Ester copolymer, preparation method thereof and embolism product

Abstract

The invention relates to an ester copolymer, a preparation method thereof and an embolism product. The ester copolymer is in a semi-solid form; the ester copolymer is obtained by carrying out polymerization reaction on glycerol, dicarboxylic acid and a monomer, and the monomer comprises lactic acid and / or caprolactone. The ester copolymer provided by the invention shows a semi-solid character. The ester copolymer cannot be cured or dissolved at room temperature and under the in-vivo condition of 37 DEG C, convenience and feasibility are provided for clinical use, and the characteristics of easy use and delivery can be achieved especially at the positions, which are not easy to operate, in blood vessels, deep wounds and the like.

Description

Technical Field

[0001] The invention relates to an ester copolymer and a preparation method thereof and an embolic product, belonging to the field of biomedicine. Background Art

[0002] Biomaterials are increasingly being used as medical device materials in clinical settings due to their good biocompatibility with human tissues. Currently, commonly used biomaterials in clinical settings include polylactic acid, polycaprolactone, hyaluronic acid, chitosan, gelatin, etc. In order to optimize the performance of biomaterials and enrich the types of biomaterials, some explorations have been conducted in the field of materials science in recent years.

[0003] In order to improve the performance of polysebacic acid glyceride, patent document 1 mixes lactic acid, polyethylene glycol and sebacic acid, stirs at a certain temperature and under nitrogen protection until the sebacic acid is completely dissolved, adds a catalyst to the reaction system, and reacts to obtain a linear chain segment with carboxyl groups at both ends formed by a random copolymer of lactic acid, polyethylene glycol and sebacic acid, adds propylene glycol thereto, and continues to react to obtain an uncrosslinked branched polyester prepolymer, and the obtained polyester prepolymer is implanted in a mold and cured to obtain a biomedical multi-copolymer cross-linked polyester elastomer material with a cross-linked network structure. However, the elastomer material is a solid material, and for specific use sites, such as: intravascular, deep wound surface, etc., solid materials are not easy to use and transport.

[0004] Similarly, Patent Document 2 also discloses a drug implant sustained-release carrier material and its preparation method. It is a mixture of sebacic acid and glycerol in a weight ratio of 1:3-3:1, a polycondensation reaction occurs at a temperature of 130-160°C to generate a prepolymer, different concentrations of lactic acid, glycolic acid, polylactic acid or polyglycolic acid are added to the prepolymer, and then the prepolymer is placed in a container of a certain shape, and further synthesized at a temperature of 120-140°C to form a material with a certain degradation rate and shape. However, the material is still a solid material, and although it has a certain mechanical strength, it is not easy to use and transport.

[0005] In addition, with the progress of research, elastomeric copolymers have also emerged due to their good elasticity and hydrophilicity. Patent document 3 discloses a highly elastic polylactic acid-based copolymer and a preparation method thereof. The preparation method uses the polymerization reaction of L-lactide and polyglycerol sebacate to prepare a highly elastic copolymer. However, the elastomeric copolymer is still not suitable for intravascular, deep wounds, etc., and the elastomeric copolymer material is still not easy to use and transport.

[0006] Therefore, studying an ester copolymer that can further provide convenience and feasibility for clinical use has become a technical problem that needs to be solved urgently.

[0007] References:

[0008] Patent document 1: CN104629026A

[0009] Patent document 2: CN100540057C

[0010] Patent document 3: CN103304785A Summary of the invention

[0011] Problem that the invention aims to solve

[0012] In view of the technical problems existing in the prior art, the present invention first provides an ester copolymer. The ester copolymer of the present invention presents a semi-solid state. It will not solidify or dissolve under room temperature and 37°C in vivo conditions, providing convenience and feasibility for clinical use.

[0013] Furthermore, the present invention also provides a method for preparing an ester copolymer, which is simple and easy to implement, and the raw materials are easy to obtain, and is suitable for mass production.

[0014] Furthermore, the present invention also provides embolic products prepared using ester copolymers, which may include semi-solid embolic agents, liquid embolic agents or copolymer spring coils. The semi-solid embolic agents have good catheter delivery and imaging characteristics, are convenient for clinical use, and can reduce the amount of contrast agents used, or even do not need to add contrast agents, thereby improving the biocompatibility and safety of the products. All three embolic products are degradable, which can avoid long-term inflammation caused by non-degradable materials.

[0015] Solutions for solving problems

[0016] The invention provides an ester copolymer, which is in the form of a semisolid; the ester copolymer is obtained by polymerization reaction of glycerol, a dicarboxylic acid and a monomer, wherein the monomer comprises lactic acid and / or caprolactone.

[0017] Further, the viscosity of the ester copolymer is in the range of 10000 Pa.s to 150000 Pa.s, preferably 80000 Pa.s to 150000 Pa.s; and / or,

[0018] The weight average molecular weight of the ester copolymer is 5000-150000 Da, preferably 10000-50000 Da.

[0019] Furthermore, the ester copolymer has a structure shown in the following formula (1):

[0020]

[0021] wherein R is -(CH2)4CH2OC(O)CH(OH)CH2CH3, -CH(OH)CH3 or -(CH2)4CH2OH;

[0022] m is an integer of 1-15, preferably an integer of 3-10;

[0023] n is an integer greater than 3, preferably greater than 10, more preferably 50-250.

