Absorbable bone wax, preparation method and application

Abstract

The invention discloses absorbable bone wax as well as a preparation method and application thereof, and relates to the technical field of medicines. The absorbable bone wax comprises the following components in parts by weight: 8-25 parts of calcium stearate, 15-35 parts of vitamin E or a derivative thereof, 12-45 parts of polyethylene glycol or a derivative thereof and 12-50 parts of calcium sulfate. The bone wax is endowed with excellent blocking and hemostasis performance through calcium stearate, the hardness of the bone wax is adjusted through vitamin E and a derivative thereof, and under the synergistic effect of calcium sulfate and polyethylene glycol or a derivative thereof, the relationship between the blocking and hemostasis performance of the bone wax and the loosening time is effectively balanced, and it is guaranteed that the bone wax has the good hemostasis effect and also has the good hemostasis effect. And in addition, the wet and slippery wet-proof coating has the characteristics of good operation performance, no wet and slippery feeling and non-sticking to gloves.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to an absorbable bone wax, its preparation method, and its application. Background Technology

[0002] Currently, the most widely used bone hemostatic material in clinical practice is a waxy substance, commonly known as bone wax. During use, bone wax is applied and squeezed onto the bone wound to physically seal blood vessels and control local bone bleeding. Therefore, the sealing and hemostatic function of bone wax is its most important performance indicator. The bone wax used in current surgical procedures is mainly non-absorbable, made from a mixture of beeswax, paraffin, petrolatum, and vegetable oils. This non-absorbable bone wax has good sealing and hemostatic properties for bleeding bone wounds and does not easily cause oozing. However, its disadvantage is that it is non-absorbable, which may cause foreign body-induced chronic inflammation and affect bone healing. Therefore, absorbable bone wax has emerged in clinical practice.

[0003] The clinical application of absorbable bone wax is still in its early stages. Current technologies use water-soluble epoxy alkyl copolymers or homopolymers, such as poloxamer or polyethylene glycol, as bone hemostatic materials, such as the commercially available Ostene. These water-soluble polymers dissolve completely in water very quickly (within tens of minutes), and when they come into contact with water or blood, they have a noticeable slippery feel and are easy to slip off. Therefore, their sealing and hemostatic performance is not as good as that of non-absorbable bone wax. For example, patent documents with publication numbers CN210992034U, CN101444635A, CN106039390A, CN108744019B, CN102727930B, CN111068101A, and US10549009B2 all disclose water-soluble bone wax containing water-soluble polymers such as polyethylene glycol and ethylene oxide-propylene oxide copolymer, carboxymethyl cellulose or carboxymethyl starch, chitosan, gelatin, polysaccharides, etc.

[0004] Given the shortcomings of water-soluble bone wax, some patents disclose water-insoluble or partially water-soluble absorbable bone wax. For example, patent documents CN108939138A and US4440789A provide water-insoluble absorbable bone wax, but these types of water-insoluble bone wax are often absorbed very slowly and have acidic degradation products. In addition, patent document CN101052360B discloses a partially water-soluble absorbable bone wax, but because the absorption of water-insoluble calcium stearate is slow, a large amount of poloxamer needs to be added to accelerate the loose absorption of the bone wax, thereby increasing the slippery feel of the bone wax, which is not conducive to sealing and hemostasis. Patent document CN111729125B discloses a partially water-soluble bone hemostatic material, in which poloxamer and sodium carboxymethyl cellulose are water-soluble polymers, which affect the sealing and hemostatic effect of bone wax.

[0005] It is evident that existing absorbable bone wax products cannot match the hemostatic performance of non-absorbable bone wax. Therefore, developing an absorbable bone wax with hemostatic performance comparable to or even better than non-absorbable bone wax, while also being easily absorbed, is a pressing problem to be solved in this field. Summary of the Invention

[0006] This invention aims to solve the technical problem that existing absorbable bone waxes cannot simultaneously possess both easy absorption and good occlusive hemostatic properties. The purpose is to provide an absorbable bone wax, its preparation method, and its application. Calcium stearate imparts excellent occlusive hemostatic properties to the bone wax, vitamin E and its derivatives adjust the hardness of the bone wax, and the synergistic effect of calcium sulfate and polyethylene glycol or their derivatives effectively balances the relationship between the occlusive hemostatic properties and the dispersing time of the bone wax. This ensures that the bone wax has both good hemostatic effect and rapid absorption, and also possesses characteristics such as good operability, no slippery feel, and no stickiness to gloves.

