Absorbable bone wax and preparation method thereof, and bone repair product or bone product comprising absorbable bone wax

Abstract

The invention belongs to the field of biomedical materials, and relates to absorbable bone wax and a preparation method thereof, and a bone repair product or a bone product comprising the absorbable bone wax. The preparation method comprises the following steps: taking required raw materials which are preheated or not preheated, and carrying out first blending stirring under the condition of 40-90 DEG C to prepare an intermediate product 1; cooling the intermediate product 1 to 10-30 DEG C, and carrying out second blending stirring under the condition of 10-30 DEG C to prepare an intermediate product 2; the intermediate product 2 is molded, and bone wax is prepared; the raw materials comprise a fat-soluble liquid component with a melting point lower than 80 DEG C and a solid component with a melting point of 100-500 DEG C. The composition is prepared from a fat-soluble liquid component with the melting point being lower than 80 DEG C and a solid component with the melting point being 100-500 DEG C. In the preparation process, by adjusting the heating condition, the situation that the cohesion of the fat-soluble liquid component with the low melting point and the solid component with the high melting point is increased due to heating in the processing process is reduced, and the content of the fat-soluble liquid component with the low melting point and the solid component with the high melting point is reduced. The finally prepared absorbable bone wax is reduced in cohesion, reduced in hardness and improved in adhesion, and can be directly used at room temperature, so that the use convenience is improved.

Description

Technical Field

[0001] This application belongs to the field of biomedical materials, specifically relating to absorbable bone wax and its preparation method, as well as bone repair products or bone products containing the same. Background Technology

[0002] Traditional bone wax is non-biodegradable and absorbable, and its presence in the body after implantation can cause a space-occupying effect, hindering the repair of damaged bone sites and thus limiting its use in areas requiring bone fusion. Furthermore, traditional bone wax contains animal-derived components such as beeswax, posing a certain risk of immunogenicity, which may manifest as adverse reactions such as infection in clinical practice. Therefore, current research primarily focuses on developing biodegradable bone wax materials using biodegradable and absorbable materials to replace traditional bone wax.

[0003] Currently, most common absorbable bone wax products are prepared from polysaccharide materials, polyoxypropylene-polyoxyethylene block copolymers, fatty acid glycerides, polyols, amphiphilic block copolymers, bioactive glass, and other additives (such as metal ions, antibiotics, bone-inducing factors, hemostatic agents, etc.).

[0004] For example: an amphiphilic block copolymer, wherein the hydrophilic segment is a water-soluble polyethylene oxide chain and the hydrophobic segment is a semi-crystalline ester chain; said ester chain is a binary copolymer of trimethylene carbonate and α-caprolactone; the general structural formula of the amphiphilic block copolymer is as follows: PEG(-PTCL) n Where n is 1~8, PEG is polyethylene glycol or polyethylene glycol monomethyl ether, and PTCL is a binary copolymer of trimethylene carbonate and ε-caprolactone. The preparation of some of the above materials involves complex processes and long processing times.

[0005] For example, an absorbable hemostatic bone wax, the materials for which the hemostatic bone wax is prepared include gelatin and poloxamer, wherein the mass ratio of gelatin to poloxamer is 1:1 to 9:1.

[0006] For example, an absorbable hemostatic bone wax comprises glycerin, carbomer gel, and unsaturated polyesteramide, wherein the mass ratio of glycerin, carbomer gel, and unsaturated polyesteramide is 1:0.2~0.3:3~4.

[0007] For example, an absorbable bone wax with hemostatic function is composed of solids and water. The solids include cross-linked hyaluronic acid, calcium phosphate and soluble starch. The weight of water is 20% to 100% of the weight of the solids. The weight ratio of the solids is: cross-linked hyaluronic acid: calcium phosphate: soluble starch is (20~70): (20~50): (0~10).

[0008] For example, a bone hemostatic material is prepared by the following steps: 1) Mix 5-30 parts of calcium phosphate, 10-30 parts of fatty acid salt, 10-30 parts of sodium carboxymethyl cellulose and 10-30 parts of poloxamer evenly; 2) Heat 20-50 parts of vitamin E acetate at 30-50°C, and add the mixture obtained in step 1) to the heated vitamin E acetate and mix evenly; 3) Slowly add 20-40 parts of water to the mixture obtained in step 2), and mix evenly to obtain the bone hemostatic material; wherein, poloxamer is selected from one or more of poloxamer 105, etc.; fatty acid salt is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, magnesium myristate and calcium myristate.