[0024] Further, the dicarboxylic acid includes one or a combination of two or more of glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid, preferably includes sebacic acid;

[0025] The lactic acid includes one or a combination of two or more of L-lactic acid, D-lactic acid, and D,L-lactic acid;

[0026] The caprolactone includes ε-caprolactone.

[0027] The present invention also provides a method for preparing the ester copolymer according to the present invention, which comprises polymerizing glycerol, dicarboxylic acid and monomer in the presence of a catalyst to obtain the ester copolymer.

[0028] Further, the molar ratio of glycerol, dicarboxylic acid and monomer is (1-3):(1-3):(1-6);

[0029] Preferably, the catalyst comprises a tin substance; more preferably, the mass volume ratio (g / μL) of the monomer to the catalyst is (1-10):(1-10).

[0030] Furthermore, the polymerization reaction is carried out under the conditions of first passing an inert gas and then evacuating the mixture, and the reaction process includes heating and stirring operations; preferably, the polymerization reaction temperature is 120°C-160°C, and the reaction time is 48h-96h, preferably 48h-72h.

[0031] The present invention also provides a use of the ester copolymer according to the present invention in preparing embolic products, wound hemostatic products, cavity filling products or soft tissue repair products.

[0032] The present invention further provides an embolic product, which comprises the ester copolymer according to the present invention; preferably, the embolic product comprises a semisolid embolic agent, a liquid embolic agent or a copolymer spring coil.

[0033] Furthermore, the semisolid embolic agent further comprises an inorganic solvent; preferably, in the semisolid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the inorganic solvent is (1-100):(1-100);

[0034] More preferably, the semisolid embolic agent further comprises an inorganic solvent and a hydrophilic substance; in the semisolid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the mixture of the inorganic solvent and the hydrophilic substance is (1-100):(1-100).

[0035] Furthermore, the hydrophilic substance is one or more of polyethylene glycol, polyvinyl alcohol, sorbitol, ethanol, and silicate; preferably, the silicate is lithium magnesium silicate.

[0036] Furthermore, the semi-solid embolic agent is obtained by mixing an inorganic solvent, an ester copolymer and optionally a hydrophilic substance, and then grinding, stirring or homogenizing. Preferably, the semi-solid embolic agent is obtained by first mixing the hydrophilic substance with an inorganic solvent to form a hydrophilic substance solution or hydrogel, and then mixing it with the ester copolymer, and then grinding, stirring or homogenizing.

[0037] Further, the liquid embolic agent comprises the ester copolymer and an organic solvent; preferably, in the liquid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the organic solvent is (1-100):(1-100);

[0038] More preferably, the liquid embolic agent further comprises other copolymers, and the other copolymers include polylactic acid-glycolic acid copolymer and / or poly (D, L-lactide-glycolide); further preferably, the mass ratio of the ester copolymer to the other copolymers is 1: (0.1-10), preferably 1: (0.4-4).

[0039] Furthermore, the copolymer spring coil is obtained by placing a substance containing an ester copolymer in a mold and curing it; preferably, the curing temperature is 130° C.-160° C., and the curing time is 24h-72h, preferably 24h-36h.

[0040] Furthermore, the embolic product further comprises a developer and / or a drug; preferably,

[0041] The drug includes one or more of doxorubicin, epirubicin, apatinib, doxorubicin, mitomycin, and cisplatin; and / or,

[0042] The developer is one or a combination of two or more of iodized oil, iodophenyl ester, sodium iodide, diatrizoate, iohexol, iodixanol, iohexol, iopromide, iobiprole, iotrolan, tantalum powder, barium sulfate, bismuth trioxide or zirconium oxide.

[0043] Effects of the Invention

[0044] The ester copolymer of the present invention has a semi-solid state. The ester copolymer will not solidify or dissolve at room temperature and 37°C in vivo, providing convenience and feasibility for clinical use, especially for difficult-to-operate locations such as intravascular and deep wounds, and can achieve the characteristics of easy use and delivery.

[0045] Furthermore, the preparation method of the ester copolymer of the present invention is simple and easy, the raw materials are easy to obtain, and it is suitable for mass production.

[0046] Furthermore, the ester copolymers of the present invention have a wide range of applications, and can be used to prepare liquid embolic agents, semisolid embolic agents or copolymer coils, etc., and can be selected according to the conditions that require embolization, such as vascular malformations, aneurysms, multivascular tumors, etc. Therefore, the ester copolymers of the present invention can basically meet the required clinical use. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 A photograph showing the appearance of the ester copolymer sample of Example 4 of the present application.

[0048] Figure 2 The photograph showing the appearance of the ester copolymer sample prepared in Comparative Example 2 of the present application is shown.

[0049] Figure 3 A photograph showing the appearance of the semisolid embolic sample of Example 10 of the present application is shown.

[0050] Figure 4 The in vitro development photographs of the semi-solid embolic samples of Example 10 of the present application are shown (the dark-colored samples are developed after being loaded in a syringe, and the light-colored samples are developed in a blank syringe).

[0051] Figure 5 A photograph showing a sample of the semisolid plug according to Example 10 of the present application being delivered using a catheter.

