Calcium salt particle composition, artificial bone material containing calcium salt particle composition, drug-loaded artificial bone material containing calcium salt particle composition and preparation method of drug-loaded artificial bone material

Abstract

The invention relates to the technical field of medical materials, in particular to a calcium salt particle composition, an artificial bone material containing the calcium salt particle composition, a drug-loaded artificial bone material containing the calcium salt particle composition and a preparation method of the drug-loaded artificial bone material. The calcium salt particle composition comprises the following components in percentage by weight: 40%-80% of first calcium salt particles, 20%-60% of second calcium salt particles and 0%-30% of third calcium salt particles, the particle size ranges d1, d2 and d3 of the first calcium salt particles, the second calcium salt particles and the third calcium salt particles meet the following conditions: d1 is more than or equal to 1 mu m and less than or equal to 10 mu m, d2 is more than 10 mu m and less than 40 mu m, and d3 is more than or equal to 40 mu m and less than or equal to 200 mu m. The calcium salt particle composition can be used for preparing an artificial material, and the artificial bone material has good slow release performance.

Description

Technical Field

[0001] The present application relates to the technical field of medical materials, and in particular to a calcium salt granule composition, an artificial bone material containing the calcium salt granule composition, a drug-loaded artificial bone material and a preparation method thereof. Background Art

[0002] Artificial bone materials are crucial in the repair of bone structure defects. Traditional artificial bone materials include:

[0003] A document describes a composite bone graft substitute cement and a product made therefrom, wherein the composite bone graft substitute cement is formed by mixing a granular composition with an aqueous solution, and the granular composition comprises:

[0004] I) a calcium sulfate hemihydrate powder having a bimodal particle distribution and a median particle size of 5 microns to 20 microns, wherein the calcium sulfate hemihydrate is present in a concentration of at least 70% by weight, based on the total weight of the granular composition;

[0005] II) monocalcium phosphate monohydrate powder; and

[0006] III) beta-tricalcium phosphate powder having a median particle size of less than 20 micrometers,

[0007] The bimodal particle distribution comprises: based on the total volume of the hemihydrate calcium sulfate powder, 30 volume % to 60 volume % of the particles have a mode of 1.0 micron to 3.0 micron and 40 volume % to 70 volume % of the particles have a mode of 20 micron to 30 micron.

[0008] A document records an inorganic bone graft material, its preparation method and use, the inorganic bone graft material is composed of 20%-80% by mass of β-tricalcium phosphate particles with a microporous structure and 80%-20% by mass of α-calcium sulfate hemihydrate powder, the α-calcium sulfate hemihydrate powder forms a layered structure on the surface of the β-tricalcium phosphate particles with a microporous structure and / or inside the pores thereof. The diameter of the β-tricalcium phosphate particles is 0.2-10 mm.

[0009] A dry mixed composition for artificial bone salt substitute material is described in the literature, which comprises: (a) at least one calcium phosphate component; and (b) a dry mixture of at least one calcium sulfate component; (c) at least one additive contained in and combined with the calcium sulfate component, and (d) at least one accelerator for hardening the powdered calcium phosphate into a calcium phosphate cement when reacting with an aqueous liquid, wherein the at least one calcium phosphate component is a powdered calcium phosphate that can harden into a calcium phosphate cement when reacting with an aqueous liquid under the influence of the at least one accelerator, wherein the at least one calcium sulfate component is a granular hardened calcium sulfate with a particle size of less than 100 μm, and wherein the additive is a bioactive agent contained in and combined with the calcium sulfate component.

[0010] The sustained-release properties of traditional artificial bone materials need to be improved. Summary of the invention

[0011] Based on this, one or more embodiments of the present application provide a calcium salt granule composition, an artificial bone material containing the same, a drug-loaded artificial bone material, and a preparation method thereof, including the following technical solutions:

[0012] One or more embodiments of the present application provide a calcium salt granule composition, which comprises the following components in percentage by weight:

[0013] First calcium salt particles 40%-80%,

[0014] 20%-60% of the second calcium salt particles, and

[0015] The third calcium salt particles 0%-30%;

[0016] The particle size ranges d1, d2 and d3 of the first calcium salt particles, the second calcium salt particles and the third calcium salt particles satisfy the following conditions:

[0017] 0.1μm≤d1≤10μm,

[0018] 10μm<d2<40μm, and

[0019] 40μm≤d3≤200μm;

[0020] The calcium salt contained in the first calcium salt particles, the second calcium salt particles and the third calcium salt particles has the same composition, and the calcium salt includes one or more of α-calcium sulfate hemihydrate, β-tricalcium phosphate and hydroxyapatite.

[0021] In some embodiments of the present application, the calcium salt granule composition comprises the following components in weight percentage:

[0022] First calcium salt particles 40%-60%,

[0023] 30%-50% of the second calcium salt particles, and

[0024] The third calcium salt particles are 2%-20%.

[0025] In some embodiments of the present application, the particle size range d3 of the third calcium salt particles satisfies the following condition: 100 μm≤d3≤150 μm.

[0026] One or more embodiments of the present application provide an artificial bone material, which includes: the calcium salt particle composition and an aqueous liquid.

