An active organic-inorganic composite implant material, its preparation method and application

Abstract

This application relates to the technical field of medical materials, and particularly relates to an active organic-inorganic composite implant material, its preparation method and application. The raw materials of the active organic-inorganic composite implant material include an organic component and an inorganic component with a weight ratio of (30~90):(10~70). The composition of the organic component includes a thermosetting prepolymer with a molecular weight of 500 Da to 20,000 Da, which may or may not contain double bonds and contains reactive groups such as carboxyl groups, hydroxyl groups and double bonds, etc. The composition of the inorganic component includes one or several of modified or unmodified inorganic salts and metal oxides. The preparation method includes the following processes: mixing, drying, pulverizing, pressing, demolding and thermal crosslinking. The active organic-inorganic composite implant material has the characteristics of low cost, high mechanical strength, good toughness and not easy to break, and is more convenient to prepare and use.

Description

Technical Field

[0001] The present application relates to the technical field of medical materials, and particularly relates to an active organic-inorganic composite implant material, a preparation method thereof, and an application thereof. Background Art

[0002] Bone filling and fixation materials are important medical devices for repairing bone defects, and play a key role especially in the treatment of bone dysfunction caused by accidents, orthopedic diseases, etc. These materials can be divided into two categories: natural bone repair materials and artificial bone repair materials. Natural bone repair materials are not easy to shape, and their applications are relatively limited. Artificial bone repair materials have a wide range of sources and are easy to shape, and are more widely used clinically.

[0003] Artificial bone repair materials mainly include metal materials, inorganic non-metallic materials, polymer materials, etc. Among them: metal materials usually have high strength and good fixation effect, but due to their too high strength, stress concentration is likely to occur, resulting in insufficient mechanical stimulation of the surrounding bone tissue, thus delaying the growth and repair of bone tissue; inorganic non-metallic materials such as bioceramics, calcium sulfate bone cement, etc. have better biocompatibility, but are brittle, easy to break, and have a high risk of failure; polymer materials have good toughness, but low strength, and often have insufficient early support ability after implantation. Therefore, it is necessary to develop a bone filling and fixation material with appropriate strength, good toughness and biocompatibility.

[0004] Traditional artificial bone repair materials are mostly high-strength preformed materials, which are formed by injection molding, 3D printing or compression molding. In clinical applications, the equipment cost of 3D printing and compression molding is relatively high, and injection molding and compression molding require separate matching molds. The manufacturing process is complex, and the material and labor costs are relatively high, which greatly limits the application scope and production efficiency.

[0005] Based on this, it is necessary to provide an artificial bone repair material with a simpler preparation method, low cost, appropriate strength and good toughness, which better meets the application requirements of clinical bone fixation and filling materials. Summary of the Invention

[0006] Based on this, one or more embodiments of the present application provide an active organic-inorganic composite implant material, a preparation method thereof, and an application thereof. The active organic-inorganic composite implant material has appropriate strength, and also has the advantages of low cost, good toughness and not easy to break, and realizes that the thermal cross-linking is completed in the last step, which can more conveniently prepare materials of various required shapes, reduce the mold loss, and save the preparation cost.

[0007] The technical solution of the present application includes the following content:

[0008] A preparation method of an active organic-inorganic composite implant material, wherein the raw materials of the active organic-inorganic composite implant material include an organic component and an inorganic component in a weight ratio of (30~90):(10~70);

[0009] The composition of the organic component includes a thermosetting prepolymer;

[0010] The thermosetting prepolymer includes a polyester prepolymer containing reactive groups, and the reactive groups include one or more of carboxyl groups, hydroxyl groups, and double bonds. The molecular weight of the polyester prepolymer is 500 Da to 20,000 Da;

[0011] The composition of the inorganic component includes one or more of modified or unmodified inorganic salts and metal oxides,

[0012] The inorganic salts include one or more of hydroxyapatite, calcium phosphate, whitlockite, and calcium carbonate,

[0013] The metal oxides include one or more of zinc oxide and magnesium oxide;

[0014] The modification includes surface coating with one or more of polyphenols, dopa, and dopamine;

[0015] The preparation method of the active organic-inorganic composite implant material includes the following processes: mixing, drying, pulverizing, pressing, demolding, and thermal crosslinking, wherein:

[0016] The mixing process includes stirring and mixing the raw materials of the active organic-inorganic composite implant material in an organic solvent;

[0017] The drying process includes drying the mixed material, and the drying temperature is 60°C to 120°C, and the time is 1 h to 6 h;

[0018] The pulverizing process includes pulverizing the dried material to a particle size of ≤500 mesh;

[0019] The pressing process includes pressing the pulverized material into a mold, and the pressing time is 1 min to 60 min;

[0020] The demolding process includes demolding the pressed material from the mold;

[0021] The thermal crosslinking process includes heating the demolded material to form crosslinking.

[0022] In some embodiments, the thermosetting prepolymer is selected from a polyester prepolymer without double bonds or a polyester prepolymer with double bonds;

[0023] Optionally, the polyester prepolymer with double bonds contains 5% to 30% by mole of double bonds.