[0009] However, as exemplified above, bone wax has weak adhesion and is hard at room temperature. In clinical practice, it is still necessary to obtain the appropriate hardness by hand kneading and heating in order to effectively balance the hardness and viscosity of the bone wax. This operation is not convenient for the actual application of bone wax, especially in the humid environment of laparoscopy. Humid environments such as UBE surgery and water-based surgery require repeated irrigation, rinsing and cooling. How to maintain the appropriate hardness and viscosity of existing products is the key to solving the problem. Summary of the Invention

[0010] Based on this, one or more embodiments of this application provide absorbable bone wax and its preparation method, as well as bone repair products or bone products including the same. The technical solutions include the following: One or more embodiments of this application provide a method for preparing bone wax, the method comprising the following steps: Take the required raw materials, whether preheated or not, and carry out the first mixing and stirring at 40~90℃ to prepare intermediate product 1; The intermediate product 1 is cooled to 10-30°C and subjected to a second blending and stirring at 10-30°C to prepare intermediate product 2; and, The intermediate product 2 is shaped to prepare bone wax; The raw materials include a fat-soluble liquid component and a solid component. The melting point of the fat-soluble liquid component is below 80°C, and the melting point of the solid component is 100~500°C.

[0011] In some embodiments of this application, the preparation method satisfies one or more of the conditions shown in (A1) to (A3): (A1) The first mixing time is 1~10h; (A2) The second mixing time is 1~10h; (A3) The required temperature of each raw material after preheating is 40~60℃.

[0012] In some embodiments of this application, the preparation method satisfies one or more of the conditions shown in (B1) to (B2) below: (B1) The stirring speed for the first mixing step is 5~100 rpm; (B2) The second mixing speed is 5~100 rpm.

[0013] In some embodiments of this application, the raw material further includes reinforcing components, which include one or more of stearates, stearates, inorganic calcium salts, amphoteric surfactants, and polyethylene glycol.

[0014] In some embodiments of this application, the raw materials, by weight, include: 5 to 60 parts of the fat-soluble liquid component, 5 to 80 parts of the solid component, and no more than 160 parts of the reinforcing component.

[0015] In some embodiments of this application, the reinforcing component satisfies one or more of the following conditions (C1) to (C5): (C1) The amphoteric surfactant comprises a polyoxypropylene-polyoxyethylene block copolymer; optionally, the polyoxypropylene-polyoxyethylene block copolymer comprises one or more of poloxamer 188, poloxamer 338, poloxamer 407, poloxamer 105, poloxamer 124, poloxamer 184, poloxamer 237, poloxamer 335, poloxamer 403 and poloxamer 401; (C2) The stearate includes one or more of sodium stearate, calcium stearate and zinc stearate; (C3) The stearate includes glyceryl stearate; (C4) The polyethylene glycol includes one or more of polyethylene glycol 1000, polyethylene glycol 1500 and polyethylene glycol 4000; (C5) The inorganic calcium salt includes calcium phosphate; optionally, the calcium phosphate includes one or more of tricalcium phosphate, hydroxyapatite, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, calcium sulfate, bioactive glass and calcium carbonate.

[0016] In some embodiments of this application, the fat-soluble liquid component includes one or more of vitamin E acetate, polyethylene glycol vitamin E succinate, sesame oil, castor oil, oleic acid, ethyl oleate, sorbitan oleate, cinnamon oil, glyceryl linoleate, glyceryl laurate, and glyceryl palmitate.

[0017] In some embodiments of this application, the solid component includes one or more of the components shown in (D1) to (D3): (D1) A substance containing one or more of carboxyl and hydroxyl groups, with a melting point of 250-500°C; optionally, the substance includes one or more of carboxymethyl chitosan, sodium carboxymethyl cellulose, potato starch, alginate and sodium hyaluronate. (D2) Polylactic acid, with a melting point of 160~330℃; optionally, the polylactic acid includes one or more of poly-DL-lactic acid and poly-L-lactic acid; (D3) Polyglycolic acid, melting point 220~231℃.

[0018] In some embodiments of this application, after molding, the resulting bone wax with predetermined properties is sterilized; optionally, the sterilization method includes irradiation sterilization.

[0019] One or more embodiments of this application provide a bone wax, which is prepared by the preparation method described above.

[0020] One or more embodiments of this application provide a bone repair product or bone product, wherein the bone repair product or bone product includes the aforementioned bone wax.

[0021] Compared with traditional technologies, this application has the following advantages: The absorbable bone wax prepared in this application is made from a fat-soluble liquid component with a melting point below 80°C and a solid component with a melting point of 100~500°C. During the preparation process, by adjusting the heating conditions, the increase in cohesion of the low-melting-point fat-soluble liquid component and the high-melting-point solid component due to heating during processing is reduced. As a result, the absorbable bone wax obtained in the final product has reduced cohesion, decreased hardness, and improved adhesion. It can be used directly at room temperature, which improves the ease of use. Attached Figure Description

[0022] To more clearly illustrate the technical solutions in the embodiments of this application and to more completely understand this application and its beneficial effects, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0023] Figure 1 Figure A shows the SEM images of bone wax obtained in Example 3, and Figure B shows the SEM image of bone wax obtained in Comparative Example 1.