[0027] In some embodiments of the present application, the aqueous liquid is water or an aqueous solution of a water-soluble additive;

[0028] Optionally, the water-soluble additive in the aqueous solution of the water-soluble additive includes one or more of a soluble inorganic salt and a non-ionic contrast agent;

[0029] Further optionally, the soluble inorganic salt includes sodium chloride; further, the aqueous liquid includes 0.8wt%-1wt% sodium chloride;

[0030] Further optionally, the non-ionic contrast agent includes one or more of iohexol, iodixanol and iopromide; further, the aqueous liquid includes 100 g / mL-200 g / mL of the non-ionic contrast agent.

[0031] In some embodiments of the present application, the usage ratio of the calcium salt granule composition and the aqueous liquid is (1-5) g: 1 mL.

[0032] One or more embodiments of the present application provide a method for preparing the artificial bone material, the method comprising:

[0033] Mixing the calcium salt particle composition and the aqueous liquid, forming, and preparing an artificial bone material;

[0034] Optionally, the mixing conditions include: frequency of 10 r / min-20 r / min, and time of 25 min-35 min.

[0035] One or more embodiments of the present application provide a drug-loaded artificial bone material, the drug-loaded artificial bone material comprising:

[0036] The calcium salt granule composition;

[0037] An aqueous liquid as defined above; and

[0038] drug.

[0039] In some embodiments of the present application, the drug-loaded artificial bone material satisfies one or more of the following conditions 1) to 3):

[0040] 1) The drug includes antibiotics; optionally, the antibiotics include one or more of glycopeptide antibiotics and aminoglycoside antibiotics; further optionally, the glycopeptide antibiotics include vancomycin and its hydrochloride; further optionally, the aminoglycoside antibiotics include one or more of gentamicin and its sulfate and tobramycin;

[0041] 2) the dosage ratio of the drug to the calcium salt particle composition in the drug-loaded artificial bone material is (0.01-0.2):1; and,

[0042] 3) The dosage ratio of the mixture of the inorganic calcium salt composition and the drug to the aqueous liquid is (1-5) g: 1 mL.

[0043] One or more embodiments of the present application provide a method for preparing the drug-loaded artificial bone material, the method comprising the following steps:

[0044] Mixing the calcium salt particle composition in the artificial bone material and the drug to prepare a mixture; and,

[0045] Mixing the mixture and the aqueous liquid of the artificial bone material, forming the mixture, and preparing the drug-loaded artificial bone material;

[0046] Optionally, in the step of preparing the mixture, the mixing conditions include: a frequency of 10 r / min-20 r / min, and a time of 25 min-35 min.

[0047] The details of one or more embodiments of the present application are set forth in the description which follows, and other features, objects, and advantages of the present application will be apparent from the description and its claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more completely understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present application, and those skilled in the art can obtain other drawings based on these drawings without creative work.

[0049] Figure 1 This is a diagram showing the curing effect of the drug-loaded artificial bone material in Example 3. DETAILED DESCRIPTION

[0050] The present application will be further described in detail below in conjunction with the accompanying drawings, embodiments and examples. It should be understood that these embodiments and examples are only used to illustrate the present application and are not used to limit the scope of the present application. The purpose of providing these embodiments and examples is to make the understanding of the disclosure of the present application more thorough and comprehensive. It should also be understood that the present application can be implemented in many different forms, is not limited to the embodiments and examples described herein, and those skilled in the art can make various changes or modifications without violating the connotation of the present application, and the equivalent form obtained also falls within the protection scope of the present application. In addition, in the description below, a large number of specific details are given in order to provide a more comprehensive understanding of the present application, and it should be understood that the present application can be implemented without one or more of these details.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing implementation modes and embodiments and are not intended to limit this application.

[0052] the term

[0053] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0054] The terms "and / or", "or / and", and "and / or" used in this article include any one of two or more related listed items, and also include any and all combinations of related listed items, and the 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 that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of 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, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0055] In the present application, "plurality", "multiple", "multiple times", "multiples", etc., unless otherwise specified, refer to a number greater than 2 or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0056] As used herein, "combination thereof", "any combination thereof", "any combination thereof" etc. include all suitable combinations of any two or more of the listed items.

[0057] Herein, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc., shall be based on the ability to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0058] Herein, “preferred”, “better”, “more preferred” and “suitable” are merely used to describe implementation methods or examples with better effects, and it should be understood that they do not constitute limitations on the scope of protection of this application.

[0059] In the present application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present application.

[0060] In this application, "optionally", "optional", and "optional" mean optional or dispensable, that is, any one of the two parallel schemes of "yes" or "no". If multiple "options" appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" is independent.

[0061] In the present application, the terms "first", "second", "third", "fourth", etc. in "the first aspect", "the second aspect", "the third aspect", "the fourth aspect", etc. are used only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "first", "second", "third", "fourth", etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation on quantity.

[0062] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0063] In the present application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical range, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In this article, it is equivalent to directly listing each integer, such as t is an integer selected from 1 to 10, indicating that t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges included therein.