[0024] In some embodiments, the raw materials for preparing the thermosetting prepolymer include reactive monomers;

[0025] The reactive monomers include a first acid monomer and a first alcohol monomer;

[0026] The first acid monomer includes one or more of citric acid, malic acid, sebacic acid, α-ketoglutaric acid, tartaric acid, oxalic acid, and fumaric acid;

[0027] The first alcohol monomer includes one or more of small molecule polyols and polymer polyols, and the molecular weight of the polymer polyol is 1000 Da to 2000 Da.

[0028] Optionally, the reactive monomers further include one or more of a second acid monomer and a second alcohol monomer;

[0029] The second acid monomer is a polybasic acid containing double bonds, and the second alcohol monomer is a polyhydric alcohol containing double bonds.

[0030] In some embodiments, based on parts by weight, the raw materials for preparing the thermosetting prepolymer include:

[0031] 10 to 50 parts of the first acid monomer;

[0032] 10 to 90 parts of the first alcohol monomer;

[0033] 0 to 40 parts of at least one of the second acid monomer and the second alcohol monomer.

[0034] In some embodiments, the raw materials for preparing the thermosetting prepolymer further include a catalyst;

[0035] Optionally, the catalyst includes at least one of stannous octoate, organic bismuth catalyst, and tetrabutyl titanate.

[0036] In some embodiments, when the thermosetting prepolymer includes a polyester prepolymer containing double bonds, the raw materials for preparing the thermosetting prepolymer further include a free radical thermal initiator;

[0037] Optionally, the free radical thermal initiator includes one or more of azobisisobutyronitrile, dicumyl peroxide, ammonium persulfate, and tetramethylethylenediamine.

[0038] In some embodiments, when the thermosetting prepolymer includes a polyester prepolymer containing double bonds, the heating temperature is 80°C to 140°C;

[0039] When the thermosetting prepolymer does not include a polyester prepolymer containing double bonds, the heating temperature is 25°C to 140°C.

[0040] In some embodiments, the raw materials of the active organic-inorganic composite implant material further include active ingredients for promoting bone repair or inhibiting osteoclasts;

[0041] Optionally, the active ingredients for promoting bone repair or inhibiting osteoclasts include one or more of alendronate sodium, zoledronic acid, neridronate sodium, and olpadronate sodium;

[0042] The active ingredients for promoting bone repair or inhibiting osteoclasts are introduced onto the thermosetting prepolymer or the modified inorganic salt or metal oxide by chemical bonding.

[0043] An active organic-inorganic composite implant material prepared by the preparation method described above.

[0044] Use of the active organic-inorganic composite implant material described above in the preparation of a bone repair material;

[0045] Optionally, the bone repair material includes composite bone screws, implant materials, and porous degradable scaffolds.

[0046] The present application provides an active organic-inorganic composite implant material and a preparation method thereof. The raw materials of the active organic-inorganic composite implant material include organic components and inorganic components in a suitable ratio. The composition of the organic components includes a polyester prepolymer containing reactive groups, the molecular weight of the polyester prepolymer is 500 Da to 20,000 Da, and the reactive groups include at least one of carboxyl groups, hydroxyl groups, and double bonds. The composition of the inorganic components includes one or two of modified or unmodified inorganic salts and metal oxides. After the above raw materials are processed through the processes of mixing, drying, pulverizing, pressing, demolding, and thermal crosslinking, an active organic-inorganic composite implant material with a composition ratio and mechanical properties close to those of human bones can be obtained. The active organic-inorganic composite implant material can be used to prepare bone repair materials and has good biodegradability and mechanical properties.

[0047] The present application obtains an active organic-inorganic composite implant material through the processes of mixing, drying, pulverizing, pressing, demolding, and thermal crosslinking, ensuring that thermal crosslinking is achieved in the last step, thereby providing the possibility of obtaining clinical bone repair materials of different shapes, and avoiding the problems of mold loss and occupation. The preparation cost is low, the manufacturing process is simple, and a broader clinical application prospect is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0049] Figure 1 This is the structure and synthesis route diagram of the second alcohol monomer (dihydric alcohol containing double bond) exemplified in an embodiment of the present application;

[0050] Figure 2 This is the synthesis schematic diagram of the thermosetting prepolymer in an embodiment of the present application;

[0051] Figure 3 This is the structural schematic diagram of the mold in an embodiment of the present application;

[0052] Figure 4 This is the physical diagram of the bone filling material made of the active organic-inorganic composite implant material in an embodiment of the present application ( Figure 4 A in it) and the physical diagram of the bone screw ( Figure 4 B in it);

[0053] Figure 5 This is the compression performance of the composite material in an embodiment of the present application;

[0054] Reference numerals:

[0055] 10 - Extrusion part, 11 - Handle, 12 - Extrusion portion, 20 - Hollow mold, 30 - Base. Detailed implementation manners

[0056] The present application will be further elaborated below in combination with the implementation manners and embodiments. It should be understood that these embodiments are only used to illustrate the present application and not to limit the scope of the present application. In addition, it should be understood that after reading the content taught in the present application, those skilled in the art can make various changes or modifications to the present application, and these equivalent forms also fall within the protection scope of the appended claims of the present application.