[0052] Figure 6 A photograph of the abdominal aorta of a rat after injection of the semisolid embolic agent of Example 9 is shown.

[0053] Figure 7 A photograph of the left kidney of a rabbit before injection of the semisolid embolic agent of Example 9 is shown, and the color is bright red.

[0054] Figure 8 A photograph of the left kidney of a rabbit after injection of the semisolid embolic agent of Example 9 is shown, and the color is dark red. DETAILED DESCRIPTION

[0055] Various exemplary embodiments, features and aspects of the present invention will be described in detail below. The word "exemplary" used here means "used as an example, embodiment or illustrative". Any embodiment described here as "exemplary" is not necessarily interpreted as being superior or better than other embodiments.

[0056] In addition, in order to better illustrate the present invention, numerous specific details are provided in the following specific embodiments. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In other examples, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the subject matter of the present invention.

[0057] Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0058] In this specification, the word "may" means both performing a certain process and not performing a certain process.

[0059] In this specification, the references to "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", etc., mean that the specific elements (e.g., features, structures, properties and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0060] In this specification, the numerical range expressed using "numerical value A - numerical value B" means a range including the endpoint numerical values ​​A and B.

[0061] In this specification, when "normal temperature" or "room temperature" is used, the temperature may be 10-25°C.

[0062] In this specification, the "water" used can be any feasible "water" in the field of medical materials, such as high-purity water, purified water, deionized water, distilled water, double-distilled water, etc.

[0063] <First aspect>

[0064] The first aspect of the present invention provides an ester copolymer in the form of a semisolid, which is obtained by polymerization of glycerol, a dicarboxylic acid and a monomer, wherein the monomer includes lactic acid and / or caprolactone.

[0065] The ester copolymer of the present invention has a semi-solid property and will not solidify or dissolve under the in vivo conditions of room temperature and 37° C., thus providing convenience and feasibility for clinical use.

[0066] The ester copolymer of the present invention is in the form of a semi-solid. In the present invention, a semi-solid is a substance between a solid and a liquid. A semi-solid can support its own weight and maintain its own shape, but also has some properties of a liquid, such as being able to change shape under pressure and being able to flow under low pressure.

[0067] Furthermore, in the present invention, the viscosity of the ester copolymer is in the range of 10000 Pa.s to 150000 Pa.s, preferably 80000 Pa.s to 150000 Pa.s. When the viscosity of the ester copolymer is in the range of 10000 Pa.s to 150000 Pa.s, the semi-solid state of the ester copolymer can be better maintained.

[0068] Furthermore, in the present invention, the weight average molecular weight of the ester copolymer is 5000-150000Da, preferably 10000-50000Da. When the weight average molecular weight of the ester copolymer is 5000Da-150000Da, the semi-solid form of the ester copolymer can be better maintained.

[0069] In some specific embodiments, the ester copolymer has a structure shown in the following formula (1):

[0070]

[0071] wherein R is -(CH2)4CH2OC(O)CH(OH)CH2CH3, -CH(OH)CH3 or -(CH2)4CH2OH;

[0072] m is an integer of 1-15, preferably an integer of 3-10;

[0073] n is an integer greater than 3, preferably greater than 10, more preferably 50-250.

[0074] Specifically, in the present invention, m can be an integer of 1-15, preferably an integer of 3-10, such as 5, 7, 8, 9, 11, 13, etc.; n is an integer greater than 3, preferably greater than 10, more preferably 50-250, such as 80, 100, 120, 150, 180, 200, 220, etc. When m is an integer of 1-15, and n is an integer greater than 3, preferably greater than 10, especially 50-250, the desired semi-solid ester copolymer can be obtained.

[0075] In some specific embodiments, the dicarboxylic acid may include one of glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid. By using a suitable dicarboxylic acid, the corresponding ester copolymer can be prepared.

[0076] Further, the present invention can prepare a semi-solid ester copolymer by using specific monomers. The monomers can be lactic acid and / or caprolactone. When lactic acid and / or caprolactone are used, a semi-solid ester copolymer can be obtained by a suitable polymerization method. Specifically, the lactic acid includes at least one of left-lactic acid (L-lactic acid), right-lactic acid (D-lactic acid), and D,L-lactic acid, and the caprolactone includes ε-caprolactone.

[0077] <Second Aspect>

[0078] The second aspect of the present invention provides a method for preparing an ester copolymer, comprising polymerizing glycerol, a dicarboxylic acid and a monomer in the presence of a catalyst to obtain an ester copolymer.

[0079] The present invention does not specifically limit the catalyst, and it can be a catalyst commonly used in the art, such as a tin catalyst, etc. Specifically, the tin catalyst can include one or a combination of two or more of stannous octoate, stannous chloride, dibutyltin oxide, dibutyltin dibutyrate, dimethyltin dibutyrate, dioctyltin dibutyrate, dibutyltin diacetate, dimethyltin diacetate, dioctyltin diacetate, dibutyltin dilaurate, dimethyltin dilaurate, dioctyltin dilaurate, dibutyltin dioleate, dimethyltin dioleate, dioctyltin dioleate, etc.