[0024] Figure 2 Gross observation was conducted 12 weeks post-surgery on a canine tibial defect model experimental group (Example 3).

[0025] Figure 3Gross observation was conducted 12 weeks after bone wax grafting in a blank control group of a canine tibial defect model.

[0026] Figure 4 MicroCT was used to observe samples taken 12 weeks after surgery in the experimental group of canine tibial defect model (Example 3).

[0027] Figure 5 MicroCT was used to observe tissue samples taken 12 weeks after surgery in a blank control group of a canine tibial defect model. Detailed Implementation

[0028] The present application will be further described in detail below with reference to the accompanying drawings, embodiments, and examples. It should be understood that these embodiments and examples are for illustrative purposes only and are not intended to limit the scope of the present application. The purpose of providing these embodiments and examples is to enable a more thorough and comprehensive understanding of the disclosure of the present application. It should also be understood that the present application can be implemented in many different forms and is not limited to the embodiments and examples described herein. Those skilled in the art can make various modifications or alterations without departing from the spirit of the present application, and the equivalent forms obtained also fall within the protection scope of the present application. Furthermore, numerous specific details are set forth in the following description to provide a fuller understanding of the present application. It should be understood that the present application can be implemented without one or more of these details.

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein in the specification of this application is for descriptive purposes only and is not intended to be limiting of the application.

[0030] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings: The terms "and / or," "or / and," and "and / or" as used herein include any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that in this application, the technical solution undoubtedly includes technical solutions connected by "logical AND," and also undoubtedly includes technical solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: A, B, and A+B. For 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, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0031] In this application, the terms "multiple", "various", "multiple times", "multi-dimensional", etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, "one or more" means one or more than or equal to two.

[0032] The terms “combinations of,” “any combination of,” and “any combination of” used in this article include all suitable combinations of any two or more of the listed items.

[0033] In this document, the term "suitable" as used in phrases such as "suitable combination," "suitable method," and "any suitable method" refers to the ability to implement the technical solution of this application, solve the technical problem of this application, and achieve the expected technical effect of this application.

[0034] In this document, terms such as “preferred,” “better,” “more suitable,” and “ideal” are merely used to describe implementation methods or examples that achieve better results, and should be understood not to limit the scope of protection of this application.

[0035] In this application, terms such as "further," "even further," and "particularly" are used to describe purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0036] In this application, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "optional" entries in a technical solution, unless otherwise specified, and there are no contradictions or mutual constraints, each "optional" entry shall be independent.

[0037] In this application, the terms "first aspect," "second aspect," "third aspect," "fourth aspect," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor should they be construed as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first," "second," "third," "fourth," etc., serve only as a non-exhaustive enumeration and should be understood not to constitute a closed limitation on quantity.

[0038] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0039] In this application, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, the selected numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. In this document, this is equivalent to directly listing every integer. For example, if t is an integer selected from 1 to 10, it means that t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0040] Unless otherwise specified, the temperature parameters in this application are permitted to be either constant-temperature treatment or variations within a certain temperature range. It should be understood that the constant-temperature treatment allows temperature fluctuations within the precision range of the instrument control, such as ±5℃, ±4℃, ±3℃, ±2℃, or ±1℃.

[0041] In this application, %(w / w) and wt% both represent weight percentage, %(v / v) refers to volume percentage, and %(w / v) refers to mass-volume percentage.

[0042] All references to this application are incorporated herein by reference as if each document were individually incorporated herein by reference. Unless they conflict with the purpose and / or technical solution of this application, all cited references are incorporated herein by reference in their entirety and for all purposes. When references are cited in this application, the definitions of relevant technical features, terms, nouns, phrases, etc., are also incorporated herein by reference. Examples and preferred embodiments of the cited technical features may also be incorporated herein by reference, but only to the extent that they enable the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or modifications shall be made adaptably to the description in this application.

[0043] A first aspect of this application provides a method for preparing bone wax, the method comprising the following steps: Take the required raw materials, whether preheated or not, and carry out the first blending and stirring at 40~90℃ (e.g., 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90℃) to prepare intermediate product 1; Intermediate product 1 is cooled to 10-30°C (e.g., 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30°C) and subjected to a second blending at 10-30°C (e.g., 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30°C) to prepare intermediate product 2; and, The intermediate product 2 is shaped to prepare bone wax; The raw materials include a fat-soluble liquid component and a solid component. The melting point of the fat-soluble liquid component is below 80°C (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80°C), and the melting point of the solid component is 100~500°C (e.g., 100, 150, 200, 250, 300, 350, 400, 450, 500°C).

[0044] The mixing of low-melting-point fat-soluble liquid components and high-melting-point solid components can easily lead to increased cohesiveness in the material. This application addresses the issue of excessively high cohesiveness due to differences in the melting points of different components and temperature variations, resulting in a hard material at room temperature. By controlling the temperature throughout the preparation process and further enhancing the stirring intensity, the cohesiveness at room temperature is improved. Without affecting the viscosity and adhesion of the material, the resulting bone wax product has suitable hardness and can be used directly at room temperature, facilitating clinical application and offering a simple and convenient operation.

