POLYHYDROXYL-CONTAINING POLYMER, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

A polyhydroxyl-containing polymer has good biocompatibility, strong binding performance with substances the same surface of which contains oxygen, nitrogen, and so on and that easily form hydrogen bonds. A solution formed by the polymer adheres poorly to an intubation microcatheter, but adheres strongly to blood vessels, skin, and glass, and may be used as a vascular embolization agent.

Claims

1. A polymer characterized in that, the polymer comprises units represented by the following formula 1, formula 2, formula 3 and formula 4: ##STR00004## wherein, m is greater than or equal to 1, n, j, k is greater than or equal to 0; R.sub.1, R.sub.2 are the same or different, independently selected from H, at least one of C.sub.1-8 alkanes; R.sub.3 and R.sub.4 are selected from H or hydroxyl and R.sub.3 and R.sub.4 are different, R.sub.5 and R.sub.6 are the same or different, independently selected from H or hydroxyl.

2. The polymer according to claim 1, characterized in that, the polymer is a homopolymer or a random copolymer or a block copolymer; preferably, R.sub.1 and R.sub.2 are the same or different and are independently selected from H or methyl; preferably, k=0 and/or j>0.

3. The polymer according to claim 1, characterized in that, in the polymer, the number of the repeating unit represented by formula 1 is 0.1-100% of a total number of repeating units, the number of the repeating unit represented by formula 2 is 0-99.9% of the total number of repeating units, the number of the repeating unit represented by formula 3 is 0-99.9% of the total number of repeating units, the number of the repeating unit represented by formula 4 is 0-99.9% of the total number of repeating units; preferably, in the polymer, the number of the repeating unit represented by formula 3 is 0% of the total number of repeating units; preferably, in the polymer, the number of the repeating unit represented by formula 4 is 0% of the total number of repeating units.

4. The polymer according to claim 3, characterized in that, in the polymer, the number of the repeating unit represented by formula 1 is 25-100% of the total number of repeating units, the number of the repeating unit represented by formula 2 is 0-75% of the total number of repeating units; further preferably, the number of the repeating unit represented by formula 1 is 50-100% of the total number of repeating units, the number of the repeating unit represented by formula 2 is 0-50% of the total number of repeating units; further preferably, the number of the repeating unit represented by formula 1 is 75-100% of the total number of repeating units, the number of the repeating unit represented by formula 2 is 0-25% of the total number of repeating units.

5. The polymer according to claim 1, characterized in that, the number average molecular mass of the polymer is 10,000-220,000, preferably, 20,000-200,000, such as 50,000-200,000, such as 60,000-200,000; preferably, the polymer is soluble in dimethyl sulfoxide, acetic acid, and ethanol.

6. A preparation method of the polymer according to claim 1, characterized in that, the method comprises the following steps: ##STR00005## (1) the epoxidized polymer represented by formula 6 is prepared by oxidizing the polymer containing double bond represented by formula 5, wherein, R.sub.1 and R.sub.2 are defined as above, p=m+n+k, l=m+n, the definitions of j, k, m and n are as described above; (2) then the epoxidized polymer represented by formula 6 is catalyticly hydrogenated and/or hydrolyzed to prepare the polymer product.

7. The preparation method according to claim 6, characterized in that, the polymer represented by formula 5 may be obtained by self-polymerization of diene monomers, the diene monomer may be, for example, 1,3-butadiene or isoprene.

8. The preparation method according to claim 7, characterized in that, in step (1), the oxidation reaction includes but is not limited to chlorohydrin method, peroxide-epoxidation method or oxygen direct oxidation method; preferably, the peroxide can be one or more selected from hydrogen peroxide, peroxyformic acid, peroxyacetic acid, tert-butyl hydroperoxide, etc. and mixture thereof; preferably, the oxidation reaction can be carried out in an organic solution or a water/organic solvent emulsion of the polymer, the organic solvent includes but is not limited to fatty alkanes, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, naphthenes, naphtha, etc., for example, hexane, cyclohexane, heptane, methylene chloride, benzene, toluene, naphtha, etc.; preferably, the temperature of the oxidation reaction is 0-120° C., preferably 20-80° C.