[0080] The present invention does not specifically limit the amount of the catalyst, and can be set as needed. Preferably, in the present invention, the mass volume ratio (g / μL) of the monomer to the catalyst is (1-10):(1-10), that is, the mass of the monomer to the volume ratio (g / μL) of the catalyst is (1-10):(1-10); for example: (3-9):(3-9), (5-7):(5-7), (3-9):(5-7), (5-7):(3-9), etc. When the mass volume ratio (g / μL) of the monomer to the catalyst is (1-10):(1-10), the catalytic performance is excellent.

[0081] There is no particular limitation on the dicarboxylic acid and the monomer, which are the dicarboxylic acid and the monomer described in the first aspect.

[0082] In some specific embodiments, in the present invention, the molar ratio of glycerol, dicarboxylic acid and monomer is (1-3): (1-2): (1-3), for example: (1.5-2.5): (1.2-1.8): (1.5-2.5), (1.8-2.2): (1.4-1.6): (1.8-2.2), etc. When further, when the molar ratio of glycerol, dicarboxylic acid and monomer is (1-3): (1-2): (1-3), the desired ester copolymer can be obtained. In addition, when the monomer contains lactic acid and caprolactone, the molar ratio of glycerol, dicarboxylic acid, lactic acid and caprolactone is (1-3):(1-2):(1-3):(1-3), for example: (1.5-2.5):(1.2-1.8):(1.5-2.5), (1.8-2.2):(1.4-1.6):(1.8-2.2), etc.

[0083] In some specific embodiments, in the present invention, in order to obtain an ester copolymer with better performance, the polymerization reaction of the present invention is first introduced with an inert gas and then carried out under vacuum conditions, and the reaction process includes heating and stirring operations; specifically, the inert gas described in the present invention refers to a gas that does not participate in the chemical reaction, and can specifically be argon or nitrogen.

[0084] In the present invention, the conditions of the polymerization reaction are not particularly limited, as long as the desired ester copolymer can be obtained. Specifically, the polymerization reaction temperature is 120°C-160°C, for example: 130°C, 135°C, 140°C, 145°C, 150°C, etc.; the reaction time is 48h-72h, for example: 52h, 56h, 60h, 64h, 68h, etc.

[0085] In addition, it should be noted that during the polymerization reaction, the present invention requires continuous stirring. By stirring, the semi-solid ester copolymer of the present invention can be obtained.

[0086] <Third Aspect>

[0087] The third aspect of the present invention provides a use of the ester copolymer described in the present application for preparing embolic products, wound hemostatic products, cavity filling products or soft tissue repair products. For embolic products, they can be used for varicose vein embolism, arteriovenous sinus embolism, aneurysm embolism, peripheral vascular embolism, etc. Specifically, the present invention also provides an embolic product, which can include a liquid embolic agent, a semi-solid embolic agent or a copolymer coil.

[0088] Furthermore, the embolic preparation of the present invention further comprises a developer and / or a drug. Specifically, the drug comprises one or more of adriamycin, epirubicin, apatinib, doxorubicin, mitomycin, and cisplatin.

[0089] Developer refers to a drug that turns the latent image produced by the photosensitive material after exposure into a visible image. From the perspective of chemical components, developers can be divided into two categories: inorganic compounds and organic compounds. For inorganic compounds, it can be one or a combination of two or more of micron or nanometer-level barium sulfate, tantalum powder, bismuth trioxide, zirconium oxide, etc.; for organic compounds, it can be one or a combination of two or more of the developers including iodized oil, iodophenyl ester, sodium iodide, diatrizoate, iohexol, iodixanol, iopromide, iobiprole, iotrolan, etc.

[0090] Preferably, in the present invention, the mass ratio of the developer to the copolymer is: (1-30):(99-70), for example: (5-25):(75-95), (10-20):(80-90), 15:85, etc.

[0091] Liquid embolic agents

[0092] In the present invention, the liquid embolic agent comprises the ester copolymer and an organic solvent; preferably, in the liquid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the organic solvent is (1-100):(1-100); that is, the ratio (g / mL) of the mass of the ester copolymer to the volume of the organic solvent is (1-100):(1-100), for example: (10-90):(10-90), (20-80):(20-80), (30-70):(30-70), (40-60):(40-60), etc.

[0093] The present invention does not specifically limit the organic solvent, and it can be any feasible organic solvent in the art, such as one or a combination of two or more of dimethyl sulfoxide (DMSO), dichloromethane, chloroform, methanol, petroleum ether or ethyl acetate.

[0094] Further, in the present invention, other copolymers can be added as needed to prepare the desired liquid embolic agent. The other copolymers can include, for example, polylactic acid-co-glycolic acid copolymer, poly (D, L-lactide-co-glycolide) and other suitable copolymers. Specifically, the mass ratio of the ester copolymer to the other copolymers is 1: (0.1-10), preferably 1: (0.4-4), for example: 1: 0.3, 1: 0.7, 1: 1, 1: 3, 1: 5, 1: 7, 1: 9, etc.

[0095] The liquid embolic agent of the present invention is degradable, and can avoid long-term inflammation caused by non-degradable materials in the body. The liquid embolic agent can be injected into the body to form an embolism in situ, and is particularly suitable for embolism of irregular vascular malformations. The present invention does not specifically limit the preparation method of the liquid embolic agent, and can specifically be prepared by dissolving the ester copolymer and other optional copolymers in an organic solvent.