[0064] The temperature parameters in this application, unless otherwise specified, are allowed to be either constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are allowed.

[0065] In the present application, % (w / w) and wt% both represent weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass volume percentage.

[0066] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the application purpose and / or technical solution of this application, the cited documents involved in this application are cited with all contents and all purposes. When the cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the cited documents are involved in this application, the examples and preferred methods of the cited relevant technical features can also be incorporated into this application as references, but are limited to the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be modified adaptively according to the description of this application.

[0067] In a first aspect of an embodiment of the present application, a calcium salt granule composition is provided, wherein the calcium salt granule composition comprises the following components in percentage by weight:

[0068] First calcium salt particles 40%-80%,

[0069] 20%-60% of the second calcium salt particles, and

[0070] The third calcium salt particles 0%-30%;

[0071] The particle size ranges d1, d2 and d3 of the first calcium salt particles, the second calcium salt particles and the third calcium salt particles satisfy the following conditions:

[0072] 0.1μm≤d1≤10μm,

[0073] 10μm<d2<40μm, and

[0074] 40μm≤d3≤200μm;

[0075] The calcium salt contained in the first calcium salt particles, the second calcium salt particles and the third calcium salt particles has the same composition, and the calcium salt includes one or more of α-calcium sulfate hemihydrate, β-tricalcium phosphate and hydroxyapatite.

[0076] In some examples, the calcium salt granule composition includes the following components in weight percentage:

[0077] First calcium salt particles 40%-60%,

[0078] 30%-50% of the second calcium salt particles, and

[0079] The third calcium salt particles are 2%-20%.

[0080] In some examples, the particle size range d3 of the third calcium salt particles satisfies the following condition: 100 μm≤d3≤150 μm.

[0081] According to a second aspect of the embodiments of the present application, an artificial bone material is provided. The artificial bone material comprises: the calcium salt particle composition and an aqueous liquid.

[0082] In some examples, the aqueous liquid is water or an aqueous solution of a water-soluble additive.

[0083] The aqueous liquid can be distilled water and / or a solution containing one or more inorganic salts and / or organic salts. The aqueous liquid can meet the main requirements for the injectability of the artificial bone material, that is, it gives the artificial bone material a certain viscosity and other properties so that it can be injected into the bone several minutes after the mixing step begins. In addition, the initial setting time is suitable, which is also a necessary condition for injectable artificial materials.

[0084] The artificial bone material provided in the embodiment of the present application can be used through minimally invasive surgery, can harden in situ, and stabilize any defective geometric structure, and can also be used for implantation after being cured in vitro. The artificial bone material in the embodiment of the present application is an injectable composition that can be used as a bone salt substitute material, which can harden in body fluids in vivo, so its injection performance is guaranteed.

[0085] The water-soluble additive that may be contained in the artificial bone material may also be a non-ionic X-ray contrast agent.

[0086] Suitable agents of this type are conventional water-soluble nonionic X-ray contrast agents, i.e. iodinated aromatic compounds having one or more aromatic nuclei which are at least triiodinated. Such agents are described in US Pat. No. 5,695,742 and include CAS (Chemical Abstracts Service) registration numbers 31112-62-6 (mepanicol), 60166-93-0 (iopamidol), 78649-41-9 (iomeprol), 73334-07-3 (iopromide), 877771-40-2 (ioversel), 66108-95-0 (iohexol), 89797-00-2 (iopentol), 107793-72-6 (ioxilan), 99139-49-8 (II-1 )、75751-89-2(iogulamide)、63941-73-1(iodine alcohol)、63941-74-2(iodine glucamide)、56562-79-9(iodine glucamide)、76984-84-0(MP-7011)、64965-50-0(MP-7012)、77111-65-0(MP-10007)、79944-49-3(VA-7-88)、79944-51-7(also found in EP 033426), 79211-10-2 (iodoxamine), 79211-34-0 (iocibidol), 103876-29-5 (also found in EP0177414), 141660-63-1 (iodoxanol), 92339-11-2 (iodixanol), 79770-24-4 (iotrolan), 71767-13-0 (iodoxanol), 81045-33-2 (iodoxanol), 143200-04-8 (also found in WO 92 / 086), 143199-77-3 (also found in WO 92 / 08691), 143200-00-4 (also found in WO 92 / 08691), 78341-84-1 (also seen in US4348377), 122731-47-9 (also seen in EP 0308364), 122731-49-1 (also seen in EP 0308364), 99139-65-8 (also seen in WO 85 / 01727), 99139-62-5 (also seen in WO 85 / 01727) and 78341-84-1 (also seen in EP 0023992).

[0087] Other such X-ray contrast agents are described in US 5,447,711 and include iotrolan, iodixanol, iodixanol and iosacol. Other suitable contrast agents are iotusal, ioxilane and iofrotal.

[0088] Alternative X-ray contrast agents are non-ionic and have a low osmomolality, such as iohexol, iodixanol, ioversol, iopamidol, and iotrolane.

[0089] For example, iohexol (C19H26I3N3O9) can be advantageously used as an X-ray contrast agent. This substance does not affect bone formation and has good biocompatibility in bone. It is used for different purposes in medicine. For example, it can be used in patients with renal failure to determine the plasma clearance of the kidney.