9. The preparation method according to claim 7, characterized in that, in step (2), the catalytic hydrogenation can open the epoxy ring of the epoxidized polymer by catalytic hydrogenation to obtain polymers containing hydroxyl on the C—C chain; the hydrolysis can hydrolyze the epoxidized polymer by conventional acidic or basic substances, and open the epoxy ring to obtain the polymer containing adjacent dihydroxyl groups on the C—C chain; preferably, the acidic substance comprises inorganic acids such as aqueous hydrogen halide, sulfuric acid, nitric acid etc.; organic acids such as alkyl sulfonic acid etc.; solid acids and heteropoly acids, etc.; preferably, the catalytic hydrogenation is catalyzed by raney nickel or platinum, palladium and the like; preferably, the catalytic hydrogenation reaction can be carried out in an organic solution or a water/organic solvent emulsion of the polymer, the organic solvent includes but is not limited to fatty alkanes, halogenated aliphatic hydrocarbons, naphthenes, naphtha, cyclic ether compounds, alcohols, etc., preferably are selected from hexane, cyclohexane, tetrahydrofuran, methanol, ethanol, etc.; the temperature of the catalytic hydrogenation reaction is 0-120° C., preferably 20-80° C.; preferably, the hydrolysis reaction can be carried out in an organic solution of polymer or a water/organic solvent emulsion of the polymer, the organic solvent includes but is not limited to aliphatic alkanes, halogenated aliphatic hydrocarbons, aromatic hydrocarbons, naphthenes, naphtha, cyclic ether compounds, sulfoxides, sulfones, pyrrolidone, methylpyrrolidone, etc., preferably is tetrahydrofuran, dimethyl sulfoxide, methylpyrrolidone, etc.; the temperature of the hydrolysis reaction is −20-150° C., preferably −10-80° C.

10. Use of the polymer according to claim 1 for vascular embolization.

Description

BRIEF DESCRIPTION OF THE DRAWING

[0046] FIG. 1 is a schematic structural diagram of an in vitro experimental device for liquid embolic agent.

DETAILED DESCRIPTION OF THE INVENTION

[0047] The preparation method of the present invention will be further described in detail below in conjuction with specific examples. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention; and should not to be construed as limiting the protection scope of the present invention. All technologies implemented based on the above contents of the present invention are covered by the scope of the present invention.

[0048] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples can be obtained commercially.

[0049] The material structure tests .sup.1HNMR, .sup.13CNMR employ the 600M pulse Fourier transform nuclear magnetic resonance spectrometers from JOEL company, IR is tested on Nicoletis 50, a Fourier infrared transform spectrometer from Thermofisher; the test of Tg values determined by using the Q100 Differential Scanning calorimeter from TA company. The polymer molecular weight was tested on Agilent PL-GPC50 (equipped with differential refractive index detector and evaporative light scattering detector).

[0050] EVOH-1, EVOH-2 and EVOH-3 were all purchased from Kuraray, the differences among the three were the contents of ethylene. See the table in Test Example 1 for details.

Example 1

[0051] cis-Polybutadiene: Commercially available polybutadiene mass (purchased from Sichuan Petrochemical Ltd., 1,4-cis content≥98%, and 2% 1,4-trans and the structure represented by formula 4; number average molecular weight M.sub.n=170,000) were cut into approximately 2 mm mass particles.