[0096] Semisolid embolic agents

[0097] In the present invention, the semi-solid embolic agent comprises the ester copolymer and an inorganic solvent; preferably, in the semi-solid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the inorganic solvent is (1-100):(1-100), that is, the mass volume ratio (g / mL) of the ester copolymer to the inorganic solvent is (1-100):(1-100). When the mass volume ratio (g / mL) of the ester copolymer to the inorganic solvent is (1-100):(1-100), the desired semi-solid embolic agent can be obtained. The present invention does not specifically limit the inorganic solvent, and it can be any feasible inorganic solvent commonly used in the art. For example: water.

[0098] Furthermore, the semi-solid embolic agent comprises the ester copolymer, an inorganic solvent and a hydrophilic substance; in the semi-solid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the mixture of the inorganic solvent and the hydrophilic substance is (1-100):(1-100), that is, the mass ratio (g / mL) of the ester copolymer to the volume ratio (g / mL) of the mixture of the inorganic solvent and the hydrophilic substance is (1-100):(1-100), for example: (10-90):(10-90), (20-80):(20-80), (30-70):(30-70), (40-60):(40-60), etc. When the mass volume ratio (g / mL) of the ester copolymer to the mixture of the inorganic solvent and the hydrophilic substance is (1-100):(1-100), not only will the function of the semi-solid embolic agent not be affected, but the desired semi-solid embolic agent can also be further prepared.

[0099] In some specific embodiments, the semisolid embolic agent also contains a hydrophilic substance; more preferably, the mass ratio of the hydrophilic substance to the ester copolymer is 1:(2-99), for example: 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, etc.

[0100] The hydrophilic substance includes, but is not limited to, polyethylene glycol (weight average molecular weight of 200-6000 Da), polyvinyl alcohol (weight average molecular weight of 8500-15000 Da), ethanol, sorbitol, silicate (eg, lithium magnesium silicate), polyacrylamide and its derivatives.

[0101] Specifically, the preparation method of the semi-solid embolic agent includes mixing an inorganic solvent, an ester copolymer and optionally a hydrophilic substance, and grinding, stirring or homogenizing to obtain a semi-solid embolic agent; preferably, the semi-solid embolic agent is obtained by first mixing the hydrophilic substance with the inorganic solvent to form a hydrophilic substance solution or hydrogel, and then mixing it with the ester copolymer, and then grinding, stirring or homogenizing at high speed. Preferably, the concentration of the hydrophilic substance solution or hydrogel ranges from 1% to 20%, for example: 3%, 5%, 7%, 9%, 10%, 12%, 15%, 18%, etc.

[0102] The semisolid embolic agent of the present invention has good catheter transportability and imaging characteristics, is convenient for clinical use and operation, reduces the amount of contrast agent used or does not need to increase the contrast agent, and can be used for multi-vascular tumor embolization, especially aneurysm embolization.

[0103] Copolymer Spring Coil

[0104] The copolymer spring coil of the present invention can be obtained by curing the ester copolymer in a mold. Specifically, the curing temperature is 130°C-160°C, for example: 135°C, 140°C, 145°C, 150°C, 155°C, etc.; the curing time is 24h-72h, preferably 24h-36h, for example: 28h, 32h, 40h, 44h, 48h, 52h, 56h, 60h, 64h, 68h, etc.

[0105] Furthermore, an appropriate amount of contrast agent may be added to the copolymer spring coil of the present invention. The contrast agent may be the contrast agent described in the first aspect. Specifically, in the copolymer spring coil, the content of the ester copolymer is 80%-99%, preferably 90%-99%, for example: 82%, 85%, 88%, 90%, 92%, 95%, 98%, etc.

[0106] The copolymer spring coil of the present invention does not need metal material support, is completely degradable, and can avoid long-term inflammation caused by non-degradable materials. It can be used for embolization of irregular vascular malformations, embolization of aneurysms, etc.

[0107] Example

[0108] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0109] Example 1

[0110] Glycerol, sebacic acid and lactic acid (CAS: 50-1-5) were weighed in a molar ratio of 1:1:1, 9.2 g, 20.2 g and 9 g were added to a reactor, 90 μL of stannous octoate was added, and the mixture was heated to 150°C under argon and then vacuum conditions. The reaction was stirred continuously for 48 hours to obtain a semi-solid poly(glycerol sebacate-lactic acid) copolymer.

[0111] Example 2

[0112] Glycerol, sebacic acid and ε-caprolactone were weighed in a molar ratio of 1:1:1, 9.2 g, 20.2 g and 11.4 g were added to a reactor, and 110 μL of stannous octoate was added. The reaction was heated to 160°C under argon gas and then vacuum conditions. The reaction was stirred continuously for 48 hours to obtain a semi-solid poly(glycerol sebacate-ε-caprolactone) copolymer.

[0113] Example 3

[0114] According to the molar ratio of glycerol, sebacic acid, lactic acid (CAS: 50-1-5), and ε-caprolactone of 3:1.5:1:1, 27.6 g, 30.3 g, 9 g, and 11.4 g are weighed respectively, and the above materials are added into a reactor, 80 μL of stannous octoate is added, argon is first passed, and then under vacuum conditions, heated to 130°C, and the reaction is stirred continuously for 48 hours to obtain a semi-solid poly(sebacic acid glyceryl-lactic acid-caprolactone) copolymer.