[0090] The artificial bone material containing a water-soluble additive as an X-ray contrast agent can itself be used as an X-ray contrast agent. The artificial bone material of the present application obtains an additional X-ray effect, so it is no longer necessary to include a ceramic radioactive contrast agent such as barium sulfate and zirconium dioxide in the injectable artificial bone material of the present application. When such hard ceramic particles are separated from the bone substitute, they will wear out the joint. They will cause physical damage at the joint and eventually lead to an inflammatory reaction.

[0091] Therefore, when the artificial bone material of the present application comprises a water-soluble nonionic X-ray contrast agent, it can be injected into the vicinity of the joint, and the resulting artificial bone material can be used for bone defects communicating with the joint. Such applications include the repair of osteochondral joint defects and fractures or bone defects involving joints.

[0092] When the resulting artificial bone material containing a water-soluble non-ionic X-ray contrast agent is replaced by endogenous bone, the water-soluble agent will slowly disappear. This results in a gradual decrease in X-ray density, which can be monitored.

[0093] In some examples, the water-soluble additive in the aqueous solution of the water-soluble additive includes one or more of an inorganic salt and a non-ionic contrast agent. The inorganic salt includes sodium chloride, for example, the aqueous solution includes 0.8wt%-1wt% of sodium chloride. The non-ionic contrast agent includes iohexol, iodopamine and iopromide, for example, the aqueous solution includes 100g / mL-200g / mL of iohexol.

[0094] In some of the examples, the usage ratio of the calcium salt granular composition and the aqueous liquid is (1-5) g:1 mL, for example, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5.

[0095] In a third aspect of the embodiments of the present application, a method for preparing the artificial bone material is provided, the method comprising:

[0096] Mixing the calcium salt particle composition and the aqueous liquid, forming, and preparing an artificial bone material;

[0097] Optionally, the mixing conditions include: a frequency of 10 r / min-20 r / min (for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 r / min) and a time of 25 min-35 min (for example, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 min).

[0098] In a fourth aspect of the embodiments of the present application, a drug-loaded artificial bone material is provided, wherein the drug-loaded artificial bone material comprises:

[0099] The calcium salt granule composition;

[0100] An aqueous liquid as defined above; and

[0101] drug.

[0102] The present application does not specifically limit the type of drug, and the drug may have several functions. It may be, for example, an antioxidant, vitamin, hormone, antibiotic, cell growth inhibitor, bisphosphonate, growth factor or protein. The at least one water-soluble additive is advantageously a substance that induces, stimulates and / or promotes bone formation, such as an osteoinductive compound and / or a compound that reduces bone turnover. Suitable osteoinductive substances that stimulate and / or promote bone formation are growth factors and hormones. For example, growth factors and their derivatives, which act locally, are autologous, and are effective for bone, tendon or cartilage. Such growth factors are, for example, transforming growth factor (TGFβ3), bone morphogenetic protein (BMP-2), PTHrP, osteoprotegerin (osteoprotegrin, OPG), Indian Hedgehog, RANKL, basic fibroblasts, insulin-like growth factor (IgF1), platelet-derived growth factor and vascular growth factor. These endogenously produced growth factors are either combined as a single entity or in a mixture of growth factors to be used as additives to promote bone growth. Therefore, endogenously produced bioactive molecules may be selected as substances that induce bone formation.

[0103] Examples of other bone stimulating compounds are parathyroid hormone and its derivatives, estrogens, progesterone, androgens, testosterone, calcitonin, somatomedin and oxytocin, which are likewise preferably autologous, but which can also be produced according to methods known in the art.

[0104] The matrix proteins amelin-1, amelin-2 and ameloblastin can also be included as additives in the inorganic calcium salt composition, which are either autologous, or extracted or produced from tissues or cells of other species, or produced synthetically or produced by other living cells or organisms.

[0105] Likewise, cholesterol-lowering compounds such as statins may also be included to induce, stimulate and / or promote bone formation.

[0106] Examples of suitable bone destruction inhibitors are bisphosphonates, osteocalcin, osteonectin and their derivatives, which may be included as additives in the artificial bone material of the present application.

[0107] In addition, other materials that affect bone metabolism can also be included in the granular hardened calcium sulfate component that slowly releases from the gained artificial bone material. This class of materials includes ergocalciferol, calcitriol and other vitamin D classes and derivatives thereof. These compounds help regulate the normal calcification of calcium metabolism and bone in the body and affect the utilization of mineral phosphorus. It can also include prostaglandins, precursors or metabolites of prostaglandins, prostaglandin analogs that are naturally or synthetically produced, induce or suppress endogenous prostaglandins to produce or induce or suppress the compound of prostaglandin metabolism, or affect the generation of precursors or the further metabolic compound of active prostaglandin metabolites. Analgesics such as lidocaine hydrochloride, bupivacaine hydrochloride and ketorolac tromethamine can also be used as the additive that releases from the artificial bone material.

