprost-5(Z), 13(E)-dienoic acid and its sodium and potassium salts and its methyl.

Ethyl, In-7'lopyl, isopropyl ester 15
) 6,9α-methylene-11α, 15α-dihydroxy-ω-norprost-5(E), 13(E)-dienoic acid and its sodium and potassium salts and its methyl, ethyl, n-7'lopyl and impropyl esters 16
) 6,9α-methylene-11α, 15β-dihydroxy-ω-norprost-5(E), 13(E)-dienoic acid and its sodium and potassium salts as well as its methyl, ethyl, n-7′, and isopropyl Ester 17) 6,9α-methylene-11α,15α-dihydroxy-20-methylzorost-5(Z), 13(
E)-Dienoic acid and its sodium, potassium salts and their methyl, ethyl, n-7'lopyl, isopropyl esters 18) 6.9α-methylene-11α, 15β-dihydroxy-20-/tylzolost 5(Z), 13(
E) - Citric acid and its sodium, potassium salts and their methyl, ethyl, n-7'lopyl, isopropyl esters 19) 6.9α-methylene-11α, 15α-dihydroxy-20-methylprost-5(E), 13 (
E)-Dienoic acid and its sodium, potassium salts and their methyl, ethyl, n-propyl, isopropyl esters20) 6,9α-methylene-11α,15β-dihydro-20-methylprost-5(E), 13( E)
-dienic acid and its sodium and potassium salts and their methyl, ethyl, n-7'ropyl and isopropyl esters21) 6,9α-methylene-11α, 15α-dihydroxy-17-fiflupus) -5(Z), 13
(E)-Dienoic acid and its sodium, potassium salts and their methyl, ethyl, n-70ropyl, isopropyl esters22) 6,9α-methylene-11α,15β-dihydroxy-17-melglost-5 (Z), 13(E)
- Citric acid and its sodium and potassium salts and their methyl, ethyl, n-, o-lopyl, and inpropyl esters23) 6,9α-methylene-11α,15α-dihydroxy-17-methylzorost-5(E), 13 (
E)-Dienoic acid and its sodium, potassium salts and their methyl, ethyl, n-7'lopyl, isopropyl esters24) 6,9α-methylene-11α,15β-dihydroxy-17-methylzolostose 5(E), 13 (E)
- Dienic acid and its sodium, potassium salts and their methyl, ethyl, n-propyl, isopropyl esters25) 6.9α-methylene-11α,15α-dihydroxy-16,16-di)ethylprost-5 (Z),
13(E)-Dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters26) 6.9α-methylene-11α,15β-dihydroxy-16,16-dimethylprostole 5 (Z ), 1
3(E)-Dienoic acid and its sodium, potassium salts and methyl, ethyl, n-7'lopyl, isopropyl esters 27) 6°9α-methylene-11α, 15α-dihydroxy-16,16-dimethylprostol 5( E),
13(E)-Dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters28) ),
13(E)-Dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters29) 6.9α-methylene-11α, 15α-dihydroxy-20-ethyl 7t, Prost-5(Z) , 13(
E)-Dienoic acid and its sodium, potassium salts and their methyl, ethyl, -70 lobil, isopropyl esters30) 6,9α-methylene-11α,15β-dihydroxy-2Q-xfluprost-5(Z), 13(E) )
-Dienoic acids and their sodium and potassium salts and their methyl, ethyl, n-nia"lopyl, and isopropyl esters 31) 6.9α-methylene-11α, 15α-dihydroxy-20-ethylprostole 5(E), 13(
E)-Nononic acid and its sodium, potassium salts and their methyl, ethyl% n-propyl, isopropyl esters 32) 6.9α-methylene-11α,15β-dihydroxy-20-ethylprost-5(E), 13(
E)-Dienoic acid and its sodium, potassium salts and their methyl, ethyl, n-7'lopyl, isopropyl esters33) 6,9α-methylene-11α,15α-dihydroxy-19-ethylidene-ω-norgrostose S (
Z).

13 (E)-Dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters34) 6.9α-methylene-11α,15β-dihydroxy-19-ethylidene-ω-norprost-5 (Z
).

13(E)-Dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters35) 6,9α-methylene-11α,15α-dihydroxy-19-ethylidene-ω-norzolost-5 (E
).

13(E)-dienoic acid and its sodium, potassium salts and its methyl, ethyl, n-propyl.

Isopropyl ester 36) 6.9α-methylene-11α,15β-dihydroxy-19-ethylidene-ω-norgrostose 5 (E
).