[0115] Example 4

[0116] According to the molar ratio of glycerol, sebacic acid, L-lactic acid and ε-caprolactone of 1:1:1:1.5, 9.2g, 20.2g, 9g and 17.1g were weighed respectively, and the above materials were added into a reactor. 20μL of stannous octoate was added, and the reaction was heated to 120°C under argon gas and then vacuum conditions for 48h to obtain a semi-solid poly(sebacic acid glyceryl-L-lactic acid-ε-caprolactone) copolymer.

[0117] Example 5

[0118] According to the molar ratio of glycerol, sebacic acid, D-lactic acid, and ε-caprolactone of 3:3:1:3, 27.6 g, 60.6 g, 9 g, and 34.2 g were weighed respectively and added to the reactor, 250 μL of stannous octoate was added, and the mixture was heated to 160° C. and reacted for 48 hours under the conditions of first passing argon gas and then evacuating the vacuum. A semi-solid poly(sebacic acid glyceride-D-lactic acid-ε-caprolactone) copolymer was obtained.

[0119] Example 6

[0120] According to the molar ratio of glycerol, sebacic acid, D,L-lactic acid and ε-caprolactone of 2:1.5:1:3, 18.4g, 30.3g, 9g and 34.2g were weighed respectively and added into the reactor, 200μL of stannous octoate was added, argon was first passed, and then vacuum was evacuated, and the reaction was heated to 120°C for 72h to obtain a semi-solid poly(sebacic acid glyceryl-D,L-lactic acid-ε-caprolactone) copolymer.

[0121] Example 7

[0122] Take 9 g of the poly(glycerol sebacate-lactic acid) copolymer synthesized in Example 1 into a container, add 1 ml of a 5% polyethylene glycol (weight average molecular weight of 200-6000 Da) solution, and stir at high speed to make the copolymer uniformly white to obtain a semisolid embolic agent.

[0123] Example 8

[0124] 10 g of the poly(glycerol sebacate-ε-caprolactone) copolymer synthesized in Example 2 was placed in a container, and 6 ml of a 1% polyvinyl alcohol (weight average molecular weight 8500-15000 Da) solution was added, and stirred at high speed until the copolymer was uniformly white, thereby obtaining a semisolid embolic agent.

[0125] Example 9

[0126] Take 10g of the poly(glycerol sebacate-L-lactic acid-ε-caprolactone) copolymer synthesized in Example 4 in a container. Measure 10mL of water in another container, slowly add 1g of lithium magnesium silicate to the water under high-speed stirring conditions to obtain lithium magnesium silicate hydrogel. Then add the above 10g of copolymer to the lithium magnesium silicate hydrogel, continue to stir at high speed until the copolymer is uniformly white, and add 2g of tantalum powder as a developer. A semisolid embolic agent is obtained.

[0127] Example 10

[0128] 10 g of the poly(glycerol sebacate-D,L-lactic acid-ε-caprolactone) copolymer synthesized in Example 6 was placed in a centrifuge tube, and 2 ml of a 5% sorbitol solution was added, and the mixture was stirred at high speed until the copolymer became white, thereby obtaining a semisolid embolic agent.

[0129] Embodiment 11

[0130] 3 g of the poly(glyceryl sebacate-lactic acid) copolymer synthesized in Example 1 was placed in a beaker, 3 mL of DMSO was added, and the mixture was stirred to dissolve to prepare a liquid embolic agent.

[0131] Example 12

[0132] 3 g of PLGA was dissolved in 10 mL of DMSO and stirred to dissolve. 5 g of the poly(glycerol sebacate-lactic acid-ε-caprolactone) copolymer synthesized in Example 3 was slowly added to the above container and stirred until dissolved to prepare a liquid embolic agent.

[0133] Example 13

[0134] 2 g of PDLGA was dissolved in 6 mL of DMSO and stirred to dissolve. 1.2 g of the poly(glycerol sebacate-D-lactic acid-ε-caprolactone) copolymer synthesized in Example 5 was slowly added to the above container and stirred until dissolved to prepare a liquid embolic agent.

[0135] Embodiment 14

[0136] 0.5 g of the poly(glycerol sebacate-ε-caprolactone) copolymer synthesized in Example 2 was added to a spring coil mold and vacuum cured at 130° C. for 73 h to obtain a degradable copolymer spring coil.

[0137] Embodiment 15

[0138] Take 0.8 g of the poly(glycerol sebacate-L-lactic acid-ε-caprolactone) copolymer synthesized in Example 4 into a container, add 0.2 g of tantalum powder, stir evenly, then add it into a spring coil mold, and vacuum cure at 150°C for 48 hours to obtain a degradable copolymer spring coil.

[0139] Example 16

[0140] Take 1 g of the poly(glycerol sebacate-D,L-lactic acid-ε-caprolactone) copolymer synthesized in Example 6 into a container, add 0.01 g of barium sulfate, stir evenly, then add it into a spring coil mold, and vacuum cure at 160°C for 36 hours to obtain a degradable copolymer spring coil.