[0108] The drug of the embodiment of the present application should be released from the artificial bone material within several weeks after injection. This can be achieved by controlling the composition of the inorganic calcium salt particle composition, and the dissolution rate depends on the formulation of the inorganic calcium salt particle composition.

[0109] Medicine can also be anti-infective substance, i.e. compound with the effect of suppressing or killing external invasive living substance. Such compound includes natural antibiotic and other semi-synthetic and synthetic antibacterial or antibacterial compound, and they resist pathogenic and / or infectious microorganisms such as staphylococcus. The example of antibiotic for bone infection has tetracycline hydrochloride, vancomycin, tobramycin, gentamicin and cephalosporin. Cytostatic agent such as cisplatin, ifosfamide, methotrexate, doxorubicin hydrochloride, arsenic trioxide, retinoid or its derivative can also be used as additive. Similarly, additive can be antiviral compound, antifungal compound, antituberculosis or tuberculocidal compound or parasiticidal compound.

[0110] In some examples, the drug-loaded artificial bone material satisfies one or more of the following conditions 1) to 3):

[0111] 1) The drug includes antibiotics; optionally, the antibiotics include one or more of glycopeptide antibiotics and aminoglycoside antibiotics; further optionally, the glycopeptide antibiotics include vancomycin and its hydrochloride; further optionally, the aminoglycoside antibiotics include one or more of gentamicin and its sulfate and tobramycin;

[0112] 2) the dosage ratio of the drug to the calcium salt particle composition in the drug-loaded artificial bone material is (0.01-0.2):1 (for example, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.12:1, 0.14:1, 0.16:1, 0.18:1, 0.2:1); and,

[0113] 3) The dosage ratio of the mixture of the calcium salt granule composition and the drug to the aqueous liquid is (1-5) g:1 mL (e.g., 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1).

[0114] In a fifth aspect of the embodiments of the present application, a method for preparing the drug-loaded artificial bone material is provided, the method comprising the following steps:

[0115] Mixing the calcium salt particle composition in the artificial bone material and the drug to prepare a mixture; and,

[0116] Mixing the mixture and the aqueous liquid of the artificial bone material, forming the mixture, and preparing the drug-loaded artificial bone material;

[0117] Optionally, in the step of preparing the mixture, the mixing conditions include: a frequency of 10r / min-20r / min (for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20r / min) and a time of 25min-35min (for example, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35min).

[0118] The present application does not particularly limit the mixing conditions in the preparation step of the drug-loaded artificial bone material. For example, manual stirring can be used, and the stirring time is 0.5min-1.5min, for example, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5min.

[0119] The embodiments of the present application will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are preferably referred to the guidance provided in the present application, and can also be based on the experimental manual or normal conditions in this area, can also be based on the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0120] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0121] Vancomycin hydrochloride: Livzon Group Fuzhou Fuxing Pharmaceutical Co., Ltd. Content (dry basis): 1102IU / mg.

[0122] Normal saline: Sichuan Kelun Pharmaceutical Co., Ltd. National Medicine Approval No. H20083400.

[0123] Example 1

[0124] (1) α-calcium sulfate hemihydrate, with a particle size range of 0.1-200 μm and an average particle size D50 of 6 μm, wherein the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 60%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 38%, and the weight percentage of the third calcium sulfate particle A (100 μm ≤ d3A ≤ 150 μm) is 2%.

[0125] (2) Weigh 2 kg of α-calcium sulfate hemihydrate and 200 g of vancomycin hydrochloride API, pour them into a three-dimensional mixing device, set the mixing frequency to 15 r / min, and mix for 30 min to prepare a powder component.

[0126] (3) The liquid component is physiological saline.

[0127] (4) Take 10 g of the powder component in (2), take 4 mL of normal saline, inject the normal saline into the powder component, quickly stir evenly, mix for 1 min, and then prepare a cylindrical sample for testing to test the setting time, compressive strength, injectable time, anti-collapse performance and in vitro release.

[0128] Example 2

[0129] (1) The particle size range of α-calcium sulfate hemihydrate is 0.1 μm-200 μm, and the average particle size D50 is 6 μm. The weight percentage of the first calcium sulfate (0.1 μm≤d1≤10 μm) is 50%, the weight percentage of the second calcium sulfate (10 μm<d2<40 μm) is 30%, and the weight percentage of the third calcium sulfate particles A (100 μm≤d3A≤150 μm) is 20%.

[0130] (2) Weigh 2 kg of α-calcium sulfate hemihydrate and 200 g of vancomycin hydrochloride API, pour them into a three-dimensional mixing device, set the mixing frequency to 15 r / min, and mix for 30 min to prepare a powder component.

[0131] (3) The liquid component is physiological saline.

[0132] (4) Take 10 g of the powder component in (2), take 4 mL of normal saline, inject the normal saline into the powder component, quickly stir evenly, mix for 1 min, and prepare a cylindrical sample for testing to test the setting time, compressive strength, antibacterial property and in vitro release.

[0133] Example 3

[0134] (1) The particle size of α-calcium sulfate hemihydrate is 0.1 μm-200 μm, and the average particle size D50 is 6 μm. The weight percentage of the first calcium sulfate (0.1 μm≤d1≤10 μm) is 40%, the weight percentage of the second calcium sulfate (10 μm<d2<40 μm) is 50%, and the weight percentage of the third calcium sulfate particles A (100 μm≤d3A≤150 μm) is 10%.