[0007] This invention is achieved through the following technical solution:

[0008] The first objective of this invention is to provide an absorbable bone wax comprising, by weight, the following components: 8-25 parts calcium stearate, 15-35 parts vitamin E or its derivatives, 12-45 parts polyethylene glycol or its derivatives, and 12-50 parts calcium sulfate.

[0009] In the absorbable bone wax of the present invention, calcium stearate is a relatively hard waxy solid that is insoluble in water. In the present invention, it can give the bone wax a waxy texture and excellent sealing and hemostatic properties. However, its absorption in the body is relatively slow. Therefore, bone wax with less calcium stearate is more suitable under the premise of satisfying the sealing and hemostatic properties.

[0010] In the absorbable bone wax of the present invention, vitamin E and its derivatives are viscous liquids that are insoluble in water. The hardness of the bone wax can be adjusted in the present invention, and calcium stearate and other components can be bound together. Therefore, the bone wax with the desired hardness can be obtained by combining the components and calcium stearate in an appropriate ratio. However, the bone wax obtained by using only these two components is absorbed very slowly.

[0011] In the absorbable bone wax of this invention, polyethylene glycol (PEG) is a solid, waxy, water-soluble polymer. It exhibits some slipperiness upon contact with water, but the slipperiness produced by PEG is not as pronounced as that of poloxamer. PEG's functions are twofold: first, to promote the loosening and absorption of the bone wax; and second, to impart a certain degree of hardness and a waxy texture. The higher the PEG content in the bone wax of this invention, the easier it is to absorb. However, excessively high PEG content can cause a slippery feel and reduce its occlusive and hemostatic properties. Therefore, to achieve rapid loosening and absorption of the bone wax, relying solely on water-soluble polymers is insufficient.

[0012] In the absorbable bone wax of this invention, calcium sulfate is a slightly water-soluble calcium salt with a solubility of approximately 0.2 g / 100 mL in water. The aqueous solution is not slippery. Adding calcium sulfate promotes the loose absorption of the bone wax without increasing its slippery feel. Furthermore, in this invention, the combined use of calcium sulfate and polyethylene glycol has a synergistic effect, significantly enhancing the hemostatic and occlusive properties of the bone wax. During in vitro degradation, it also loosens the bone wax more quickly, resulting in better effects than using polyethylene glycol or calcium sulfate alone.

[0013] In summary, the absorbable bone wax of the present invention imparts excellent occlusive and hemostatic properties to the bone wax through calcium stearate, adjusts the hardness of the bone wax through vitamin E and its derivatives, and achieves or exceeds the occlusive and hemostatic properties of non-absorbable bone wax under the synergistic effect of calcium sulfate and polyethylene glycol or its derivatives. At the same time, it can be quickly and loosely absorbed, and has the characteristics of good handling performance, no slippery feeling, and no stickiness to gloves.

[0014] Furthermore, the vitamin E derivative is vitamin E acetate.

[0015] Furthermore, the polyethylene glycol derivative is at least one of polyethylene glycol monomethyl ether and polyethylene glycol dimethyl ether.

[0016] Furthermore, the molecular weight of the polyethylene glycol or its derivatives is 300 Da to 30000 Da.

[0017] Preferably, the molecular weight of the polyethylene glycol or its derivative is 1500 Da to 10000 Da.

[0018] Furthermore, the calcium sulfate is selected from at least one of anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium sulfate dihydrate, or other hydrated calcium sulfate.

[0019] Furthermore, the absorbable bone wax also contains at least one of the following: a substance with good bone compatibility, an anti-inflammatory drug, poloxamer 188, and poloxamer 407. The substance with good bone compatibility is selected from at least one of hydroxyapatite, β-tricalcium phosphate, BCP biphasic ceramics, and bioactive glass.

[0020] Furthermore, the bone-compatible substances, poloxamer 188, and poloxamer 407, are added to absorbable bone wax at a mass fraction not exceeding 10%.

[0021] It should be noted that, in addition to the components mentioned above, the absorbable bone wax of the present invention may also contain other components, such as drugs or compounds that promote bone healing, hemostasis, anti-inflammation, and treatment of bone diseases, growth factors, vitamins, trace metal compounds; fatty acids, fatty acid soaps, fatty acid esters, disintegrants, water-soluble polymers, and surfactants to regulate the degradation and absorption rate; liquid or paste-like diluents to regulate the hardness of the bone wax, such as oils formed from fatty acid esters, plasticizers, and emulsifiers; and radiopaque substances, etc.