[0045] In some embodiments of this application, the preparation method satisfies one or more of the conditions shown in (A1) to (A3): (A1) The first mixing time is 1~10h (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10h); (A2) The second mixing time is 1 to 10 hours (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours). (A3) The required temperatures of the preheated raw materials are 40~60℃. For example, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, and 60℃. In this application, preheating allows the raw materials to be rapidly heated during the later blending process. Preheating can be performed while blending all the required raw materials, or each raw material can be preheated before blending. The specific method of preheating is not limited here.

[0046] In some embodiments of this application, the preparation method satisfies one or more of the conditions shown in (B1) to (B2) below: (B1) The speed of the first mixing stirring is 5~100 rpm (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 rpm); (B2) The second mixing speed is 5~100 rpm (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 rpm).

[0047] In some embodiments of this application, the raw material further includes reinforcing components, which include one or more of stearates, stearates, inorganic calcium salts, amphoteric surfactants, and polyethylene glycol.

[0048] In some embodiments of this application, the raw materials, by weight, comprise: 5 to 60 parts (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 parts) of the fat-soluble liquid component, and 5 to 80 parts (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 parts) of the fat-soluble liquid component. The solid component is in parts of 160 parts (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160 parts).

[0049] In some embodiments of this application, the reinforcing component satisfies one or more of the following conditions (C1) to (C5): (C1) The amphoteric surfactant comprises a polyoxypropylene-polyoxyethylene block copolymer; optionally, the polyoxypropylene-polyoxyethylene block copolymer comprises one or more of poloxamer 188, poloxamer 338, poloxamer 407, poloxamer 105, poloxamer 124, poloxamer 184, poloxamer 237, poloxamer 335, poloxamer 403 and poloxamer 401; (C2) The stearate includes one or more of sodium stearate, calcium stearate and zinc stearate; (C3) The stearate includes glyceryl stearate; (C4) The polyethylene glycol includes one or more of polyethylene glycol 1000, polyethylene glycol 1500 and polyethylene glycol 4000; (C5) The inorganic calcium salt includes calcium phosphate; optionally, the calcium phosphate includes one or more of tricalcium phosphate, hydroxyapatite, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, calcium sulfate, bioactive glass and calcium carbonate.

[0050] In some embodiments of this application, the fat-soluble liquid component includes one or more of vitamin E acetate, polyethylene glycol vitamin E succinate, sesame oil, castor oil, oleic acid, ethyl oleate, sorbitan oleate, cinnamon oil, glyceryl linoleate, glyceryl laurate, and glyceryl palmitate.

[0051] In some embodiments of this application, the solid component includes one or more of the components shown in (D1) to (D3): (D1) A substance containing one or more carboxyl and hydroxyl groups, with a melting point of 250~500℃ (e.g., 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 41). (0, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490, 495, 500℃); In some examples, the substance is a polysaccharide, such as a natural polysaccharide, or a modified polysaccharide; Optionally, the substance includes one or more of carboxymethyl chitosan, sodium carboxymethyl cellulose, potato starch, alginate, and sodium hyaluronate; (D2) Polylactic acid, with a melting point of 160~330℃ (e.g., 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325℃); optionally, the polylactic acid includes one or more of poly-DL-lactic acid and poly-L-lactic acid; (D3) Polyglycolic acid, melting point 220~231℃.

[0052] In some embodiments of this application, after molding, the resulting bone wax with a predetermined shape is sterilized.

[0053] This application does not specifically limit the sterilization method; any suitable method can be used, including but not limited to: irradiation sterilization, such as that mentioned in the embodiments. 60 Co-ray sterilization.

[0054] A second aspect of this application provides a bone wax prepared by the aforementioned preparation method.

[0055] A third aspect of this application provides a bone repair product or bone product, wherein the bone repair product or bone product includes the aforementioned bone wax.

[0056] The embodiments of this application will be described in detail below with reference to examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of this application. For experimental methods in the following embodiments where specific conditions are not specified, please refer to the guidelines given in this application, or follow experimental manuals or conventional conditions in the art, or follow the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0057] In the specific embodiments described below, the measurement parameters involving raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Temperature and time parameters are subject to acceptable deviations due to instrument testing accuracy or operational precision.

[0058] This application provides an absorbable bone wax and its preparation method. The absorbable bone wax is prepared from a fat-soluble liquid component with a melting point below 80°C and a solid component with a melting point of 100-500°C. During the preparation process, reinforcing components may or may not be added. During the preparation of the bone wax, the low-melting-point fat-soluble liquid component and the high-melting-point solid component experience increased cohesion due to heating during processing. Directly heating and mixing these raw materials can affect the hardness and viscosity of the final bone wax product. To address this, this application adjusts the heating conditions and further adjusts the mechanical action intensity, resulting in reduced cohesion and hardness of the final putty-like component, while improving adhesion. This allows for direct use at room temperature, improving ease of use for doctors.