[0135] (2) Weigh 2 kg of calcium sulfate and 200 g of vancomycin hydrochloride API, pour them into a three-dimensional mixing device, set the mixing frequency to 15 r / min, and mix for 30 min to prepare a powder component.

[0136] (3) The liquid component is physiological saline.

[0137] (4) Take 10 g of the powder component in (2), take 4 mL of saline, inject the saline into the powder component, quickly stir evenly, mix for 1 min, and prepare a cylindrical sample for testing. Test the setting time, compressive strength, antibacterial property and in vitro release. Figure 1 shown.

[0138] Example 4

[0139] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0140] In step (1), the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 40%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 50%, and the weight percentage of the third calcium sulfate particles A (100 μm ≤ d3A ≤ 150 μm) is 10%.

[0141] Example 5

[0142] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0143] In step (1), the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 60%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 39%, and the weight percentage of the third calcium sulfate particles A (100 μm ≤ d3A ≤ 150 μm) is 1%.

[0144] Example 6

[0145] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0146] In step (1), the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 80%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 20%, and the weight percentage of the third calcium sulfate particles A (100 μm ≤ d3A ≤ 150 μm) is 0%.

[0147] Example 7

[0148] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0149] In step (1), the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 40%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 60%, and the weight percentage of the third calcium sulfate particles A (100 μm ≤ d3A ≤ 150 μm) is 0%.

[0150] Example 8

[0151] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0152] In step (1), the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 40%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 50%, and the weight percentage of the third calcium sulfate particles B (40 μm ≤ d3B < 100 μm) is 10%.

[0153] Example 9

[0154] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0155] In step (1), the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 40%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 50%, and the weight percentage of the third calcium sulfate particles C (150 μm < d3C ≤ 200 μm) is 10%.

[0156] Example 10

[0157] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0158] In step (2), the weight ratio of vancomycin hydrochloride bulk drug and calcium sulfate composition is 0.05:1, the mixing frequency is 10r / min, and the mixing time is 25min.

[0159] In step (3), the liquid component is water for injection.

[0160] In step (4), the amount of powder component and injection water is 1g:1mL.

[0161] Embodiment 11

[0162] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0163] In step (2), the weight ratio of vancomycin hydrochloride bulk drug and calcium sulfate composition is 0.2:1, the mixing frequency is 20r / min, and the mixing time is 35min.

[0164] In step (3), the liquid component is an iohexol aqueous solution, and the concentration of iohexol is 100 g / mL.

[0165] In step (4), the amount of the powder component and the iohexol aqueous solution used is 5g:1mL.

[0166] Example 12

[0167] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0168] β-tricalcium phosphate is used instead of α-calcium sulfate hemihydrate, that is, the three kinds of particles are all β-tricalcium phosphate particles.

[0169] Example 13

[0170] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0171] Hydroxyapatite is used instead of α-calcium sulfate hemihydrate, that is, the three particles are all hydroxyapatite particles.

[0172] Embodiment 14

[0173] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0174] The three particles are all a mixture of α-calcium sulfate hemihydrate and β-tricalcium phosphate, and the mass ratio of α-calcium sulfate hemihydrate to β-tricalcium phosphate is 1:1.

[0175] Embodiment 15

[0176] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0177] The three particles are all a mixture of α-calcium sulfate hemihydrate and hydroxyapatite, and the mass ratio of α-calcium sulfate hemihydrate to hydroxyapatite is 1:1.

[0178] Example 16

[0179] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0180] The three particles are all a mixture of β-tricalcium phosphate and hydroxyapatite, and the mass ratio of β-tricalcium phosphate to hydroxyapatite is 1:1.

[0181] Embodiment 17

[0182] This embodiment is a variation of Embodiment 3, and the only difference compared with Embodiment 3 is that:

[0183] All three particles use a mixture of α-calcium sulfate hemihydrate, β-tricalcium phosphate and hydroxyapatite instead of α-calcium sulfate hemihydrate, and the mass ratio of α-calcium sulfate hemihydrate, β-tricalcium phosphate and hydroxyapatite is 1:2:2.

[0184] Comparative Example 1

[0185] (1) The particle size of α-calcium sulfate hemihydrate is 0.1 μm-200 μm, and the average particle size D50 is 6 μm. The weight percentage of the first calcium sulfate (0.1 μm≤d1≤10 μm) is 60%, the weight percentage of the second calcium sulfate (10 μm<d2<40 μm) is 38%, and the weight percentage of the third calcium sulfate particle A (100 μm≤d3A≤150 μm) is 2%. No antibiotics are added.

[0186] (2) The liquid component is physiological saline.

[0187] (3) Take 10 g of the powder component in (1), take 4 mL of normal saline, inject the normal saline into the powder component, quickly stir evenly, mix for 1 min, and then prepare a cylindrical sample for testing to test the setting time, compressive strength, antibacterial property and in vitro release.