13 (8 loaves of dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters 37) 6,9α-methylene-11α,15α-dihydroxy-20-isozolobylideneprost-5 (E)
, 13(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters38) 6.9α-methylene-11α,15β-dihydroxy-20-isopropylideneprost-5(Z)
, 13(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters39) 6.9α-methylene-11α,15α-dihydroxy-20-isopropylidenegrost 5(Z)
, 13(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters 40) 6,9α-methylene-11α,15β-dihydroxy-20-isopropylidene zolost-5 ( E)
, 13(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters41) 6,9α-methylene-11α,15α-dihydroxy-17-methyl-20-isopropylidenezorost -5(Z),13(E)-dienoic acid and its sodium.

Potassium salts and their methyl, ethyl, n-propyl,
Isopropyl ester 42) 6.9α-methylene-11α,15β-dihydroxy-17-methyl-20-isopropylidenepros)-5(Z),13(E)-dienoic acid and its sodium and potassium salts and its methyl and ethyl , n-propyl, isopropyl ester 43) 6.9α-methylene-11α, 15α-dihydroxy-17-methyl-20-isopropylidenepros)-5(E), 13(E)-dienoic acid and its sodium and potassium salts and its methyl, ethyl, n-propyl, isopropyl esters44) 6.9α-methylene-11α,15β-dihydroxy-17-methyl-20-isopropylidenepros)-5(E), 13(E)-dienoic acid and That sodium.

Potassium salts and their methyl, ethyl, n-propyl,
Isopropyl ester 45) 6.9α-methylene-11α, 15α-dihydroxy-20-(1-ethylpropylidene) Frost-
5(Z), 13(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-propyl and isopropyl esters46) 6,9α-methylene-11α, 15β-dihydroxy-20-(1-ethyl Propylidene) Prost
5(E), 13(E)-dienoic acid and its sodium and potassium salts and its methyl, ethyl, n-propyl and isopropyl esters47) 6.9α-methylene-11α, 15α-dihydroxy-20-(1- ethylpropylidene) frost
5(E), 13(E)-dienoic acid and its sodium and potassium salts and their methyl, ethyl, n-globil and isopropyl esters48) 6.9α-methylene-11α, 15β-dihydroxy-20-(1-ethyl propylidene) frost
5(E), 13(E)-dienoic acid and its sodium, potassium salts and its methyl, ethyl, n-propyl, inglovir esters, especially 1), 2), 3), 4), 21)
, 22), 23).

24), 25), 26), 27
), 28), 37), 38)
.

39), 40), 41), 42), 4
Compounds 3) and 44) are preferred.

especially 6,9α-methylene-11α, 15α-dihydroxy-17-methyl-20-isopropylidene gloss)
-5(E), 13(E)-dienoic acid (hereinafter referred to as compound A) is optimal.

Prostacyclin derivatives having the above-mentioned maximum (1) and/or pharmacologically acceptable salts thereof (hereinafter referred to as "prostacyclin derivatives").

The prostacyclin derivative having the formula (I) is used by uniformly dispersing it in a polymeric material.

The polymeric material used in the present invention has a mobility of 2×10”
It is more than 117cm"/s@e"'. Here, mobility is [saturated solubility of prostacyclin derivative having formula (I) in polymeric material] x [saturation solubility of prostacyclin derivative having formula (1) in polymeric material]
) Diffusion constant of prostacyclin derivative with 1″
shows.

In order for the prostacyclin derivative having the formula (I) that is uniformly dispersed in the polymeric material to ooze out onto the surface of the polymeric material and exhibit antihemodominant properties, the prostacyclin derivative having the formula (1) must be used when applied to a living body. This is achieved by migration of the polymer through the polymeric material and gradual release from the surface.

On the other hand, proteins present in the blood are adsorbed to the surface of the polymeric material, and a pseudointima is then generated. Since the formation of pseudointima naturally imparts antithrombotic properties, the formula (1) in polymeric materials
It is sufficient for a prostacyclin derivative having the following to exhibit antithrombotic properties on the surface of a polymeric material until pseudointima occurs.

From the above, the migration of the prostacyclin derivative having the formula (1) until the formation of pseudointima on the surface of the polymer material is concentration] × [diffusion constant of prostacyclin derivative having formula (I) in polymeric material]
Proportional to 1″ ( ” Appli@dPolymer
5sciences 2nd Ed,”, edit
ed by R,W.

Tags and G, W, Poehlein, Am
erlcan Ch@m1calSociety,
Washington' D, C, 1985).