[0022] The second objective of this invention is to provide a method for preparing absorbable bone wax, characterized by comprising the following steps:

[0023] All components are added to a stirred reactor according to the formula, and after being melted and mixed evenly above the melting point temperature of the fusible material, the mixture is cooled to room temperature to obtain the absorbable bone wax.

[0024] The third objective of this invention is to provide an application of absorbable bone wax in the preparation of hemostatic materials and in filling bone defects.

[0025] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0026] The absorbable bone wax of this invention imparts excellent occlusive and hemostatic properties to the bone wax through calcium stearate, adjusts the hardness of the bone wax through vitamin E and its derivatives, and, with the synergistic effect of calcium sulfate and polyethylene glycol or its derivatives, achieves or exceeds the occlusive and hemostatic properties of non-absorbable bone wax while also having a faster loosening and absorption effect. This effectively balances the relationship between the occlusive and hemostatic properties of bone wax and the loosening time, ensuring that the bone wax has both good hemostatic effect and rapid absorption, and has the characteristics of good handling performance, no slippery feeling, and no stickiness to gloves. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the illustrative embodiments and descriptions of the present invention are only used to explain the present invention and are not intended to limit the present invention.

[0028] The embodiments of the present invention will be described in detail below. However, unnecessary details may be omitted. For example, detailed descriptions of well-known matters and repeated descriptions may be omitted. This is to avoid making the following description unnecessarily lengthy and to facilitate understanding by those skilled in the art.

[0029] The "scope" disclosed in this invention is defined in the form of a lower limit and an upper limit. A given scope is defined by selecting a lower limit and an upper limit, which define the boundaries of the specific scope. The scope defined in this way can include or exclude end values, and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a scope.

[0030] Unless otherwise specified, all embodiments and optional embodiments of the present invention can be combined with each other to form new technical solutions.

[0031] Unless otherwise specified, all technical features and optional technical features of this invention can be combined to form new technical solutions.

[0032] Unless otherwise specified, the terms "comprising" and "including" as used in this invention can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other substances not listed may also be included, or that only the listed substances may be included.

[0033] Unless otherwise specified, all steps of the present invention may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the mention that the method may also include step (c) indicates that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0034] The technical solution of the present invention will be further described in detail below with reference to the embodiments.

[0035] It should be noted that, unless otherwise specified, the experimental methods used in the embodiments are conventional methods. Unless otherwise specified, the materials, reagents, methods, and instruments used are all conventional materials, reagents, methods, and instruments in the art, and can be obtained commercially by those skilled in the art.

[0036] Example 1

[0037] Absorbable bone wax 1 (W1) ingredients:

[0038] Component 1: Calcium stearate 18g

[0039] Component 2: Vitamin E acetate 28g

[0040] Component 3: Polyethylene Glycol 4000 30g

[0041] Component 4: Calcium sulfate dihydrate 24g

[0042] The resulting bone wax has similar hardness and workability to non-absorbent bone wax, does not stick to gloves, has no slippery feel, exhibits excellent pressure resistance and occlusion performance, and is easily loosened. The occlusion and hemostasis performance described in this invention is characterized using a simulated vascular occlusion test model, primarily evaluated by the pressure resistance and occlusion time of the bone wax, which will be detailed in the performance testing section. The loosening of bone wax in this invention refers to the time required for the bone wax to lose its mechanical properties and become loose or incomplete after immersion in a phosphate buffer solution at 37°C, reaching this state; this time is defined as the loosening time.

[0043] Example 2

[0044] Absorbable bone wax 2 (W2) components:

[0045] Component 1: Calcium stearate 22g

[0046] Component 2: Vitamin E acetate 30g

[0047] Component 3: Polyethylene Glycol 4000 24g

[0048] Component 4: Calcium sulfate dihydrate 24g

[0049] The composition was improved by increasing the content of calcium stearate. To achieve the same hardness, the content of vitamin E acetate was also increased. The resulting bone wax is non-sticky to gloves, easy to apply, and has no slippery feel. The increased calcium stearate content makes the bone wax more pressure-resistant and sealing, with the longest pressure-resistant sealing time. However, the time required for the bone wax to loosen is also the longest. Further increasing the calcium stearate content would hinder the absorption of the bone wax.