[0141] Comparative Example 1

[0142] The molar ratio of glycerol to sebacic acid was 1:1. 9.2 g and 20.2 g were weighed respectively and added to a reactor. Argon was first introduced and then vacuumed. The reactor was heated to 130° C. and stirred continuously for 48 hours to obtain a solid poly(sebacic acid glyceride) polymer.

[0143] Comparative Example 2

[0144] Glycerol, sebacic acid and ε-caprolactone were weighed in a molar ratio of 1:1:1, 9.2g, 20.2g, and 11.4g were added to the reactor, and 90μL of stannous octoate was added. Argon was first passed, and then vacuum was evacuated, and the mixture was heated to 150°C and stirred for 6h to obtain a prepolymer. The mixture was stirred statically and vacuum was continued to maintain a low vacuum degree in the reactor, and the mixture was heated to 140°C and reacted for 30h to obtain a solid poly(sebacic acid glyceride-ε-caprolactone) elastomer.

[0145] Performance Testing

[0146] 1. Performance test of ester copolymers

[0147] 1.1 Weight average molecular weight test

[0148] Take the samples of Example 1, Example 2, Example 6, Comparative Example 1 and Comparative Example 2, and use tetrahydrofuran as the solvent to perform molecular weight detection on the samples using GPC. Specifically, the samples of Example 1, Example 2, Example 6 and Comparative Example 1 can be dissolved in tetrahydrofuran, but the sample of Comparative Example 2 is difficult to dissolve in tetrahydrofuran, and cannot be dissolved in organic solvents such as DMSO, dichloromethane, and ethyl acetate, so the sample cannot be tested. The detection results are shown in Table 1 below.

[0149] Table 1

[0150] sample Weight average molecular weight / Da Example 1 13295 Example 2 18299 Example 6 20621 Comparative Example 1 3572 Comparative Example 2 /

[0151] It can be seen from Table 1 that the crosslinking degree of the ester copolymer of the present invention is lower than that of Comparative Example 2, but higher than that of Comparative Example 1. Therefore, the ester copolymer is in a semi-solid state.

[0152] 1.2 Viscosity test

[0153] Take the samples of Example 1, Example 2, Example 6, Comparative Example 1 and Comparative Example 2, and use a viscometer to test the viscosity of the samples at (25±2)°C. The test results are summarized in Table 2 below.

[0154] Because Comparative Example 1 and Comparative Example 2 are solid at room temperature, their viscosity cannot be tested.

[0155] Table 2

[0156] sample Viscosity (mPa.S) Example 1 108000 Example 2 88900 Example 6 93210 Comparative Example 1 / Comparative Example 2 /

[0157] It can be seen from Table 2 that the viscosity of the ester copolymer of the present invention is relatively high, and therefore, the ester copolymer is in a semi-solid state.

[0158] 2. Performance evaluation of embolic products

[0159] 2.1 Stability at room temperature

[0160] The samples of Example 7, Example 8, Example 9, Example 10 and Comparative Example 1 and Comparative Example 2 were placed in a beaker, and the beaker mouth was sealed. The samples were placed in a room overnight, and the appearance of the samples was observed. The results are shown in Table 3.

[0161] 2.2 Stability at 37°C

[0162] The samples of Example 7, Example 8, Example 9, Example 10 and Comparative Example 1 were injected into silicone tubes with openings at both ends, then immersed in artificial blood and placed in a 37° C. water bath to observe whether the samples in the test silicone tubes flowed out. The results are shown in Table 3.

[0163] 2.3 In vitro imaging evaluation

[0164] The samples of Example 7, Example 8, Example 9, Example 10 and Comparative Example 1 were observed in vitro using a direct-view angiography (DSA). The results are shown in Table 3.

[0165] 2.4 Catheter deliverability assessment

[0166] In order to simulate the clinical operation of vascular embolism, the samples of Example 7, Example 8, Example 9, Example 10 and Comparative Example 1 were respectively loaded into 1 mL syringes at room temperature, and a catheter with a Luer head (the inner diameter of the catheter was 1 mm) was connected to the outlet of the syringe, and the outlet of the catheter was immersed in water, and the load in the syringe was pushed out with water. Whether blockage occurred during the delivery process was evaluated, and the results are shown in Table 3.

[0167] Table 3

[0168]

[0169] As can be seen from Table 3, the samples of Comparative Examples 1 and 2 have the problems of low freezing point and instability under human body temperature, and do not meet the requirements for clinical embolization. The copolymer synthesized in the present invention maintains a complete morphology under human body temperature, and by adding water or aqueous solution or hydrogel, the synthesized copolymer has good catheter transportability and developability, which meets the physical and chemical performance requirements of ideal embolization products.

[0170] 2.5 Animal experiments

[0171] The samples of Example 7, Example 9 and Example 12 were respectively taken to carry out the following animal experiments to verify the embolization effect of the material of the present invention.

[0172] Nine rats were anesthetized and placed on an experimental operating table. The abdominal aorta of the rats was exposed and the above samples were injected into the abdominal aorta of the rats respectively. Three animals were tested for each sample. After injection, the injection site was observed for blood leakage and movement of the embolic material.