The present invention has a mobility of 2 X I F'11/cm"/
When using a polymeric material with a
A useful medical material having antithrombotic properties was obtained by uniformly dispersing a prostacyclin derivative having 1) in a polymeric material.

The [diffusion constant of the prostacyclin derivative having the formula (I) in a polymeric material] can be determined from the following equation by a membrane permeation experiment under sufficient stirring.

Mobility is 2 x I F' I 7cm"/sea"
``Silicon and polyether urethane are examples of polymeric materials mentioned above.

polyether urethaneurea, polyamino acids, colladan, atelocollagen, gelatin, cellulose, cellulose acetate, fibrin, chitin, chitosan, alginic acid or polyhydroxyethyl methacrylate or copolymers thereof, especially silicone, polyether urethaneurea or acetic acid Cellulose or copolymers thereof are preferred.

However, polyethylene and polyvinyl chloride have extremely low mobility and are outside the scope of the present invention.

Generally known methods are used to impregnate the polymer material of the present invention with the prostacyclin derivative having formula (1). For example, by immersing a polymeric material in a solution of the prostacyclin derivative having the formula (1), the prostacyclin derivative having the formula (I) can be adsorbed and distributed onto the polymeric material, or the prostacyclin derivative having the formula (1) or The surface of the medical material is coated with a liquid obtained by dissolving or dispersing the carrier-impregnated product in a polymeric material solution, or the prostacyclin derivative having formula (I) or its carrier-impregnated product is kneaded during polymerization or crosslinking. This can be achieved by

The content of the prostacyclin derivative having the formula (I) to be uniformly dispersed in the polymeric material depends on the migration speed in the polymeric material, the duration of the antithrombotic effect, etc. Therefore, it is difficult to indicate the limit of the content, but it is usually 1 μi
/cm3 to 750 q/cm”, preferably 50 μ
l 7cm3 to 500 m97cm3. The most preferred range is 100 μg/α3 to 100 μg/α3.

The prostacyclin derivative having the formula (1) can be impregnated into a polymeric material as it is, or by adsorption onto a carrier such as cyclodextrins, other sugars, or light silicic anhydride. The prostacyclin derivatives having formula (1) can also be used in combination with anticoagulant drugs such as heparin to ensure antithrombotic properties.

The medical materials of the present invention include blood bags used outside the body, artificial organs, artificial blood vessels, catheters used in the living body, and materials intermediate between the two, such as extracorporeal circulation (hemodialysis, heart-lung machine), plasma 7 elesis. etc. may be used without particular limitation.

〔Example〕

Next, the present invention will be explained in more detail with reference to experimental examples and examples.

Experimental example 1. Mobility of silicon...0... (1) Saturation solubility of compound A Silicon sheet with Ji 0.0125 cm (Dow Corning's product name Medical Grade)
5ilastie 5heetJ) of compound A
μl 7 cm” of an aqueous solution (PH 6,5) overnight at 37°C and shaken, the concentration of Compound A in the aqueous solution and in the silicone sheet was measured by HPLC.The concentration of Compound A in the silicone sheet was After adding chloroform to extract and drying, the obtained compound A was dissolved in phosphate buffer (S7.4) and quantified by HPLC.

From the obtained partition coefficient of 8 and the solubility of compound A in water, the saturated solubility of compound A in the silicon sheet is 8.
00 μll/cm”.

(2) Silicon sheet with diffusion constant N-sa of compound A of 0.012.5 cm (trade name: Medial Grade, manufactured by Dow Corning ■)
5ilastic 5heetJ) with a transmission area of 3 cm
” was set in a glass diffusion cell.

Put a 50 ttl/cm" aqueous solution (PH6.5) of Compound A on the donor side, put a phosphate buffer (p) 17.3) on the rs+ceptor side, and keep it at 37°C.
The receptor fluid was sampled over time, and the concentration of compound A was measured by HPLC. Unit area of membrane (ct
n2) The permeation amount of this product was 1.3μI at 6 hours, 4.0μ9 at 22 hours, and 5.0μg at 27 hours. From this, the flux of membrane permeation is 4.9XIO11/cm2/8ec
Met.

From these values, the diffusion constant is 1.5 x 10"9cm"
/sec.

(3) Mobility The mobility of silicon is (sooxlo-'
1/'cm") X (1,5X 1'O-'z"
/ sac )”” = 3゜I X 10-81/c
m2/sea.