[0050] Example 3

[0051] Absorbable bone wax 3 (W3) components:

[0052] Component 1: Calcium stearate 18g

[0053] Component 2: Vitamin E acetate 28g

[0054] Component 3: Polyethylene Glycol 4000 38g

[0055] Component 4: Calcium sulfate dihydrate 16g

[0056] The addition of polyethylene glycol to the composition results in bone wax with similar hardness and workability to non-absorbent bone wax. It is non-sticky to gloves, easy to apply, has no obvious slippery feel, is easy to loosen, and has excellent pressure-resistant sealing performance.

[0057] Example 4

[0058] Absorbable bone wax 4 (W4) components:

[0059] Component 1: Calcium stearate 18g

[0060] Component 2: Vitamin E acetate 28g

[0061] Component 3: Polyethylene Glycol 4000 16g

[0062] Component 4: Calcium sulfate dihydrate 38g

[0063] The increased calcium sulfate content in the composition results in bone wax that is non-sticky to gloves, easy to handle, easy to loosen, and has excellent pressure-resistant sealing performance.

[0064] Example 5

[0065] Absorbable bone wax 5 (W5) ingredients:

[0066] Component 1: Calcium stearate 10g

[0067] Component 2: Vitamin E acetate 21g

[0068] Component 3: Polyethylene Glycol 6000 34g

[0069] Component 4 Anhydrous calcium sulfate 35g

[0070] The calcium stearate content in the composition was reduced, resulting in bone wax that does not stick to gloves, is easy to apply, has no slippery feel, is easier to disperse, and has excellent pressure-resistant sealing performance.

[0071] Example 6

[0072] Absorbable bone wax 6 (W6) ingredients:

[0073] Component 1: Calcium stearate 12g

[0074] Component 2: Vitamin E 21g

[0075] Component 3: Polyethylene glycol 10000 22g

[0076] Component 4: Calcium sulfate hemihydrate 45g

[0077] The component uses vitamin E instead of vitamin E acetate, resulting in a slightly yellow appearance. The resulting bone wax is non-sticky to gloves, easy to handle, has no slippery feel, is easy to loosen, and exhibits excellent pressure-resistant sealing performance.

[0078] Example 7

[0079] Absorbable bone wax 7 (W7) ingredients:

[0080] Component 1: Calcium stearate 18g

[0081] Component 2: Vitamin E acetate 28g

[0082] Component 3: Polyethylene Glycol 6000 20g

[0083] Component 4: Calcium sulfate dihydrate 24g

[0084] Component 5: Poloxamer 188 10g

[0085] The addition of poloxamer 188 to the composition results in a bone wax that is non-sticky to gloves, easy to handle, has a slightly slippery feel, excellent pressure-resistant sealing performance, and disperses faster than bone wax made with polyethylene glycol alone.

[0086] Example 8

[0087] Absorbable bone wax 8 (W8) ingredients:

[0088] Component 1: Calcium stearate 15g

[0089] Component 2: Vitamin E acetate 25g

[0090] Component 3: Polyethylene Glycol 6000 24g

[0091] Component 4: Calcium sulfate dihydrate 30g

[0092] Component 5: Poloxamer 188g (6g)

[0093] Adding a small amount of poloxamer 188 to the composition results in bone wax that is non-sticky to gloves, easy to handle, has no slippery feel, excellent pressure-resistant sealing performance, and disperses quickly.

[0094] Example 9

[0095] Absorbable bone wax 9 (W9) ingredients:

[0096] Component 1: Calcium stearate 15g

[0097] Component 2: Vitamin E acetate 25g

[0098] Component 3: Polyethylene Glycol 6000 30g

[0099] Component 4: Calcium sulfate dihydrate 20g

[0100] Component 5: β-tricalcium phosphate 10g

[0101] The addition of β-tricalcium phosphate and the reduction of calcium sulfate content result in bone wax that is non-sticky to gloves, easy to handle, non-slippery, easy to loosen, and has excellent pressure-resistant sealing performance.

[0102] Example 10

[0103] Absorbable bone wax 10 (W10) ingredients:

[0104] Component 1: Calcium stearate 15g

[0105] Component 2: Vitamin E acetate 25g

[0106] Component 3: Polyethylene Glycol 4000 30g

[0107] Component 4: Calcium sulfate dihydrate 28.5g

[0108] Component 5: Gentamicin sulfate 1.5g

[0109] Anti-inflammatory drugs were added to the composition. The resulting bone wax is non-sticky to gloves, easy to handle, non-slip, easily loosened, has excellent pressure-resistant sealing properties, and also has anti-infective and anti-inflammatory functions.