[0057] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present application belongs. The terms used in the specification of the present application herein are only for the purpose of describing specific embodiments and are not intended to limit the present application.

[0058] Term

[0059] Unless otherwise stated or there is a contradiction, the terms or phrases used herein have the following meanings:

[0060] As used herein, the term "and / or" includes any one of two or more related listed items, and also includes any and all combinations of the related listed items, and the any and all combinations include combinations of any two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctive combinations selected from "and / or", "or / and", and "and / or", it should be understood that in this application, this technical solution undoubtedly includes the technical solution connected by "logical AND", and also undoubtedly includes the technical solution connected by "logical OR". For example, "A and / or B" includes three parallel solutions: A, B, and A + B. Another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, it includes combinations of any two or any three of A, B, C, and D, and also includes the four-item combination of A, B, C, and D (that is, the technical solution connected by "logical AND").

[0061] In this application, terms such as "preferred", "better", "even better", etc. are only used to describe embodiments or examples with better effects, and it should be understood that they do not constitute a limitation on the protection scope of this application.

[0062] In this application, terms such as "further", "even further", "especially", etc. are used for descriptive purposes to indicate differences in content, but should not be construed as a limitation on the protection scope of this application.

[0063] In this application, among the technical features described in an open-ended manner, it includes a closed technical solution composed of the listed features, and also includes an open technical solution containing the listed features.

[0064] In this application, regarding numerical intervals (that is, numerical ranges), unless otherwise specified, the optional numerical values are considered continuous within the above numerical intervals, and include the two numerical endpoints of the numerical range (that is, the minimum value and the maximum value), as well as each numerical value between these two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to integers within the numerical interval, it includes the two endpoint integers of the numerical range, as well as each integer between the two endpoints. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0065] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and fluctuations within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within ranges such as ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are allowed.

[0066] In this application, the weight can be mass units well-known in the chemical industry such as μg, mg, g, kg, etc.

[0067] Based on this, one or more embodiments of this application provide an active organic-inorganic composite implant material, its preparation method, and applications. The active organic-inorganic composite implant material has the characteristics of low cost, high mechanical strength, and good toughness and is not easily broken.

[0068] In one aspect of this application, a preparation method of an active organic-inorganic composite implant material is provided. The raw materials of the active organic-inorganic composite implant material include an organic component and an inorganic component with a weight ratio of (30~90):(10~70);

[0069] The composition of the organic component includes a thermosetting prepolymer;

[0070] The thermosetting prepolymer includes a polyester prepolymer containing reactive groups. The reactive groups include one or several of carboxyl groups, hydroxyl groups, and double bonds. The molecular weight of the polyester prepolymer is 500 Da~20000 Da;

[0071] The composition of the inorganic component includes one or several of modified or unmodified inorganic salts and metal oxides,

[0072] The inorganic salts include one or several of hydroxyapatite, calcium phosphate, whitlockite, and calcium carbonate,

[0073] The metal oxides include one or several of zinc oxide and magnesium oxide;

[0074] The modification includes surface coating with one or several of polyphenols, dopa, and dopamine;

[0075] The preparation method of the active organic-inorganic composite implant material includes the following processes: mixing, drying, pulverizing, pressing, demolding, and thermal crosslinking, where:

[0076] The mixing process includes stirring and mixing the raw materials of the active organic-inorganic composite implant material in an organic solvent;

[0077] The drying process includes drying the mixed material. The drying temperature is 60°C~120°C, and the time is 1 h~6 h;

[0078] The pulverizing process includes pulverizing the dried material to a particle size of ≤500 mesh;

[0079] The pressing process includes pressing the crushed material into a mold, and the pressing time is 1 min to 60 min;

[0080] The demolding process includes demolding the pressed material from the mold;

[0081] The thermal crosslinking process includes heating the demolded material to form crosslinks.

[0082] In this embodiment, the molecular weight of the polyester prepolymer is 500 Da to 20,000 Da, which can improve the crosslinking degree of the active organic-inorganic composite implant material, thereby improving its compressive strength, elastic modulus and elongation at break.

[0083] Optionally, the molecular weight of the polyester prepolymer is selected from 500 Da to 20,000 Da, and more preferably from 500 Da to 2,000 Da. Examples include 500 Da, 600 Da, 700 Da, 800 Da, 900 Da, 1,000 Da, 1,100 Da, 1,200 Da, 1,300 Da, 1,400 Da, 1,500 Da, 1,600 Da, 1,700 Da, 1,800 Da, 1,900 Da, 2,000 Da, etc.