[0059] Castor oil: CAS: 8001-79-4, Shanghai Mengtong Chemical Co., Ltd.

[0060] Sodium carboxymethyl cellulose: CAS: 9004-32-4, Spico Biopharmaceutical Co., Ltd.

[0061] Polyglycolic acid: CAS: 26009-03-0, Shenzhen Boli Biomaterials Co., Ltd.

[0062] Polosham 188: CAS: 9003-11-6, BASF (China) Company Ltd.

[0063] Polosham 338: CAS: 9003-11-6, BASF (China) Company Ltd.

[0064] Vitamin E acetate: CAS: 7695-91-2, BASF (China) Company Ltd.

[0065] Zinc stearate: CAS: 557-05-1, Hangzhou Zanyu Oils & Fats Technology Co., Ltd.

[0066] Calcium stearate: CAS: 1592-23-0, Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.

[0067] Tricalcium phosphate: CAS: 7758-87-4, Suzhou Ding'an Technology Co., Ltd.

[0068] Polyethylene glycol 1000: CAS: 25322-68-3, Suzhou Kemei Biosynthesis Co., Ltd.

[0069] Example 1 This embodiment relates to a bone wax and its preparation method. The preparation method includes the following steps: (1) First mixing: Take 40g poloxamer 188, 8g calcium stearate, 10g tricalcium phosphate, 20g sodium carboxymethyl cellulose and 20g vitamin E acetate and mix them at 40℃. The mixing speed is 20rpm and the mixing time is 2h to prepare a clay-like intermediate product 1.

[0070] (2) Second mixing: Cool the above clay-like intermediate product 1 to 10°C and continue mixing for 2 hours at a stirring speed of 20 rpm to prepare clay-like intermediate product 2.

[0071] (3) Shaping and sterilization: The prepared clay-like intermediate product 2 is shaped into block absorbable bone wax in a mold, and then packaged. 60 Sterilized with Co rays, absorbable bone wax is obtained and stored in a sealed container at room temperature.

[0072] Example 2 This embodiment is a variation of Embodiment 1, with the only difference being that in step (1), the mixing and stirring are carried out at 75°C. All other aspects are the same as in Embodiment 1.

[0073] Example 3 This embodiment is a variation of Embodiment 1, with the only difference being that in step (1), the mixing and stirring are carried out at 90°C. All other aspects are the same as in Embodiment 1.

[0074] Example 4 This embodiment is a variation of Embodiment 1. The only difference from Embodiment 1 is that in step (2), the above-mentioned clay-like intermediate product 1 is cooled to 20°C and then mixed. All other aspects are the same as in Embodiment 1.

[0075] Example 5 This embodiment is a variation of Embodiment 1. The only difference from Embodiment 1 is that in step (2), the above-mentioned clay-like intermediate product 1 is cooled to 30°C and mixed. All other aspects are the same as in Embodiment 1.

[0076] Example 6 This embodiment is a variation of Embodiment 1, with the only difference being that in step (1), the mixing and stirring are performed at 90°C, and in step (2), the above-mentioned clay-like intermediate product 1 is cooled to 30°C for mixing and stirring. All other aspects are the same as in Embodiment 1.

[0077] Example 7 This embodiment provides a bone wax and its preparation method, including the following steps: (1) Take the required raw materials according to Table 1, mix them at 40°C, stir at a speed of 5 rpm for 1 hour, and prepare a clay-like intermediate product 1.

[0078] (2) Cool the above clay-like intermediate product 1 to 30°C and continue to mix and stir for 1 hour at a stirring speed of 5 rpm to prepare clay-like intermediate product 2.

[0079] (3) The prepared clay-like intermediate product 2 is molded in a mold to obtain blocky absorbable bone wax, which is then packaged and used... 60 Sterilized with Co rays, absorbable bone wax is obtained and stored in a sealed container at room temperature.

[0080] Example 8 This embodiment provides a bone wax and its preparation method, including the following steps: (1) Take the required raw materials according to Table 1, mix them at 90°C, stir at 100 rpm for 10 hours to prepare clay-like intermediate product 1.

[0081] (2) Cool the above clay-like intermediate product 1 to 10°C and continue to mix and stir for 10 hours at a stirring speed of 100 rpm to prepare clay-like intermediate product 2.

[0082] (3) The prepared clay-like intermediate product 2 is molded in a mold to obtain blocky absorbable bone wax, which is then packaged and used... 60 Sterilized with Co rays, absorbable bone wax is obtained and stored in a sealed container at room temperature.