Experimental example 2. Polyether urethane urea...
Mobility of (11) Saturated solubility of Compound A Segmented polyurethane with thickness of 0.008 crn (4
, 4'-diphenylmethane diisocyanate, z-ritetramethylene glycol, and ethylene diamine) was added to compound
After immersion in an aqueous solution (pH 7,4) of 00 μg/cW13 at 37° C. for 2 days and shaking, the concentration of Compound A in the aqueous solution and in the segmented polyurethane was measured by HPLC. From the determined distribution coefficient of 2550 and the solubility of Compound A in water, the saturated solubility of Compound A in the segmented polyurethane was 3I/α3.

(2) Diffusion constant of compound A Using segmented polyurethane with a thickness of 0.008 crn, 500 μJi' 7 cm of compound A on the donor side
An aqueous solution of No. 3 (pH 7, 4) was added, and the other conditions were the same as in Experimental Example 1.

The amount of permeation per unit area (ctn”) of the membrane is 52 in 4 hours.
0μ, F, 1.0115J in 8 hours, 3. in 24 hours.
Omy.

It was 3.5119 Da at 30 hours and 5.0 Da at 48 hours. From this, the flux of the permeable membrane is 3.4 x 10-21
It was 7cm” type 7.

From these values, the diffusion constant is 2. I X 10-”'m”
/sec.

(3) Mobility The mobility of segmented polyurethane is (3
1/cm3)
) ”” =4.3 X 10-5. lit 7cm
"/see"".

Experimental example 3. Mobility of cellulose acetate (1)
Cellulose acetate (Daicel Chemical Industries, Ltd., trade name: R I, L-10J) with a saturated solubility thickness of 0.004c111 was added to Compound A.
37°C in an aqueous solution (PH6,5) of 50μm1/cm3 of
After immersion and shaking for one day, the concentrations of Compound A in the aqueous solution and cellulose acetate were measured by HPLC. From the determined partition coefficient 30 and the solubility of compound A in water,
The saturation solubility of compound A in cellulose acetate is 4~/Cr
It was n3.

(Diffusion constant of 21 Compound A: Using cellulose acetate with a thickness of 0.004 cm,
An aqueous solution of 77.5 μg/α3 of compound A (pi
16.5), and the other conditions were the same as in Experimental Example 1.

The amount of permeation per unit area (Crn2) of the membrane is 1.
6 μp, 5.2 pfi in 8 hours and 2 in 24 hours
It was 168μI. From this, the flux of the permeable membrane is 2.45
x10”17 mouths 2/[1@e.

From these values, the diffusion constant is 4.2 x 10”10cm
It was 27 seconds.

(3) Mobility The mobility of cellulose acetate...O.0. is (4x(10-
310-3l7 X (4,2XI O-”crn2/
ssc)”” = 8.2X 10= i 7cm2
/ see"'.

Example 1 Aqueous solutions of compound A at various concentrations (PH 6-7, concentration 0.
1 to 100 Ag/ml) K silicone sheet (thickness 270 μm, Dow Corning (trade name: Medi)
calGrade 5ilastic 5heat J
) was soaked for 2 days to prepare silicone containing Compound A in various amounts, and the sheets were cut into 0.8 m wide and 6 on long sheets to prepare samples.

Example 2 10y of compound A and light anhydrous silicic acid 409 were placed in a mortar, 32N of distilled water was added and kneaded, and this kneaded product was heated to 60°C.
, dried in an air dryer for 1 hour.

The compound A adsorbed light silicic acid anhydride 10I was added to silicone (product name of Dow Corning Co., Ltd. MDX4-4210J).
Knead in 90I using 3 rollers, add 10.9% of crosslinking agent (polymethylhydrodiene siloxane),
After mixing, the mixture was placed in a mold and crosslinked. By this method, it was confirmed that Compound A hardly suffered from decomposition due to crosslinking and was dispersed in silicon in a stable state.

Example 3 Compound A 61 and light silicic anhydride 40. Put F into a mortar and add 32% distilled water. Add P and mix, ? : The kneaded product of , was dried at 60° C. for 1 hour in a ventilation dryer.

The compound A adsorbed light silicic anhydride 16.511 was mixed with silicone oil (product name: rF1uid3, manufactured by Dow Corning ■).
60 J) 24.5 i, added to silicone oil 7841 containing a crosslinking agent (polymethylhydrodiene siloxane), and mixed and dispersed using two rollers.

This was extruded into a tube shape with an outer diameter of 1.7
A catheter with an internal diameter of 0.811111 was obtained.

The obtained catheter was heat treated at 120°C for 1.5 minutes, then sterilized with ethylene oxide gas at 55°C for 24 hours, and further degassed at 55°C for 1 day.

By this method, it was confirmed that Compound A was hardly decomposed and was dispersed in silicon in a stable state.