[0084] In some embodiments, the thermosetting prepolymer is selected from polyester prepolymers without double bonds or polyester prepolymers with double bonds;

[0085] Optionally, the polyester prepolymer with double bonds contains 5% to 30% double bonds.

[0086] In this embodiment, when the thermosetting prepolymer is selected from polyester prepolymers with double bonds, the content of double bonds should be 5% to 30%. If the content of double bonds is too low, crosslinking may not occur. If the content is too high, such as 40%, the crosslinking degree is too high, which will make the material brittle and reduce its degradability.

[0087] In this embodiment, when the inorganic component is selected from modified inorganic salts and metal oxides, the compressive strength can be better improved because the modified surface contains rich active groups, which can better form intermolecular crosslinks. In some embodiments, the preparation raw materials of the thermosetting prepolymer include active monomers;

[0088] The active monomers include a first acid monomer and a first alcohol monomer;

[0089] The first acid monomer includes one or more of citric acid, malic acid, sebacic acid, α-ketoglutaric acid, tartaric acid, oxalic acid and fumaric acid;

[0090] The first alcohol monomer includes one or two of small molecule polyols and polymer polyols, and the molecular weight of the polymer polyol is 1,000 Da to 2,000 Da.

[0091] Optionally, the reactive monomer further includes one or more of a second acid monomer and a second alcohol monomer;

[0092] The second acid monomer is a polybasic acid containing a double bond, and the second alcohol monomer is a polyhydric alcohol containing a double bond.

[0093] In some embodiments, the second alcohol monomer is selected from the compound of formula I:

[0094] I;

[0095] R is methyl or ethyl.

[0096] In some embodiments, the preparation method of the compound of formula I may include the following steps:

[0097] The compound of formula II is heated under alkaline conditions to obtain a salt of the compound of formula II;

[0098] II;

[0099] The salt of the compound of formula II reacts with allyl bromide to obtain the compound of formula I. By way of example, the preparation method of the compound of formula I can be seen in Figure 1 the reaction route shown. First, the compound of formula II is heated and stirred under alkaline conditions, where the base is potassium hydroxide (KOH), the solvent is N,N-dimethylformamide (DMF), the heating temperature is 45 °C, and the heating time is 24 h. After obtaining the salt of the compound of formula II, allyl bromide is added and stirred continuously to obtain the compound of formula I.

[0100] In some embodiments, based on parts by weight, the raw materials for preparing the thermosetting prepolymer include:

[0101] 10 - 50 parts of the first acid monomer;

[0102] 10 - 90 parts of the first alcohol monomer;

[0103] At least one of the second acid monomer and the second alcohol monomer: 0 - 40 parts. In some embodiments, based on parts by weight, the raw materials for preparing the thermosetting prepolymer include:

[0104] 10 - 50 parts of the first acid monomer;

[0105] 10 - 90 parts of the first alcohol monomer;

[0106] 1 - 40 parts of the second acid monomer or the second alcohol monomer;

[0107] Among them, the weight portion of the first acid monomer can be 10 to 50 parts, further can be 10 to 30 parts, and by way of example, the weight portions are such as 10 parts, 12 parts, 14.6 parts, 15 parts, 17.3 parts, 18 parts, 19.2 parts, 20 parts, 22 parts, 23 parts, 25 parts, 28 parts, 30 parts, 40 parts, 50 parts, etc.; the weight portion of the first alcohol monomer can be 10 to 90 parts, further can be 10 to 50 parts, and by way of example, the weight portions are such as 10 parts, 10.2 parts, 12 parts, 14.6 parts, 15 parts, 16.8 parts, 18 parts, 20 parts, 22 parts, 25 parts, 28 parts, 30 parts, 40 parts, 44 parts, 50 parts, 60 parts, 70 parts, 80 parts, 90 parts, etc.; the weight portion of the second acid monomer or the second alcohol monomer can be 1 to 40 parts, further can be 1 to 10 parts, and by way of example, the weight portions are such as 1 part, 2 parts, 2.9 parts, 3 parts, 4 parts, 5 parts, 5.23 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, etc.

[0108] Preferably, the weight ratio of the first acid monomer to the first alcohol monomer is 1:(0.5 to 2), which can better form crosslinks and improve the compressive strength, elastic modulus and elongation at break.

[0109] Preferably, the weight ratio of the first acid monomer to the second alcohol monomer is 1:(0.1 to 0.5), which can better form crosslinks and improve the compressive strength, elastic modulus and elongation at break.

[0110] In some embodiments, the raw materials for preparing the thermosetting prepolymer further include a catalyst;

[0111] Optionally, the catalyst includes at least one of stannous octoate, organic bismuth catalyst, and tetrabutyl titanate.

[0112] In some embodiments, when the thermosetting prepolymer includes a polyester prepolymer containing double bonds, the raw materials for preparing the thermosetting prepolymer further include a free radical thermal initiator;

[0113] Optionally, the free radical thermal initiator includes one or more of azobisisobutyronitrile, dicumyl peroxide, ammonium persulfate, and tetramethylethylenediamine.