[0083] Example 9 This embodiment provides a bone wax and its preparation method, including the following steps: (1) Take the required raw materials according to Table 1, mix them at 65°C, stir at 55 rpm for 6 hours to prepare clay-like intermediate product 1.

[0084] (2) Cool the above clay-like intermediate product 1 to 20°C and continue to mix and stir for 6 hours at a stirring rate of 55 rpm to prepare clay-like intermediate product 2.

[0085] (3) The prepared clay-like intermediate product 2 is molded in a mold to obtain blocky absorbable bone wax, which is then packaged and used... 60Sterilized with Co rays, absorbable bone wax is obtained and stored in a sealed container at room temperature.

[0086] Table 1

[0087] Example 10 This embodiment is a variation of embodiment 1. The only difference from embodiment 3 is that each raw material is preheated to 40°C before performing steps (1) to (3) of embodiment 1.

[0088] Example 11 This embodiment is a variation of embodiment 3. The only difference from embodiment 3 is that the conditions for co-mixing in step (2) are: the mixing speed is 1 rpm and the mixing time is 15 h.

[0089] Example 12 This embodiment is a variation of embodiment 6. The only difference from embodiment 3 is that the conditions for co-mixing in step (2) are: the mixing speed is 1 rpm and the mixing time is 15 h.

[0090] Comparative Example 1 This comparative example is a comparative example of Example 3. The difference between Example 3 and Example 3 is that in step (2), the prepared clay-like intermediate product 1 is not cooled down and is continued to be mixed and stirred for 2 hours at a stirring rate of 20 rpm to prepare clay-like intermediate product 2. The rest is the same as in Example 3.

[0091] Comparative Example 2 This comparative example is a comparative example of Example 3. The difference between Example 3 and Example 3 is that in step (2), the obtained clay-like intermediate product 1 is cooled to 40°C and then mixed and stirred for 2 hours at a stirring rate of 20 rpm to prepare clay-like intermediate product 2. The rest is the same as in Example 3.

[0092] Comparative Example 3 This comparative example is a comparative example of Example 3. The difference between Example 3 and Example 3 is that in step (2), the obtained clay-like intermediate product 1 is cooled to 5°C and then mixed and stirred for 2 hours at a stirring rate of 20 rpm to prepare clay-like intermediate product 2. The rest is the same as in Example 3.

[0093] Comparative Example 4 This comparative example is a comparative example of Example 3. The difference between Example 3 and Example 3 is that in step (1), each substance is mixed and stirred at 100°C with a stirring rate of 20 rpm for 2 hours to prepare a clay-like intermediate product 1. The rest is the same as in Example 3.

[0094] Comparative Example 5 This comparative example is the comparative example of Example 3, and relates to a bone wax and its preparation method. The preparation method includes the following steps: (1) Take 40g poloxamer 188, 8g calcium stearate, 10g tricalcium phosphate, 20g sodium carboxymethyl cellulose and 20g vitamin E acetate and mix them at 100℃ with a stirring speed of 20rpm for 2h to prepare a clay-like intermediate product 1.

[0095] (2) Cool the above clay-like intermediate product 1 to 5°C and continue to mix and stir for 2 hours at a stirring speed of 20 rpm to prepare clay-like intermediate product 2.

[0096] (3) The prepared clay-like intermediate product 2 is molded in a mold to obtain blocky absorbable bone wax, which is then packaged and used... 60 Sterilized with Co rays, absorbable bone wax is obtained and stored in a sealed container at room temperature.

[0097] Comparative Example 6 Non-absorbable bone wax is prepared by mixing 75% beeswax, 15% paraffin wax, and 10% palmitopropyl ester at 32°C.

[0098] Using the bone waxes provided in the above examples as test samples, the following performance evaluations were conducted:

[0099] Place the test sample on a flat, hard surface, keeping the indenter parallel to the surface of the test sample so that the indenter is perpendicular to the surface of the test sample. Apply 1 kg of pressure to make the indenter and the surface of the test sample in close contact, hold for 2-3 seconds, and read the value after the value stabilizes. Perform the test in accordance with GB / T 531.1-2008 Test method for indentation hardness of vulcanized rubber or thermoplastic rubber - Part 1 Shore hardness test (Shore hardness) at an environment of 23±2℃ and 50±5% relative humidity.

[0100] (2) Adhesion strength The specific procedure for testing adhesive strength is as follows: Two cortical bone rings, each 10 mm wide, are prepared using bovine femur. The test sample is evenly applied to the surface of one of the cortical bone rings (surface area S). After the other cortical bone ring is brought into contact with the test sample, a pressure of 78 N is applied at a speed of 1 mm / min for 1 min. Then, the two sides of the bone rings are connected to the tensile clamps of a multi-functional mechanical testing machine, and the two bone rings are pulled apart at a speed of 1 mm / min until the adhesive joint breaks. The maximum tensile force F at the point of breakage is recorded, and the adhesive strength (MPa) is calculated as F / S.