[0188] Comparative Example 2

[0189] (1) α-calcium sulfate hemihydrate, with a particle size of 0.1 to 200 μm and an average particle size D50 of 60 μm, wherein the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 2%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 48%, and the weight percentage of the third calcium sulfate particles A (100 μm ≤ d3A ≤ 150 μm) is 50%.

[0190] (2) Weigh 2 kg of α-calcium sulfate hemihydrate and 200 g of vancomycin hydrochloride API, pour them into a three-dimensional mixing device, set the mixing frequency to 15 r / min, and mix for 30 min to prepare a powder component.

[0191] (3) The liquid component is physiological saline.

[0192] (4) Take 10 g of the powder component in (1), take 4 mL of normal saline, inject the normal saline into the powder component, quickly stir evenly, mix for 1 min, and then prepare a cylindrical sample for testing to test the setting time, compressive strength, injectable time, anti-collapse performance and in vitro release.

[0193] Comparative Example 3

[0194] This comparative example is a comparative example of Example 3, and the differences relative to Example 3 include:

[0195] In step (1), the weight percentage of the first calcium sulfate (0.1 μm ≤ d1 ≤ 10 μm) is 35%, the weight percentage of the second calcium sulfate (10 μm < d2 < 40 μm) is 30%, and the weight percentage of the third calcium sulfate particles A (100 μm ≤ d3A ≤ 150 μm) is 35%.

[0196] Comparative Example 4

[0197] This comparative example is a comparative example of Example 3, and the differences relative to Example 3 include:

[0198] The fifth calcium sulfate particles (d5<0.1 μm) are used to replace the first calcium sulfate particles.

[0199] Comparative Example 5

[0200] This comparative example is a comparative example of Example 3, and the differences relative to Example 3 include:

[0201] The third calcium sulfate particles A are replaced by fourth calcium sulfate particles (200 μm<d4≤250 μm).

[0202] Comparative Example 6

[0203] This comparative example is a comparative example of Example 3, and the differences with respect to Example 3 include: only the first calcium sulfate particles are used.

[0204] Comparative Example 7

[0205] This comparative example is a comparative example of Example 3, and the differences with respect to Example 3 include: only the second calcium sulfate particles are used.

[0206] Comparative Example 8

[0207] This comparative example is a comparative example of Example 3, and the differences with respect to Example 3 include: only the third calcium sulfate particle A is used.

[0208] Table 1

[0209]

[0210] Table 2. Test results of artificial bone materials prepared in Examples and Comparative Examples

[0211] serial number Solidification time / min Injectable time / min Compressive strength / MPa Anti-collapse performance / % In vitro release time / day Example 1 11 5 62 95 98 Example 2 13 6 60 95 91 Example 3 12 5 60 96 98 Example 4 10 5 50 95 84 Example 5 10 5 52 94 84 Example 6 12 6 55 93 70 Example 7 11 5 48 92 70 Example 8 10 5 55 94 77 Example 9 9 5 53 95 84 Example 10 10 6 52 95 98 Embodiment 11 10 5 55 94 91 Example 12 14 7 25 90 120 Example 13 16 8 30 90 155 Embodiment 14 12 6 38 92 115 Embodiment 15 12 6 35 90 133 Example 16 16 8 25 88 140 Embodiment 17 18 9 35 85 155 Comparative Example 1 12 5 48 95 0 Comparative Example 2 6 2 14 60 20 Comparative Example 3 8 4 22 72 35 Comparative Example 4 6 3 27 70 35 Comparative Example 5 5 2 20 65 30 Comparative Example 6 7 4 28 75 40 Comparative Example 7 8 5 30 60 28 Comparative Example 8 6 3 20 62 21

[0212] The compressive strength and vancomycin concentration test methods are as follows:

[0213] 1. Compressive strength test

[0214] Mix the powder component and liquid component into a slurry and transfer it to the mold as much as possible for demoulding. Mold size: hollow cylinder inner diameter * height = 6mm * 12mm. Test after curing at 37℃ for 24h.

[0215] The uniaxial compression test was carried out using a universal material testing machine with a load of 5KN and a compression rate of 5mm / min until the sample was completely destroyed. The sample was tested after being cured at 37℃ for 24h.

[0216] 2. Vancomycin concentration detection

[0217] The powder component and the liquid component were blended into a slurry, and a 6mm*12mm sample was made and immersed in the simulated body fluid. The buffer solution was replaced every week for the experiment.

[0218] Estimated extract volume:

[0219] Vs=100mm*Sa

[0220] Where Sa is the surface area of ​​the sample and Vs is the volume of the required extract. The surface area is calculated based on the sample size.

[0221] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler; triethylamine buffer (take 4 mL of triethylamine, add water to 2000 mL, and adjust the pH to 3.2 with phosphoric acid)-acetonitrile-tetrahydrofuran (92:7:1) was used as mobile phase A, triethylamine buffer-acetonitrile-tetrahydrofuran (70:29:1) was used as mobile phase B, and linear gradient elution was performed according to the table below; the flow rate was 1.0 mL per minute; the detection wavelength was 280 nm; the injection volume was 20 μL.