[0114] By way of example, the preparation method of the thermosetting prepolymer can refer to Figure 2 the reaction route shown. Mix the first acid monomer and the first alcohol monomer, and optionally add at least one of the second acid monomer and the second alcohol monomer for mixing ( Figure 2 taking the second alcohol monomer formula I compound as an example, "±" means adding or not adding), and after heating and stirring, obtain the thermosetting prepolymer.

[0115] In some embodiments, when the thermosetting prepolymer includes a polyester prepolymer containing double bonds, the heating temperature is 80°C to 140°C;

[0116] When the thermosetting prepolymer does not include a polyester prepolymer containing double bonds, the heating temperature is 25°C to 140°C.

[0117] In some embodiments, the raw materials of the active organic-inorganic composite implant material further include an active ingredient for promoting bone repair or inhibiting osteoclasts;

[0118] Optionally, the active ingredient for promoting bone repair or inhibiting osteoclasts includes one or more of alendronate sodium, zoledronic acid, neridronate sodium, and olpadronate sodium, and these ingredients can be introduced onto the thermosetting prepolymer by chemical bonding.

[0119] Optionally, the active ingredient for promoting bone repair or inhibiting osteoclasts is introduced onto the thermosetting prepolymer or the modified inorganic salt or metal oxide by chemical bonding.

[0120] In some embodiments, the modified inorganic salt or metal oxide is obtained by surface coating the inorganic salt or metal oxide with at least one of polyphenol, dopa, and dopamine. Introducing the active ingredient for promoting bone repair or inhibiting osteoclasts onto the modified inorganic salt or metal oxide means that the active groups in the active ingredient for promoting bone repair or inhibiting osteoclasts react with the surface-coated substance, such as Michael addition or Schiff base reaction, to form a chemical bond.

[0121] In some embodiments of the raw materials of the active organic-inorganic composite implant material, based on the weight of the first acid monomer being 10 to 50 parts, the weight of the active ingredient for promoting bone repair or inhibiting osteoclasts is 1 to 2 parts.

[0122] It can be understood that the mold of the present application has a receiving cavity for receiving materials, and a specific shape can be formed by extruding the materials in the receiving cavity.

[0123] In some embodiments, the mold can be selected from an integral or split mold, and the shape of the receiving cavity can be various required shapes such as cylindrical, cubic, rectangular, etc. When the shape of the receiving cavity is cylindrical, its inner diameter can be 3 mm to 200 mm, and the height can be 5 mm to 600 mm.

[0124] In some embodiments, the mold can be selected from an integral or split cylindrical mold. To achieve pressing, an extrusion part and a base are also equipped to apply force from both ends to provide the pressing pressure.

[0125] See Figure 3, the pressing device according to an embodiment of the present application includes an extrusion member 10, a hollow mold 20, and a base 30. The extrusion member includes a handle 11 and an extrusion portion 12. The handle 11 is used for holding, and there is a clearance fit or a transition fit between the extrusion portion 12 and the hollow mold 20. On the other hand, the present application provides an active organic-inorganic composite implant material prepared by the above preparation method.

[0126] On the other hand, the present application provides an application of the above active organic-inorganic composite implant material in the preparation of bone repair materials;

[0127] Optionally, the bone repair material includes composite bone screws, implant materials, and porous degradable scaffolds.

[0128] The following are some specific examples.

[0129] For the experimental parameters not specified in the following specific examples, preferably refer to the guidance given in the present application document, and you can also refer to the experimental manuals in the art or other experimental methods known in the art, or refer to the experimental conditions recommended by the manufacturers.

[0130] The raw materials and reagents involved in the following specific examples can be obtained commercially, or those skilled in the art can prepare them according to known means.

[0131] I. Preparation of active organic-inorganic composite implant materials.

[0132] Example 1

[0133] This example provides an active organic-inorganic composite implant material of the present application, and the preparation method is as follows:

[0134] (1) Prepare raw materials

[0135] To prepare an ethanol solution of a polyester prepolymer, the following steps are included:

[0136] Take 19.2 g of citric acid (the first acid monomer) and 16.08 g of bio-1,8-octanediol (the first alcohol monomer) and place them in a 100 mL round-bottom flask equipped with a stirrer of appropriate size. Heat and melt at 160 °C and then cool to 140 °C and stir and react at 600 rpm. As the viscosity of the system increases, the rotation speed gradually decreases. After about 1 hour, it is difficult to stir at 60 rpm, then stop heating and add ethanol for dissolution to obtain a polyester (poly(1,8-octanediol citrate)) prepolymer solution with a solid content of 50 wt%.

[0137] Prepare inorganic materials, including the following steps:

[0138] Dry the hydroxyapatite for later use.

[0139] (2) Prepare active organic-inorganic composite implant materials

[0140] Mix 40 g of a polyester prepolymer solution (50 wt% solids content) and 40 g of hydroxyapatite and stir evenly.

[0141] Dry the mixed material. The drying temperature is 100 °C and the time is 3 h.