[0110] Example 11

[0111] Absorbable bone wax 11 (W11) ingredients:

[0112] Component 1: Calcium stearate 15g

[0113] Component 2: Vitamin E acetate 25g

[0114] Component 3: Polyethylene glycol monomethyl ether 5000 30g

[0115] Component 4: Calcium sulfate dihydrate 30g

[0116] The resulting bone wax does not stick to gloves, is easy to handle, has no slippery feel, is easy to loosen, and has excellent pressure-resistant sealing performance.

[0117] Example 12

[0118] Absorbable bone wax 12 (W12) components:

[0119] Component 1: Calcium stearate 15g

[0120] Component 2: Vitamin E acetate 25g

[0121] Component 3: Polyethylene glycol monomethyl ether 5000 27g

[0122] Component 4: Calcium sulfate dihydrate 25g

[0123] Component 5: Sodium carboxymethyl cellulose 8g

[0124] The addition of water-soluble sodium carboxymethyl cellulose to the composition results in bone wax that is non-sticky to gloves, easy to handle, has no obvious slippery feel, is easy to loosen, and has excellent pressure-resistant sealing performance.

[0125] Comparative Example 1

[0126] Bone wax (C1) components:

[0127] Component 1: Calcium stearate 15g

[0128] Component 2: Vitamin E acetate 28g

[0129] Component 3: Polyethylene Glycol 4000 57g

[0130] The bone wax prepared by using polyethylene glycol alone without adding calcium sulfate has a noticeable slippery feel when exposed to water, and therefore its pressure-resistant sealing performance is not as good as that of the bone wax in the example and the non-absorbent bone wax.

[0131] Comparative Example 2

[0132] Bone wax (C2) components:

[0133] Component 1: Calcium stearate 15g

[0134] Component 2: Vitamin E acetate 25g

[0135] Component 3: Calcium sulfate dihydrate 60g

[0136] The bone wax produced by using calcium sulfate alone without adding polyethylene glycol has a poor texture, is slightly sticky to gloves, and its pressure-resistant sealing performance is not as good as that of the example bone wax and the non-absorbent bone wax. In addition, the bone wax is extremely difficult to loosen.

[0137] Comparative Example 3

[0138] Bone wax (C3) components:

[0139] Component 1: Calcium stearate 15g

[0140] Component 2: Vitamin E acetate 26g

[0141] Component 3: Polyethylene Glycol 4000 49g

[0142] Component 4: Calcium sulfate dihydrate 10g

[0143] The bone wax prepared by reducing the amount of calcium sulfate and increasing the content of polyethylene glycol in the composition has a certain slippery feel when it comes into contact with water. Therefore, its operability and pressure-resistant sealing performance are not as good as those of the example and the non-absorbent bone wax.

[0144] Comparative Example 4

[0145] Bone wax (C4) components:

[0146] Component 1: Calcium stearate 15g

[0147] Component 2: Vitamin E acetate 24g

[0148] Component 3: Polyethylene Glycol 4000 10g

[0149] Component 4: Calcium sulfate dihydrate 51g

[0150] Reducing the amount of polyethylene glycol used in the components resulted in a slower dispersibility of the bone wax, and its pressure-resistant sealing performance was not as good as that of the example and the non-absorbent bone wax.

[0151] Comparative Example 5

[0152] Bone wax (C5) components:

[0153] Component 1: Calcium stearate 15g

[0154] Component 2: Vitamin E acetate 25g

[0155] Component 3: Polyethylene Glycol 4000 35g

[0156] Component 4: Sodium carboxymethyl cellulose 25g

[0157] The bone wax prepared by replacing calcium sulfate with water-soluble sodium carboxymethyl cellulose in the composition has a noticeable slippery feel when exposed to water, and therefore its pressure-resistant sealing performance is not as good as that of the bone wax in the example and the non-absorbent bone wax.

[0158] Comparative Example 6

[0159] Bone wax (C6) components:

[0160] Component 1: 30g of triglyceride stearate

[0161] Component 2: 40g of lactide-ε-caprolactone oligomer

[0162] Component 3: Polyethylene Glycol 6000 30g

[0163] According to relevant reports, the prepared oligomer bone wax is extremely difficult to break apart, and its hardness is highly sensitive to temperature, being relatively soft at 37°C. Therefore, its pressure-resistant sealing performance is not as good as that of the bone wax in the example and the non-absorbent bone wax.