[0052] Epoxidation: Into a 250 ml three-neck flask equipped with a stirrer and thermometer, 7 g of the above polybutadiene mass particles and 100 ml of methylene chloride was added, the mass was dissolved and stirred under constant temperature in water bath. Nitrogen was introduced for a few minutes when the mass was completely dissolved and became a sticky state. 9.90 g formic acid was added; 21.40 g of 30% aqueous hydrogen peroxide solution was added dropwise with stirring; the reaction temperature was held for about 15 h; according to .sup.1HNMR (CDCl.sub.3) analysis, the characteristic chemical shift peaks of 1,4-cis double bond disappeared (the characteristic chemical shift of epoxy group δ=2.98, the characteristic chemical shift of 1,4-cis double bond δ=5.40). The reaction product was neutralized with 10% sodium carbonate solution to pH=7, the water phase was seperated, the organic phase was washed and the phases were separated; absolute ethanol was added to the separated gel to precipitate, the precipitate was separated and washed with absolute ethanol once, waste liquid was filtered out to obtain a wet mass, which was dried at room temperature for 12 h, and then dried in a vacuum oven at 40° C. for about 24 hours to constant weight to obtain 7.3 g of epoxidized butadiene rubber.

[0053] Hydrolysis: 1 g of the epoxidized butadiene rubber prepared above was weighted and dissolved in 100 ml of tetrahydrofuran, into which a solution of 5 ml water and 1 ml perchloric acid was added dropwise with stirring at 25° C. The addition was completed in 30 min and the stirring was continued at 25° C. for 12 hours. According to .sup.1HNMR (DMSO) analysis, the characteristic chemical shift peak of the epoxidized butadiene rubber disappeared (characteristic chemical shift of epoxy group δ=2.98, characteristic chemical shift of the adjacence dihydroxyl δ=4.18). Sodium carbonate was added into the reaction solution for neutralization. 1000 ml of water was added into the reaction solution dropwise to precipitate; the precipitate was separated, into which was added 400 ml of water and then soaked for 24 h. The water was filtered out. The resulting polymer substance was dried for 24 h at room temperature and then at 40° C. in a vacuum oven to constant weight. 1.12 g of solid matter was obtained. The molecular weight of the product Mn=146,000, and Tg value thereof was 56° C.

Example 2

[0054] cis-Polybutadiene: 180 ml dry petroleum ether (60-90° C.) was added to a 500 ml anhydrous and oxygen-free reaction flask, dry 1,3-butadiene (Chengdu Keyuan Gas Ltd., purity greater than or equal to 99.5%) was introduced at 5° C., 20 g butadiene was absorbed. The reaction flask was sealed and put into a 40° C. water bath, 0.4 ml of aged liquid of nickel naphthenate and triisobutylaluminum was introduced with stirring, then 0.38 ml BF.sub.3 diethyl ether complex and 0.4 ml n-octanol was introduced. The mixture was stirred and reacted for 2 h, 2 ml of ethanol was added to terminate the reaction. 200 ml of absolute ethanol was added to the reaction liquid to precipitate the solid mass. 19 g of cis-Poly-1,4-butadiene was obtained after drying. GPC analysis of cis-polybutadiene indicated that the number average molecular weight was 91,000. Through the determination of HNMR, the cis-1,4 double bond ratio was 98.5%, gel content was less than 0.1%.

[0055] Epoxidation: The procedure was the same as that in Example 1.

[0056] Hydrolysis: The procedure was the same as that in Example 1.

[0057] 1.1 g of solid product was obtained with a number average molecular weight of 72,000 and a Tg value of 48° C.

Example 3

[0058] cis-Polybutadiene: The steps were the same as those in Example 2, except that the polymerization temperature of 40° C. was replaced with 25° C. and the amount of n-octanol added was increased to 0.6 ml. 17.8 g of cis-polybutadiene polymer was obtained, with a number average molecular weight of 23,000 and a cis-1,4 double bond ratio of 98.5%.

[0059] Epoxidation: The procedure was the same as that in Example 1.

[0060] Hydrolysis: The procedure was the same as that in Example 1.

[0061] 1.1 g of solid matter was obtained with a number average molecular weight of 21,000 and a Tg value of 28° C.

Example 4

[0062] cis-Polybutadiene: The steps were the same as those in Example 2, except that the polymerization temperature of 40° C. was replaced with 30° C. and the amount of n-octanol added was 0.4 ml. The number average molecular weight of the polybutadiene polymer obtained was 50500, the cis-1,4 double bond ratio was 99%.