[0142] Crush the dried material to a particle size of ≤500 mesh.

[0143] Take 0.8 g of the crushed material, put it into a cylindrical mold with a diameter of 6 mm, and apply a pressure of 5 MPa for pressing.

[0144] Demold the pressed material to obtain a cylinder with a diameter of 6 mm and a height of 12 mm.

[0145] Put the demolded cylinder into an oven for heating. The heating temperature is 100 °C and the time is 36 h.

[0146] Example 2

[0147] This example provides an active organic-inorganic composite implant material of the present application, which is prepared in a substantially same manner as in Example 1, except that:

[0148] The steps for preparing an ethanol solution of a polyester prepolymer are as follows:

[0149] Take 23.0 g of citric acid, 14.6 g of 1,8-octanediol, and 1.5 g of alendronate sodium and place them in a 100 mL round-bottom flask equipped with a stirrer of appropriate size. The melting and reaction temperatures are the same as in Example 1, and the reaction time is about 4 hours. After the reaction, dissolve it with ethanol to obtain a polyester prepolymer solution with a solids content of 50% for standby. The preparation process of the organic-inorganic composite implant material is the same as that in Example 1.

[0150] Example 3

[0151] This example provides an active organic-inorganic composite implant material of the present application, which is prepared in a substantially same manner as in Example 1, except that:

[0152] The prepared polyester prepolymer contains double bonds, and the steps for preparing its ethanol solution are as follows:

[0153] Take 17.3 g of citric acid, 2.9 g of maleic anhydride, and 14.6 g of 1,8-octanediol and place them in a 100 mL round-bottom flask equipped with a stirrer of appropriate size. The melting and reaction temperatures are the same as in Example 1, and the reaction time is about 6 hours. After the reaction, dissolve it with ethanol to obtain a polyester prepolymer solution with a solids content of 50% for standby. The preparation process of the organic-inorganic composite implant material is similar to that in Example 1, but 2 wt% of azobisisobutyronitrile needs to be added as a free radical thermal initiator.

[0154] Example 4

[0155] This example provides an active organic-inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 1, except that:

[0156] The prepared polyester prepolymer contains double bonds, and the preparation steps of its ethanol solution are as follows:

[0157] Take 23.0 g of citric acid, 10.2 g of 1,8-octanediol and 5.23 g of compound a. Place them in a 100 mL round-bottom flask equipped with a stirrer of appropriate size. The melting and reaction temperatures are the same as those in Example 1, and the reaction time is about 6 hours. After the reaction, dissolve it with ethanol to obtain a polyester prepolymer solution with a solid content of 50% for standby. The preparation process of the organic-inorganic composite implant material is similar to that in Example 1, but 2 wt% of azobisisobutyronitrile needs to be added as a free radical thermal initiator.

[0158] The preparation method of compound a can be referred to Figure 1 , specifically as follows: Dissolve 18.0 g of 2,2-dimethylolpropionic acid in DMF, add 8.6 g of potassium hydroxide, stir and react at 100 °C for 1 h to form 2,2-dimethylolpotassium propionate. Then cool to 45 °C, drop 11.6 mL of 3-bromopropene within 30 min, keep the reaction at 45 °C for 48 h, and drain DMF. The residue is dissolved in 200 mL of dichloromethane, extracted with 50 mL × 2 of water, the organic phase is collected, dried over anhydrous magnesium sulfate overnight, and a yellow viscous liquid is obtained, which is a representative of compound a: allyl 2,2-dimethylolpropionate (molecular weight is 148.16). The detected 1H NMR data are: 1 H NMR (300 MHz, DMSO-d6): δ 1.34 [3H, -OO-C-C(CH 2 -) 2 (CH 3 )-], 3.84 (4H, -CH 2 OH), 4.75 (2H, -COOCH 2 -), 5.24 (2H, -CH=CH 2 ), 5.89(1H, -CH=CH 2 ), and the structure is confirmed.

[0159] Example 5

[0160] This example provides an active organic-inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 4, except that:

[0161] In the step of preparing an ethanol solution of a polyester prepolymer, the reactants are adjusted to 17.3 g of citric acid, 10.2 g of 1,8 - octanediol, 2.9 g of maleic anhydride, and 5.23 g of compound a.

[0162] Example 6

[0163] This example provides an active organic - inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 5, except that:

[0164] The addition amount of compound a is increased to 15.5 g, and the molar proportion of double bonds in the prepolymer is 45%.

[0165] Example 7

[0166] This example provides an active organic - inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 1, except that:

[0167] In the step of preparing the inorganic material, the following modification treatment is carried out on hydroxyapatite: 50 g of hydroxyapatite is ground and pulverized in a mortar, then dispersed in 250 mL of Tris - HCl (pH 8.5), 1.5 g of tannic acid is added under high - speed stirring at 1000 rpm, and 1.0 g of alendronate sodium is added, and the stirring reaction is carried out overnight (12 hours). Then it is centrifuged at 4000 rpm for 10 minutes in a centrifuge, and the supernatant is discarded. The obtained solid is ultrasonically dispersed in deionized water and then centrifuged and separated at 4000 rpm in a centrifuge, and this washing process is repeated more than three times. After the solid is freeze - dried, alendronate sodium and tannic acid - modified hydroxyapatite are obtained.