[0164] Comparative Example 7

[0165] Bone wax (C7)

[0166] Bonewax (Ethicon), a non-absorbable wax composed of beeswax, paraffin, etc., is available on the market. It does not stick to gloves, is easy to handle, has no slippery feel, is not loose, and has excellent pressure-resistant sealing performance.

[0167] Comparative Example 8

[0168] Bone wax (C8)

[0169] Bone wax (C8) components:

[0170] Component 1: Polyethylene glycol 20000 52g

[0171] Component 2: Vitamin E acetate 35g

[0172] Component 3: Poloxamer 188g 3g

[0173] Component 4: Poloxamer 407 10g

[0174] Water-soluble bone wax, without added calcium stearate, is extremely soluble in water. Vitamin E acetate is also easily dissolved along with poloxamer and other substances. It has a very obvious slippery feel when exposed to water, and its pressure-resistant sealing performance is not as good as the bone wax in the examples and the non-absorbable bone wax.

[0175] Comparative Example 9

[0176] Bone wax (C9) components:

[0177] Component 1: Calcium stearate 15g

[0178] Component 2: Vitamin E acetate 28g

[0179] Component 3: Poloxamer 188g (57g)

[0180] When poloxamer is used alone in the composition, the resulting bone wax is slightly sticky to gloves, very easy to loosen, and has a very obvious slippery feel when exposed to water. Its pressure-resistant sealing performance is not as good as that of the example and non-absorbent bone wax.

[0181] Comparative Example 10

[0182] Bone wax (C10) components:

[0183] Component 1: Calcium stearate 15g

[0184] Component 2: Vitamin E acetate 25g

[0185] Component 3: Poloxamer 188 30g

[0186] Component 4: Calcium sulfate dihydrate 30g

[0187] According to the ratio of Example 11, when poloxamer was used instead of polyethylene glycol, the resulting bone wax had a noticeably slippery feel, and its pressure-resistant sealing performance was not as good as that of the example and the non-absorbent bone wax.

[0188] The performance of the above embodiments and comparative examples is evaluated below.

[0189] 1. Evaluation of the workability of absorbable bone wax

[0190] Since the operability of bone wax during use, such as squeezing and applying, is related to its hardness, this invention adjusts the content of vitamin E and its derivatives to make the hardness as close as possible to that of non-absorbent bone wax, so that the bone wax obtained in each embodiment has better operability.

[0191] The present invention also evaluated the adhesion of bone wax to medical gloves during kneading; the degree to which bone wax sticks to gloves can be clearly felt by the researchers by hand.

[0192] In addition, this invention also evaluated the wet slip properties (slip feel) of bone wax upon contact with water. This invention found that a slippery feel in bone wax reduces its sealing and hemostatic properties, and also affects its application performance. The specific evaluation method for slip properties is to test the dynamic coefficient of friction of the bone wax; the smaller the value, the stronger the slip feel. The dynamic coefficient of friction was tested according to the method specified in ASTM-D1894. Before testing, the upper and lower contact surfaces of the bone wax were first moistened with water, and then the test was performed as described. The test results are shown in Table 1. Consistent with the feeling felt by hand, the general trend is that the higher the content of water-soluble polymers, the smaller the dynamic coefficient of friction.

[0193] Table 1. Dynamic Friction Coefficient Data

[0194]

[0195] As can be seen from the data in Table 1, the dynamic friction coefficient of the absorbable bone wax in the embodiments of the present invention is higher than 0.2, and the slippery feeling is not obvious. The dynamic friction coefficient of comparative examples C1 without calcium sulfate, comparative example C3 with low calcium sulfate content, comparative example C5 using water-soluble sodium carboxymethyl cellulose to replace calcium sulfate, comparative example C8 with water-soluble bone wax, and comparative examples C9 and C10 using poloxamer instead of polyethylene glycol, are all lower than 0.2, and the slippery feeling is obvious.

[0196] Therefore, the data in Table 1 proves that polyethylene glycol and its derivatives need to be compounded with calcium sulfate in the present invention, and within a suitable ratio range, in order to effectively reduce the slipperiness of bone wax when it comes into contact with water. Using polyethylene glycol and its derivatives alone in the formulation, or replacing polyethylene glycol and its derivatives with poloxamer, or replacing calcium sulfate with water-soluble sodium carboxymethyl cellulose, cannot achieve the effect of the present invention.