[0063] Epoxidation: The procedure was the same as that in Example 1.

[0064] Hydrolysis: The procedure was the same as that in Example 1

[0065] The number average molecular weight of the solid product obtained was 49,000, and its Tg value was 35° C.

Example 5

[0066] cis-Polybutadiene: The steps were the same as those in Example 2, except that the polymerization temperature of 40° C. was replaced with 45° C. and no n-octanol was added. The number average molecular weight of the polybutadiene polymer obtained was 250,000, the cis-1,4 double bond ratio was 99%.

[0067] Epoxidation: The procedure was the same as Example 1.

[0068] Hydrolysis: The procedure was the same as Example 1

[0069] The number average molecular weight of the solid product obtained was 245,000, and its Tg value was 72° C.

Example 6

[0070] 2 g epoxidation product of Example 1 was dissolved in 200 ml of freshly distilled tetrahydrofuran and then was added into a 500 ml stainless steel autoclave, into which 0.4 g Raney nickel (immersed in ethanol, rinsed 3 times with tetrahydrofuran before being added into the reactor) was added. The nitrogen in the autoclave was charged to a pressure of 1 MPa and released to normal pressure. The nitrogen charging and releasing were repeated for 3 times. Hydrogen was introduced with stirring at 50° C. and was charged to a pressure of 1 MPa. The hydrogen pressure was kept and the reaction was stirred for 12 hours. According to .sup.1HNMR test, the degree of ring opening of epoxy group was about 75% (mol).

[0071] The temperature of the reaction liquid was reduced to 0° C., and the pressure relief was conducted. The catalyst was filtered.

[0072] A solution formulated with 5 ml water, 1 ml perchloric acid and 5 ml tetrahydrofuran was added dropwise into the reaction liquid from which the catalyst had been filtered out. The addition was completed within 30 min, and the reaction temperature was allowed to rise to 25° C. The temperature was maintained and stirring was conducted for 12 hours. According to .sup.1HNMR (DMSO) analysis, the characteristic chemical shift peak of the epoxidized butadiene rubber had disappeared; the units with adjacent dihydroxyl accounted for 24.5%. 0.37 g solid sodium carbonate was added into the reaction liquid and the mixture was stirred for 2 hours. Water was added dropwise into the reaction liquid to precipitate, to which was add with water and soaked for 24 h. Water was filtered. The resulting polymer substance was dried for 24 h at room temperature and dried to constant weight at 40° C. in a vacuum oven. 2.35 g solid matter was obtained with a number average molecular weight of 133,000 and a Tg value of 66° C.

Example 7

[0073] 10 g of the hydrolysate from Example 1 was added into 100 ml DMSO. The mixture was stirred under nitrogen atmosphere at 50° C. for 12 h, a polymer solution was obtained. The polymer solution was placed into a container, sterilized and stored for further use.

[0074] The above polymer solution was introduced into normal saline and precipitation occurred immediately. The precipitate gradually becomes firm and dense from the inside out. The experiment showed that the embolic composition provided by the present invention may rapidly cure, and form an elastic solid after curing.

TABLE-US-00001 TABLE 1 The parameters of the polymers prepared in Examples 1-6 Number Proportion Proportion Glass average %* of %* of transition molecular structural structural tem- Dimethyl weight/Ten units of units of perature/ sulfoxide Example thousand formula 1 formula 2 ° C. dissolution 1 14.6  100% 0 56 Heat to dissolve 2 7.2  100% 0 48 Dissolve 3 2.1  100% 0 28 Dissolve 4 4.9  100% 0 35 Dissolve 5 24.5  100% 0 72 Heat to swell 6 13.3 24.5% 75.5% 66 Dissolve *Proportion of structural units of formula 1 = moles of structural units of formula 1/(moles of structural units of formula 1 + moles of structural units of formula 2) × 100%; Proportion of structural units of formula 2 = moles of structural units of formula 2/(moles of structural units of formula 1 + moles of structural units formula 2) × 100%.