[0168] Example 8

[0169] This example provides an active organic - inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 1, except that:

[0170] The addition amount of citric acid is increased to 50.2 g, and the rest remains unchanged.

[0171] Example 9

[0172] This example provides an active organic - inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 5, except that:

[0173] The addition amount of 1,8 - octanediol is reduced to 1.5 g, and the rest remains unchanged, with 17.3 g of citric acid, 2.9 g of maleic anhydride, and 5.23 g of compound a.

[0174] Example 10

[0175] This example provides an active organic-inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 5, except that:

[0176] The addition amount of 1,8-octanediol is increased to 50 g.

[0177] Comparative Example 1

[0178] This example provides an active organic-inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 1, except that:

[0179] In the step of preparing the ethanol solution of the polyester prepolymer, polyethylene glycol 400 (PEG400, molecular weight 400 Da) is used as the first alcohol monomer, the mass of PEG400 is 44 g, the melting and reaction temperatures remain unchanged, and the reaction time is extended to about 24 hours. The preparation process of the organic-inorganic composite implant material is the same as that in Example 1.

[0180] Comparative Example 2

[0181] This example provides an active organic-inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 4, except that:

[0182] The addition amount of compound a is reduced to 0.5 g, and the proportion of double bonds in the prepolymer is 2%.

[0183] Comparative Example 3

[0184] This example provides an active organic-inorganic composite implant material of the present application, which is prepared in substantially the same manner as in Example 1, except that:

[0185] The addition amount of the first acid monomer is reduced to 2.1 g, and the amounts of the other monomers remain unchanged.

[0186] II. Animal modeling and application.

[0187] An SD rat is used to construct a femoral condyle bone defect model. After anesthetizing the right hind limb of the SD rat, the hair is shaved off with a razor, and then it is cleaned with povidone iodine. With the patellar ligament as a reference, an incision 1.5 - 2.0 cm long parallel to the long axis of the femoral shaft is made on the lateral femoral condyle. Then the skin and subcutaneous tissue are incised, and a bone defect (diameter 3.5 mm, depth 5 mm) large enough to fully expose the lateral femoral condyle is constructed with an electric drill. The material prepared in Example 3 is crushed and placed in the defect site, and it is detected that the material can gradually degrade with bone regeneration while releasing the active material.

[0188] III. Mechanical property characterization.

[0189] Using a universal material testing system (Instron 34TM-10) with a 10 kN sensing unit, the compressive strength of the composite material was determined. Taking Figure 4 the cylinder shown as an example, after trimming the edges and corners of the cylinder, it was placed on the placement table, and a force of 5 N was pre-applied to ensure a tight bond. The compression process was carried out at a constant compression rate of 5 mm / min and automatically stopped after fracture. To determine the compressive strength, elastic modulus (Young's modulus), and fracture strain. The Young's modulus was determined by the slope of the stress-strain curve from 0% to 10% elongation, Figure 5 which is the stress-strain curve of Example 1.

[0190] Table 1

[0191]

[0192] According to Table 1, the compressive strength, elastic modulus, and fracture elongation of the active organic-inorganic composite implant materials in each example are within a suitable range. Among them, the compressive strength is basically similar to that of natural bone, which can provide sufficient supporting force. The elastic modulus is within a suitable range, which can provide a more ideal mechanical environment for bone cells, effectively avoid the stress shielding effect, and is beneficial to the growth and repair of bone tissue. The fracture elongation is within a suitable range, indicating that the active organic-inorganic composite implant material has good toughness and is not easily broken.

[0193] In Comparative Example 1, due to the too low molecular weight of the polyester prepolymer, although the reaction time was extended, both the compressive strength and the elastic modulus decreased significantly. In Comparative Example 2, since a polyester prepolymer containing double bonds was used as the thermosetting prepolymer and the proportion of double bonds was relatively low, the crosslinking was incomplete and it could not be molded. In Comparative Example 3, since the ratio of the first acid monomer to the first alcohol monomer was not within a suitable range, the prepolymerization reaction was incomplete and the crosslinking was incomplete, and it could not be molded.

[0194] According to Table 1, in Example 2 and Example 7, alendronate sodium was introduced onto the inorganic salts modified on the thermosetting prepolymer by chemical bonding. The introduction of the drug active ingredient does not affect the compressive strength, elastic modulus, and elongation at break. It can be seen that the active organic-inorganic composite implant material of the embodiments of the present application can be added with different active ingredients as needed and can be flexibly applied to a variety of clinical scenarios. Moreover, the active ingredient is introduced into the thermosetting prepolymer by chemical bonding, avoiding the burst release of the active ingredient and enabling its slow release, extending its action time, and being more conducive to clinical application. All the documents mentioned in the present application are cited in the present application as references, just as if each document was cited separately as a reference. Unless it conflicts with the application purpose and / or technical solution of the present application, the cited documents involved in the present application are cited for all their contents and all their purposes. When the present application involves citing documents, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the present application involves citing documents, the examples and preferred methods of the relevant technical features cited can also be incorporated into the present application as references, but only to the extent that the present application can be implemented. It should be understood that when the cited content conflicts with the description in the present application, the present application shall prevail or be modified adaptively according to the description in the present application.