[0197] 2. Evaluation of the pressure-resistant sealing performance of absorbable bone wax

[0198] The hemostatic and occlusive properties of bone wax can be evaluated by in vitro pressure-resistant occlusive time, which refers to the time the bone wax can withstand water pressure at constant pressure and temperature. Clearly, the longer the pressure-resistant occlusive time of bone wax, the better the hemostatic effect and the lower the risk of oozing or rebleeding. In vivo hemostatic efficacy tests of this invention demonstrate a positive correlation between the pressure-resistant occlusive time of bone wax and its hemostatic effect.

[0199] The specific test method for the pressure-resistant sealing time of bone wax is as follows: Using an acrylic tube with an inner diameter of 3mm and a length of 100mm, one end of the tube, filled with 37℃ pure water, is uniformly sealed with bone wax. The other end is connected to a flexible tube, which is connected to a pressure gauge and a pressurizing device. The pressure is manually increased to 19kPa (142.5mmHg). The entire device is then placed in a 37℃ oven, and the time required for the bone wax to be flushed away by the water is observed. The sealing test results are shown in Table 2.

[0200] Table 2. Blocking Time Data

[0201]

[0202] As can be seen from the data in Table 2, the bone wax in the embodiments of the present invention has a significantly longer pressure-resistant sealing time than the non-absorbable bone wax and the bone wax in the comparative example. From Examples W11 and C10, it can be seen that the bone wax prepared using polyethylene glycol and its derivatives has less noticeable slipperiness and better pressure-resistant sealing performance compared to poloxamer. From Comparative Example C1, it can be seen that if polyethylene glycol and its derivatives in the bone wax component are not compounded with calcium sulfate, not only is the slipperiness significantly enhanced, but the pressure-resistant sealing performance also decreases substantially.

[0203] This demonstrates that polyethylene glycol and its derivatives in this invention need to be compounded with calcium sulfate within a suitable ratio range to effectively improve the hemostatic performance of bone wax. Using polyethylene glycol alone, or calcium sulfate alone, or replacing polyethylene glycol with poloxamer, or replacing calcium sulfate with water-soluble sodium carboxymethyl cellulose, in the formulation will not achieve the effect of this invention.

[0204] 3. Evaluation of the dissolution time of absorbable bone wax

[0205] Absorbable bone wax degrades or is absorbed in the physiological environment, causing it to lose strength and become loose (or dispersed). Loosened bone wax is more easily absorbed and less likely to occupy space, hindering bone healing. Generally, bone wax should ideally loosen within about one week after implantation, before the bone trauma enters the callus formation stage, which is beneficial for later bone repair and bone wax absorption. However, if the bone wax loosens too quickly, such as within 6 hours, there is a risk of postoperative bleeding.

[0206] In this invention, the evaluation method for bone wax loosening time is as follows: bone wax is pressed into thin sheets of 2.5-3.0 mm and immersed in a phosphate buffer solution at 37°C. The time required for the bone wax to lose its original strength or become loose or incomplete is the loosening time. The evaluation results of the examples and comparative examples are shown in Table 3.

[0207] Table 3. Loosening Time Data

[0208]

[0209] As can be seen from the data in Table 3, non-absorbent bone wax C7 does not loosen, water-soluble bone wax C8 loosens too quickly, and polymeric bone wax C6 takes much longer than 240 hours, with the loosening time being either too short or too long. However, the bone waxes in the examples all loosen within a suitable time.

[0210] Furthermore, a comparison of the data from Comparative Examples 9 and 10 shows that when poloxamer is added alone, it promotes the loosening of bone wax too quickly, but when used in combination with polyethylene glycol (Examples 7 and 8), the bone wax loosening time can be kept at an appropriate level.

[0211] 4. In vivo hemostatic effect test

[0212] Adult rabbits were used as experimental animals. Two holes, approximately 6 mm in diameter and 10 mm deep, were drilled on the front of the left and right femoral condyles of the hind legs. Hemostasis was achieved using the following methods: Examples W1, W3, W5, W7, W9, and W12; Comparative Examples C3, C4, C5, and C6; Non-absorbable bone wax C7; and Water-soluble bone wax C8. Immediate postoperative hemostasis time and bleeding within 3 minutes postoperatively were observed. After the surgery, each layer was sutured sequentially, and the wound was disinfected with povidone-iodine. Hemostasis results are shown in Table 4.