[0222] Table 3

[0223] Time (minutes) Mobile phase A (%) Mobile phase (B) (%) 0 100 0 13 100 0 22 0 100 26 0 100

[0224] 3. Anti-collapse performance

[0225] Inject the fresh mixed slurry with a mass of W0 into phosphate buffered saline (PBS, 7.0-7.4) and soak at 37°C for 24 hours. Observe the disintegration of the sample surface, collect the undisintegrated bone cement, dry and weigh it as W1. Take another slurry with a mass of W0 and dry and weigh it under the same conditions, and calculate it as W2. Calculate the anti-disintegration ability (D) of the sample according to the following formula:

[0226]

[0227] The technical features of the above-mentioned implementation modes and examples can be combined in any appropriate manner. To make the description concise, not all possible combinations of the technical features in the above-mentioned implementation modes 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.

[0228] The above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as a limitation on the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several deformations and improvements can be made, which all belong to the protection scope of the present application. In addition, it should be understood that after reading the above-mentioned teaching content of the present application, the technicians in this field can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by the technicians in this field through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the protection scope of the claims attached to the present application. Therefore, the protection scope of the patent of the present application shall be based on the content of the attached claims, and the description and drawings can be used to explain the content of the claims.

Claims

1. A calcium salt granular composition, characterized in that: The calcium salt granule composition comprises the following components in weight percentage: First calcium salt particles 40%-80%, 20%-60% of the second calcium salt particles, and The third calcium salt particles 0%-30%; The particle size ranges d1, d2 and d3 of the first calcium salt particles, the second calcium salt particles and the third calcium salt particles satisfy the following conditions: 0.1μm≤d1≤10μm, 10μm<d2<40μm, and 40μm≤d3≤200μm; The calcium salt contained in the first calcium salt particles, the second calcium salt particles and the third calcium salt particles has the same composition, and the calcium salt includes one or more of α-calcium sulfate hemihydrate, β-tricalcium phosphate and hydroxyapatite.

2. The calcium salt granular composition according to claim 1, characterized in that The calcium salt granule composition comprises the following components in weight percentage: First calcium salt particles 40%-60%, 30%-50% of the second calcium salt particles, and The third calcium salt particles are 2%-20%.

3. The calcium salt granular composition according to any one of claims 1 to 2, characterized in that The particle size range d3 of the third calcium salt particles satisfies the following condition: 100 μm≤d3≤150 μm.

4. An artificial bone material, characterized in that: The artificial bone material comprises: the calcium salt particle composition according to any one of claims 1 to 3 and an aqueous liquid.

5. The artificial bone material according to claim 4, characterized in that: The aqueous liquid is water or an aqueous solution of a water-soluble additive; Optionally, the water-soluble additive in the aqueous solution of the water-soluble additive includes one or more of a soluble inorganic salt and a non-ionic contrast agent; Further optionally, the soluble inorganic salt includes sodium chloride; further, the aqueous liquid includes 0.8wt%-1wt% sodium chloride; Further optionally, the non-ionic contrast agent includes one or more of iohexol, iodixanol and iopromide; further, the aqueous liquid includes 100 g / mL-200 g / mL of the non-ionic contrast agent.

6. The artificial bone material according to any one of claims 4 to 5, characterized in that: The usage ratio of the calcium salt granule composition and the aqueous liquid is (1-5) g:1 mL.

7. The method for preparing the artificial bone material according to any one of claims 4 to 6, characterized in that: The preparation method comprises: Mixing the calcium salt particle composition and the aqueous liquid, forming, and preparing an artificial bone material; Optionally, the mixing conditions include: frequency of 10 r / min-20 r / min, and time of 25 min-35 min.

8. A drug-loaded artificial bone material, characterized in that: The drug-loaded artificial bone material comprises: The calcium salt granular composition according to any one of claims 1 to 3; An aqueous liquid as defined in any one of claims 4 to 6; and drug.

9. The drug-loaded artificial bone material according to claim 8, characterized in that: The drug-loaded artificial bone material meets one or more of the following conditions 1) to 3): 1) The drug includes antibiotics; optionally, the antibiotics include one or more of glycopeptide antibiotics and aminoglycoside antibiotics; further optionally, the glycopeptide antibiotics include vancomycin and its hydrochloride; further optionally, the aminoglycoside antibiotics include one or more of gentamicin and its sulfate and tobramycin; 2) the dosage ratio of the drug to the calcium salt particle composition in the drug-loaded artificial bone material is (0.01-0.2):1; and, 3) The dosage ratio of the mixture of the calcium salt granule composition and the drug to the aqueous liquid is (1-5) g: 1 mL.

10. The method for preparing the drug-loaded artificial bone material according to any one of claims 8 to 9, characterized in that: The preparation method comprises the following steps: Mixing the calcium salt particle composition in the artificial bone material and the drug to prepare a mixture; and, Mixing the mixture and the aqueous liquid of the artificial bone material, forming the mixture, and preparing the drug-loaded artificial bone material; Optionally, in the step of preparing the mixture, the mixing conditions include: a frequency of 10 r / min-20 r / min, and a time of 25 min-35 min.

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