[0195] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity of description, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered to be within the scope described in this specification.

[0196] The above-described examples only represent several embodiments of the present application, but should not be construed as limiting the scope of the patent application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can be made, and these all belong to the protection scope of the present application. In addition, it should be understood that after reading the above teachings of the present application, those skilled in the art can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning, or limited experiments based on the technical solutions provided in the present application are all within the protection scope of the appended claims of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims, and the specification can be used to explain the content of the claims.

Claims

1. A method for preparing an active organic-inorganic composite implant material, characterized in that: The raw materials of the active organic-inorganic composite implant material include organic components and inorganic components in a weight ratio of (30-90): (10-70); The organic component comprises a thermosetting prepolymer; The thermosetting prepolymer includes a polyester prepolymer containing a reactive group, wherein the reactive group includes a carboxyl group, a hydroxyl group and a double bond, the molar percentage of the double bond in the polyester prepolymer is 5% to 30%, and the molecular weight of the polyester prepolymer is 500Da to 20000Da; The raw materials for preparing the thermosetting prepolymer include active monomers; The active monomers include a first acid monomer, a first alcohol monomer and a second alcohol monomer; the first acid monomer is citric acid; the first alcohol monomer is 1,8-octanediol; and the second alcohol monomer is selected from a compound of formula I: I； R is methyl or ethyl; The weight ratio of the first acid monomer to the first alcohol monomer is 1:(0.5-2); The weight ratio of the first acid monomer to the second alcohol monomer is 1:(0.1-0.5); The preparation method of the thermosetting prepolymer comprises the following steps: mixing the first acid monomer, the first alcohol monomer and the second alcohol monomer, heating and stirring; the heating temperature is 80° C. to 140° C.; The inorganic component comprises one or more of modified or unmodified inorganic salts and metal oxides, the inorganic salts comprise one or more of hydroxyapatite, calcium phosphate, leucoderm and calcium carbonate, and the metal oxides comprise one or more of zinc oxide and magnesium oxide; The modification includes surface coating with one or more of polyphenol, dopa and dopamine; The preparation method of the active organic-inorganic composite implant material comprises the following steps: mixing, drying, crushing, pressing, demoulding and thermal cross-linking, wherein: The mixing step includes stirring and mixing the raw materials of the active organic-inorganic composite implant material in an organic solvent; The drying process includes drying the mixed materials at a temperature of 60°C to 120°C for a time of 1h to 6h; The pulverizing process includes pulverizing the dried material to a particle size of ≤500 mesh; The pressing process includes pressing the crushed material into a mold for 1 to 60 minutes; the demoulding process includes demoulding the pressed material from the mold; The thermal cross-linking process includes heating the demoulded material to form cross-links.

2. The method for preparing the active organic-inorganic composite implant material according to claim 1, characterized in that: The raw materials for preparing the thermosetting prepolymer include, by weight: 10 to 50 parts of the first acid monomer; 10 to 90 parts of the first alcohol monomer; The second alcohol monomer is 1 to 40 parts.

3. The method for preparing the active organic-inorganic composite implant material according to claim 1 or 2, characterized in that: The raw materials for preparing the thermosetting prepolymer also include a catalyst; The catalyst includes at least one of stannous isooctanoate, an organic bismuth catalyst, and tetrabutyl titanate.

4. The method for preparing the active organic-inorganic composite implant material according to claim 1 or 2, characterized in that: The raw materials for preparing the thermosetting prepolymer also include a free radical thermal initiator; The free radical thermal initiator includes one or more of azobisisobutyronitrile, dicumyl peroxide, ammonium persulfate and tetramethylethylenediamine.

5. The method for preparing the active organic-inorganic composite implant material according to claim 1 or 2, characterized in that: The raw materials of the active organic-inorganic composite implant material also include active ingredients that promote bone repair or inhibit bone resorption; The active ingredients for promoting bone repair or inhibiting osteoclastogenesis include one or more of alendronate sodium, zoledronic acid, neridronate sodium and olpadronate sodium; The active ingredient for promoting bone repair or inhibiting osteoclastogenesis is introduced into the thermosetting prepolymer or the modified inorganic salt or metal oxide by chemical bonding.

6. An active organic-inorganic composite implant material prepared by the preparation method according to any one of claims 1 to 5.

7. Use of the active organic-inorganic composite implant material according to claim 6 in the preparation of bone repair materials; The bone repair material comprises a composite bone screw, an implant material and a porous degradable scaffold.

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