[0213] Table 4. Data from in vivo hemostatic effect test

[0214]

[0215] As can be seen from Table 4, the immediate hemostasis time of both the absorbable bone wax and the non-absorbable bone wax C7 in the embodiments does not exceed 3 seconds, and there is no bleeding after 3 minutes. This indicates that the in vivo sealing and hemostasis effect of the absorbable bone wax of the present invention is comparable to that of the non-absorbable bone wax C7. However, the amounts of polyethylene glycol and calcium sulfate in comparative examples C3 and C4 deviate from the range of the present invention. In comparative example C5, after replacing calcium sulfate with sodium carboxymethyl cellulose, the hemostasis time was prolonged, and there was bleeding after 3 minutes postoperatively. All of these demonstrate the importance of the combination of polyethylene glycol and its derivatives with calcium sulfate in the present invention, and that the technical effect of the present invention can only be achieved within a suitable ratio range.

[0216] 5. In vivo absorption test of absorbable bone wax

[0217] The bone wax was implanted into the bone cavity using the bone wax implantation method in the hemostasis test. The bone defect in the animal was observed at different time points. Bone wax not visible to the naked eye at the bone defect was considered absorbed. The healing of the bone defect was then observed. The absorption of the absorbable bone wax and the bone healing of the present invention are shown in Table 5.

[0218] Table 5. Results of in vivo absorption test of absorbable bone wax

[0219]

[0220] As can be seen from the data in Table 5, the bone wax of the present invention was mostly absorbed after 6 weeks of implantation, and there was no visible bone wax in the bone pore after 12 weeks. Comparative example C6 was absorbed more slowly, and new bone ingrowth was also slower. The non-absorbable bone wax C7 showed no new bone ingrowth at any time point.

[0221] In summary, in this invention, the combination of polyethylene glycol and its derivatives with calcium sulfate plays an important role in improving the performance of bone wax. However, it is necessary to maintain a suitable ratio range. Only under the condition of combining polyethylene glycol and its derivatives with calcium sulfate can the relationship between the occlusive hemostatic performance and the dispersing time of bone wax be effectively balanced, ensuring that the bone wax has both good hemostatic effect and rapid absorption.

[0222] Finally, it should be noted that the above specific embodiments are only used to describe the purpose, technical solution, and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation of the present invention and is not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the foregoing specific embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions or improvements can be made to some or all of the technical features. These modifications, equivalent substitutions, and improvements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention, and they should all be covered within the scope of the claims and specification of the present invention.

Claims

1. An absorbable bone wax, characterized in that, By weight, it comprises the following components: 8-25 parts calcium stearate, 15-35 parts vitamin E or its derivatives, 12-45 parts polyethylene glycol or its derivatives, and 12-50 parts calcium sulfate.

2. The absorbable bone wax according to claim 1, characterized in that, The vitamin E derivative is vitamin E acetate.

3. The absorbable bone wax according to claim 1, characterized in that, The polyethylene glycol derivative is at least one of polyethylene glycol monomethyl ether and polyethylene glycol dimethyl ether.

4. The absorbable bone wax according to claim 1, characterized in that, The molecular weight of the polyethylene glycol or its derivatives is 300 Da to 30000 Da.

5. The absorbable bone wax according to claim 4, characterized in that, The molecular weight of the polyethylene glycol or its derivatives is 1500 Da to 10000 Da.

6. The absorbable bone wax according to claim 1, characterized in that, The calcium sulfate is selected from at least one of anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium sulfate dihydrate, or other hydrated calcium sulfate.

7. The absorbable bone wax according to claim 1, characterized in that, The absorbable bone wax also contains at least one of the following: a substance with good bone compatibility, an anti-inflammatory drug, poloxamer 188, and poloxamer 407. The substance with good bone compatibility is selected from at least one of hydroxyapatite, β-tricalcium phosphate, BCP biphasic ceramics, and bioactive glass.

8. The absorbable bone wax according to claim 7, characterized in that, The bone-compatible substances, poloxamer 188, and poloxamer 407, are added to absorbable bone wax at a mass fraction not exceeding 10%.

9. The method for preparing absorbable bone wax as described in claim 1, characterized in that, Includes the following steps: All components are added to a stirred reactor according to the formula, and after being melted and mixed evenly above the melting point temperature of the fusible material, the mixture is cooled to room temperature to obtain the absorbable bone wax.

10. The application of the absorbable bone wax as described in claim 1 in the preparation of hemostatic materials and filling of bone defects.

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