[0075] As can be seen from the above examples 1-6, when the number average molecular weight was less than 50,000, the Tg value of the polymer was lower than 35° C.; When the molecular weight was higher than 240,000, it was hard to dissolve the polymer in solvents such as dimethyl sulfoxide, and it was difficult to formulate a solution.

TABLE-US-00002 Test Example 1 Whether there The adhesion was embolic of the material precipitated Ethylene adhesion at the flowing out embolism content, in outlet of during the Precipitated mass to the Solution mol % micro-catheter process embolism mass skin * Example 1 / No adhesion No Elastic and sticky Adhesion to glass rod EVOH-1 27% Adhesion Yes Elastic and not No adhesion sticky to glass rod EVOH-2 38% Adhesion No Elastic and not No adhesion sticky to glass rod EVOH-3 48% Adhesion No Elastic and not No adhesion sticky to glass rod Example 11 / No adhesion No Elastic and sticky Adhesion to glass rod * naked back skin of the rat after removing hair on back of the rats with electric hair removal scissors; the EVOH solution was prepared by referring to Example 7.

[0076] Test Example 1 was completed by using the following liquid embolic agent in vitro experimental device:

[0077] for a dropper of a disposable infusion set was filled with 2 mm diameter glass beads. The upper end of the dropper was connected to a normal saline bottle, the distance between the outlet of normal saline bottle and the bottom outlet of the hanging infusion set was greater than 1.5 m. The microcatheter was placed in the container having glass beads through a Y-shaped connector. The flow rate of normal saline at 37° C. was set to 0.3 ml/s. The liquid embolic agent was slowly injected into the dropper through the microcatheter via a constant velocity injection device; during the injection process, the change of flow rate of the normal saline was continuously measured. With the injection of embolic material, the water flow slows down until it was completely stopped. As for the embolic agent containing the compound in the experimental example, there was no embolic material flew out through the container of the glass beads during embolization. The embolic material was evenly dispersed in the glass bead container to achieve a good embolization effect. The precipitated embolic mass does not stick to the outlet of the microcatheter, so it confirmed that the compounds of the examples were compatible with different types of microcatheters.

Test Example 2. Performance Test of Adhesion to Glass

[0078] The polymer prepared in Examples 1, 4 and 6 and EVOH-1 (purchased from Kuraray, ethylene mol % was 27%) was added into the DMSO to dissolve and formulate into a solution with a concentration of 10%. PVA (purchased from Shanghai Chenqi Chemical Technology Ltd., the molecular weight was 80,000, the degree of alcoholysis was 99%) was dissolved in ethanol, so as to formulate a solution with a concentration of 10%.

[0079] The above polymer solutions were poured onto a clean extra clear glass surface respectively. The glass coated with EVOH-1, the polymer prepared in Examples 1, 4 and 6 were placed in a constant humidity space with humidity of approximately 90%; after 12 hours, the film surfaces were rinsed several times with water to rinse DMSO, then dried and the polymer films were peeled off. The glass coated with PVA-ethanol solution was dired directly and the polymer film was peeled off.

TABLE-US-00003 EVOH-1 PVA Example 1 Example 4 Example 6 The difficulty Easy Easy Adhere Adhere Adhere of separation together together together of polymer and and and film from cannot be cannot be cannot be glass peeled off peeled off peeled off

[0080] Due to the adjacent dihydroxyl group, the polymer of the invention is prone to form strong hydrogen bonds with substances which contains oxygen, nitrogen and the like on the surface, and its adhesion to skin and glass is greater than that of EVOH and PVA. When applied in embolic agents, it not only has good precipitation of EVOH, but also greatly enhances the ability of dumpiness and reinforces the adhesion at the embolism site.

[0081] The embodiments of the present invention have been described above; however, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements and improvements which had made within the spirit and principle of the present invention should be included in the protection scope of the present invention.