[0173] Take 9 rabbits, anesthetize them, place them on the experimental operation table, perform surgery, expose the left renal artery of the rats, observe and record the kidney color before injection, inject the above samples into the left renal artery, and experiment on 3 animals for each sample. After injection, observe whether there is blood leakage at the injection site and observe the change of kidney color. The experimental results are summarized in Table 4 below:

[0174] Table 4

[0175]

[0176] It can be seen from Table 4 that the samples prepared by the present invention can effectively embolize blood vessels.

[0177] It should be noted that, although the technical solution of the present invention is introduced with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0178] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. An ester copolymer, characterized in that: The ester copolymer is in the form of a semisolid; the ester copolymer is obtained by polymerization of glycerol, dicarboxylic acid and monomers, and the monomers include lactic acid and / or caprolactone.

2. The ester copolymer according to claim 1, characterized in that The viscosity of the ester copolymer is in the range of 10000 Pa.s to 150000 Pa.s, preferably 80000 Pa.s to 150000 Pa.s; and / or, The weight average molecular weight of the ester copolymer is 5000-150000 Da, preferably 10000-50000 Da.

3. The ester copolymer according to claim 1, characterized in that: The ester copolymer has a structure shown in the following formula (1): wherein R is -(CH2)4CH2OC(O)CH(OH)CH2CH3, -CH(OH)CH3 or -(CH2)4CH2OH; m is an integer of 1-15, preferably an integer of 3-10; n is an integer greater than 3, preferably greater than 10, more preferably 50-250.

4. The ester copolymer according to claim 1, characterized in that: The dicarboxylic acid comprises one or a combination of two or more of glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid, preferably sebacic acid; The lactic acid includes one or a combination of two or more of L-lactic acid, D-lactic acid, and D,L-lactic acid; The caprolactone includes ε-caprolactone.

5. A method for preparing an ester copolymer according to any one of claims 1 to 4, characterized in that: The method comprises the following steps: in the presence of a catalyst, polymerizing glycerol, dicarboxylic acid and monomer to obtain an ester copolymer.

6. The preparation method according to claim 5, characterized in that: The molar ratio of glycerol, dicarboxylic acid and monomer is (1-3):(1-3):(1-6); Preferably, the catalyst comprises a tin substance; more preferably, the mass volume ratio (g / μL) of the monomer to the catalyst is (1-10):(1-10).

7. The preparation method according to claim 5, characterized in that: The polymerization reaction is carried out under the conditions of first passing an inert gas and then evacuating the air, and the reaction process includes heating and stirring operations; preferably, the polymerization reaction temperature is 120° C.-160° C., and the reaction time is 48h-96h, preferably 48h-72h.

8. Use of the ester copolymer according to any one of claims 1 to 4 in preparing embolic products, wound hemostatic products, cavity filling products or soft tissue repair products.

9. An embolic product, characterized in that: The invention comprises the ester copolymer according to any one of claims 1 to 4; preferably, the embolic product comprises a semisolid embolic agent, a liquid embolic agent or a copolymer spring coil.

10. The embolic product according to claim 9, characterized in that: The semisolid embolic agent further comprises an inorganic solvent; preferably, in the semisolid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the inorganic solvent is (1-100):(1-100); More preferably, the semisolid embolic agent further comprises an inorganic solvent and a hydrophilic substance; in the semisolid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the mixture of the inorganic solvent and the hydrophilic substance is (1-100):(1-100).

11. The embolic product according to claim 10, characterized in that: The hydrophilic substance is one or more of polyethylene glycol, polyvinyl alcohol, sorbitol, ethanol, and silicate; preferably, the silicate is lithium magnesium silicate.

12. The embolic product according to claim 10, characterized in that: The semi-solid embolic agent is obtained by mixing an inorganic solvent, an ester copolymer and optionally a hydrophilic substance, and then grinding, stirring or homogenizing. Preferably, the semi-solid embolic agent is obtained by first mixing the hydrophilic substance with the inorganic solvent to form a hydrophilic substance solution or hydrogel, and then mixing it with the ester copolymer, and then grinding, stirring or homogenizing.

13. The embolic product according to claim 9, characterized in that: The liquid embolic agent comprises the ester copolymer and an organic solvent; preferably, in the liquid embolic agent, the mass volume ratio (g / mL) of the ester copolymer to the organic solvent is (1-100):(1-100); More preferably, the liquid embolic agent further comprises other copolymers, and the other copolymers include polylactic acid-glycolic acid copolymer and / or poly (D, L-lactide-glycolide); further preferably, the mass ratio of the ester copolymer to the other copolymers is 1: (0.1-10), preferably 1: (0.4-4).

14. The embolic product according to claim 9, characterized in that: The copolymer spring coil is obtained by placing a substance containing an ester copolymer in a mold and curing it; preferably, the curing temperature is 130° C.-160° C., and the curing time is 24h-72h, preferably 24h-36h.

15. The embolic product according to any one of claims 9 to 14, characterized in that: The embolic preparation further comprises a contrast agent and / or a drug; preferably, The drug includes one or more of doxorubicin, epirubicin, apatinib, doxorubicin, mitomycin, and cisplatin; and / or, The developer is one or a combination of two or more of iodized oil, iodophenyl ester, sodium iodide, diatrizoate, iohexol, iodixanol, iohexol, iopromide, iobiprole, iotrolan, tantalum powder, barium sulfate, bismuth trioxide or zirconium oxide.

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