Example 4 The same polyether urethane urea used in Experimental Example 2 was dissolved in dimethylacetamide to a concentration of 15%. Next, 30 parts of Compound A was dissolved in 100 parts of this solution. A soft vinyl chloride tube with an outer diameter of 1.6 mm was immersed in the resulting solution and then pulled out at 70 to 80 °C for 40 to 60 °C.
Dry for a minute.

This soaking and drying process is repeated several times to create a thickness of about 25cm on the outside.
A coating layer of 0μ was formed. Next.

After further drying at 120°C for 30 minutes, it was sterilized with ethylene oxide at 55°C for 24 hours.

By the above operation, compound A was added to the surface of the vinyl chloride tube.
was stably dispersed in the polyether urethane urea to form an outer layer.

Example 5 0.002 part of Compound A was added and dissolved in the same solution used in Example 3, consisting of 5 parts of cellulose acetate, 40 parts of dioxane, 40 parts of acrylonitrile, and 15 parts of water. Next, this solution was cast onto a glass plate and dried at 40°C for 20 hours to obtain a cast film.

By this method, it was confirmed that Compound A was hardly decomposed and was dispersed in cellulose acetate in a stable state.

〔Effect of the invention〕

Test Example 1 The sample obtained in Example 1 was placed at the joint between the carotid artery and jugular vein A-v shunt of rats) (n = 6), and
After several minutes, the weight of the thrombus formed on the silicone sheet was measured.

Experimental Method Male Wistar Imamichi rats (Animal Breeding Research Institute) weighing approximately 350 g were used as rats. Rats were fixed in a dorsal position under anesthesia with intraperitoneal administration of sodium thiobutaparbital 10100In97. The right carotid artery and the left carotid artery were connected with a cannula to create an extracorporeal circulation circuit (AV shunt). The cannula consists of a medical silicone chip with a 3 Fr polyethylene tube connected to the front and back and a silicone sheet placed in the center. The inside of the cannula was filled with physiological saline in advance. The cannula was removed 15 minutes after blood flow started. Take out the silicone sheet.

The clot was rinsed with a 3.8% sodium citrate solution from a constant liquid cap, and the weight was measured by wiping off the moisture on the opening paper.The weight, which had been determined in advance before being attached to the cycannula, was subtracted to determine the thrombus weight.

The measurement results are shown below.

Significant differences relative to the control were observed at Compound A concentrations of 50 μl/I or higher.

As a result, in this experiment, as the concentration of Compound A in the silicone catheter increased, the amount of IL in the thrombus decreased, demonstrating the antithrombotic effect of the medical material of the present invention containing Compound A.

Test Example 2 The antithrombotic properties of the catheter obtained in Example 3 were evaluated using dogs. An experiment was conducted with 5 animals in each group using untreated silicone catheters as a control.

That is, the left jugular vein of an adult mongrel dog was exposed under general anesthesia, and a catheter was placed at a length of about 15 cWI toward the superior vena cava. After 4 weeks of indwelling, the animal was sacrificed, the thorax was opened, the blood vessel was incised, the catheter was removed, and the state of thrombus formation in the blood vessel and around the catheter was observed. As a result, the catheter obtained in Example 3 showed almost no thrombus formation both in the blood vessel and around the catheter compared to the control catheter.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 represents a hydrogen atom or a lower alkyl group, and R^2 has 3 to 12 carbon atoms. or an alkenyl group having 3 to 12 carbon atoms, and n is an integer of 1 to 5. 2×10^-^9g/cm^2/sec^1^
An antithrombotic medical material comprising a polymeric material having a molecular weight of /^2 or more. 2. In formula (I), R^1 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R^2 represents an alkyl group having 4 to 10 carbon atoms or an alkyl group having 5 to 12 carbon atoms. The antithrombotic medical material according to claim 1, wherein n is an integer of 3. 3. The compound having formula (I) is 6,9α-methylene-
11α,15α-dihydroxy-17-methyl-20-
The antithrombotic medical material according to claim 1 or 2, which is isopropylideneprost-5(E), 13(E)-dienoic acid. 4. The polymer material is silicone, polyether urethane, polyether urethane urea, polyamino acid, collagen, atelocollagen, gelatin, cellulose, cellulose acetate, fibrin, chitin, chitosan, alginic acid or polyhydroxyethyl methacrylate, or a copolymer thereof. The antithrombotic medical material according to claim 1, 2 or 3. 5. The antithrombotic medical material according to claim 1, 2 or 3, wherein the polymeric material is silicone, polyether urethaneurea, cellulose acetate, or a copolymer thereof.