[0101] The specific method for testing wet bond strength is basically the same as above. Simply immerse one of the cortical bone rings in physiological saline for 5 minutes and then bond it to the test sample. Immerse the other moistened cortical bone ring in physiological saline for 5 minutes, then bring it into contact with the test sample. Apply pressure of 78 N at a speed of 1 mm / min for 1 minute. After bonding, immerse the bone rings in water at room temperature for 5 minutes and then test the bond strength, following the same procedure as above.

[0102] The experimental results are shown in Table 2 below.

[0103] Table 2. Adhesion strength results of the experimental group and the bone wax control group

[0104] Due to the large difference in melting points between macromolecules, at temperatures of 40~90℃, the cohesive force increases sharply due to the entanglement of molecular chains within the substance. If not properly treated, the final product will have high hardness, poor ductility, and poor adhesion due to the tight intermolecular connections, as shown in the results of Comparative Example 1 in Table 2.

[0105] A comparison of Examples 1 to 3 shows that, under the same conditions of raw material type and dosage, mixing speed and time, as the temperature of step (1) increases, the temperature difference between step (1) and step (2) increases, the hardness of bone wax decreases, and the adhesive strength and wet adhesive strength increase.

[0106] A comparison of Examples 1, 4, and 5 shows that, under the same conditions of raw material type and dosage, and mixing speed and time, as the temperature in step (2) increases, the temperature difference between steps (1) and (2) decreases, resulting in an increasing trend in the hardness of bone wax and a decreasing trend in its adhesive strength and wet adhesive strength. Similarly, Examples 3 and 6 also exhibit the above trends. This is because changes in temperature affect the agglomeration of the mixed state of each component, thereby affecting the change in cohesive force.

[0107] like Figure 1 As can be seen from the SEM images (Figure A) of the bone wax prepared in Example 3 and the SEM image (Figure B) of the bone wax prepared in Comparative Example 1, the internal structure of the bone wax prepared by the appropriate preparation method of this application is relatively open, indicating that the cohesive force within the molecules is relatively small.

[0108] Data from Examples 11 and 12 show that the mixing conditions also affect the performance of the final product. In particular, when the temperature is low after cooling in step (2) and the stirring speed is too slow, it is not conducive to the expansion of the internal structure of the final product, which leads to a higher hardness and poorer bonding strength of the final product, which is not conducive to clinical application.

[0109] The data from Examples 2-5 show that the temperature range in steps (1) and (2) is also very important. Improper temperature control can have a significant impact on the phase state of the material, thereby affecting the cohesiveness of the bone wax and resulting in defects such as high hardness and poor adhesion strength. In particular, when the temperature in step (1) is high, it may cause damage to the internal molecular structure of the material, resulting in a higher hardness and poorer adhesion strength in the final product.

[0110] (3) Tibial defect test Twenty-four beagle dogs were used as experimental animals and divided into two groups. The absorbable bone wax prepared in Example 3 of this application was used as the experimental group, and a blank control group without any treatment was also provided.

[0111] After anesthetizing the animals, one side of the iliac bone was exposed and the periosteum of the inner and outer plates was removed. Approximately 1 mm of the surface bone of the outer plate of the iliac bone was severed using bone forceps, exposing a wound approximately 1 cm in diameter on the iliac bone surface. The injured bone was divided into an experimental group and a blank control group. In the experimental group, the lesion was treated with the absorbable bone wax prepared in Example 3 of this application, while the blank control group received no treatment. Electrocoagulation was used to stop bleeding at the surrounding soft tissue bleeding points. Each defect was covered with a piece of hemostatic gauze of known weight (m1). After 3 minutes, the bleeding at the opening was observed, and the sterile gauze was removed and weighed as m2. Therefore, the bleeding weight m = m2 - m1. After rinsing the surrounding tissue, the outer opening was sutured with the nearby periosteum, and then the skin was sutured layer by layer to close the wound.

[0112] 1) Results of blood loss

[0113] Table 3. Results of 3-minute oozing blood volume in the experimental group and the blank control group. experimental group <![CDATA[Hemorrhage weight M3 / g]]> Blank control group 0.459±0.018 experimental group 0.058±0.129

[0114] According to the data in Table 3, the bone wax prepared in this application has a good hemostatic effect.

[0115] 2) Postoperative observation Figure 2 and Figure 3 The results of 12-week observation of tibial defects in dogs using bone wax as described in Example 3 were as follows: the defect surfaces in both the experimental group and the blank control group using Example 3 had been largely repaired.

[0116] Figure 4 , Figure 5Table 4 shows the MicroCT results of bone wax grafts taken from the tibial defect sites at 12 weeks. The BV / TV (bone volume fraction) of the experimental group (using Example 3) and the blank control group were 34.05% and 22.95%, respectively. According to the MicroCT results of the 12-week-old graft sites, the repair of bone wax defects in the experimental group (using Example 3) was significantly different from that in the blank control group.

[0117] Table 4. Tissue sites 12 weeks post-surgery in canine tibial defect models experimental group BV / TV / % Blank control group 22.95±3.68 experimental group 34.05±6.53

[0118] In summary, the absorbable bone wax prepared by the method described in this application has excellent hemostatic and bone repair properties.

[0119] Overall, this application addresses the issues of different melting points of components, excessively high cohesiveness after temperature changes, and material hardness at room temperature. By adjusting the overall temperature and further coordinating with mechanical stirring conditions, it improves the material's cohesiveness at room temperature, enhances its viscosity and adhesion, and thus facilitates clinical use. The entire preparation method is simple and convenient.

[0120] The technical features of the above-described embodiments and examples can be combined in any suitable manner. For the sake of brevity, 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, they should be considered to be within the scope of this specification.

[0121] The embodiments described above are merely illustrative of several implementation methods of this application, intended to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. Furthermore, it should be understood that after reading the above teachings of this application, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the scope of protection of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A method for preparing bone wax, characterized in that, The preparation method includes the following steps: Take the required raw materials, whether preheated or not, and carry out the first mixing and stirring at 40~90℃ to prepare intermediate product 1; The intermediate product 1 is cooled to 10-30°C and subjected to a second blending and stirring at 10-30°C to prepare intermediate product 2; and, The intermediate product 2 is shaped to prepare bone wax; The raw materials include a fat-soluble liquid component and a solid component. The melting point of the fat-soluble liquid component is below 80°C, and the melting point of the solid component is 100~500°C.

2. The method for preparing bone wax according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions (A1) to (A3): (A1) The first mixing time is 1~10h; (A2) The second mixing time is 1~10h; (A3) The required temperature of each raw material after preheating is 40~60℃.

3. The method for preparing bone wax according to claim 1, characterized in that, The preparation method satisfies one or more of the following conditions (B1) to (B2): (B1) The stirring speed for the first mixing step is 5~100 rpm; (B2) The second mixing speed is 5~100 rpm.

4. The method for preparing bone wax according to any one of claims 1 to 3, characterized in that, The raw materials also include reinforcing components, which include one or more of stearates, stearates, inorganic calcium salts, amphoteric surfactants, and polyethylene glycol.

5. The method for preparing bone wax according to claim 4, characterized in that, The raw materials, by weight, comprise: 5 to 60 parts of the fat-soluble liquid component, 5 to 80 parts of the solid component, and no more than 160 parts of the reinforcing component.

6. The method for preparing bone wax according to claim 5, characterized in that, The reinforcing component satisfies one or more of the following conditions (C1) to (C5): (C1) The amphoteric surfactant comprises a polyoxypropylene-polyoxyethylene block copolymer; optionally, the polyoxypropylene-polyoxyethylene block copolymer comprises one or more of poloxamer 188, poloxamer 338, poloxamer 407, poloxamer 105, poloxamer 124, poloxamer 184, poloxamer 237, poloxamer 335, poloxamer 403 and poloxamer 401; (C2) The stearate includes one or more of sodium stearate, calcium stearate and zinc stearate; (C3) The stearate includes glyceryl stearate; (C4) The polyethylene glycol includes one or more of polyethylene glycol 1000, polyethylene glycol 1500 and polyethylene glycol 4000; (C5) The inorganic calcium salt includes calcium phosphate; optionally, the calcium phosphate includes one or more of tricalcium phosphate, hydroxyapatite, tetracalcium phosphate, octacalcium phosphate, hydroxyapatite, calcium sulfate, bioactive glass and calcium carbonate.

7. The method for preparing bone wax according to claim 1, characterized in that, The fat-soluble liquid component includes one or more of the following: vitamin E acetate, polyethylene glycol eurotin succinate, sesame oil, castor oil, oleic acid, ethyl oleate, sorbitan oleate, cinnamon oil, glyceryl linoleate, glyceryl laurate, and glyceryl palmitate.

8. The method for preparing bone wax according to claim 1, characterized in that, The solid component includes one or more of the components shown in (D1) to (D3): (D1) A substance containing one or more of carboxyl and hydroxyl groups, with a melting point of 250-500°C; optionally, the substance includes one or more of carboxymethyl chitosan, sodium carboxymethyl cellulose, potato starch, alginate and sodium hyaluronate. (D2) Polylactic acid, with a melting point of 160~330℃; optionally, the polylactic acid includes one or more of poly-DL-lactic acid and poly-L-lactic acid; (D3) Polyglycolic acid, melting point 220~231℃.

9. A bone wax, characterized in that, The bone wax is prepared by the preparation method according to any one of claims 1 to 8.

10. A bone repair product or bone product, characterized in that, The bone repair product or bone product includes the bone wax as described in claim 9.

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