Drug-loaded bone filling material, preparation method thereof and application of drug-loaded bone filling material in inhibition of relapse of opioid drugs

Abstract

The invention relates to a drug-loaded bone filling material, a preparation method thereof and application of the drug-loaded bone filling material in inhibition of relapse of opioid drugs. The drug-loaded bone filling material is prepared from the following raw materials: powder and curing liquid, the powder comprises a mixture of an opioid receptor antagonist and inorganic calcium salt; in the powder, the mass ratio of the opioid receptor antagonist to the inorganic calcium salt is 4-20%. After a performance test, the drug-loaded bone filling material has the advantages of proper coagulation time, good compressive strength and better drug sustained release characteristic, on one hand, artificial bones capable of promoting osteoblast differentiation can be filled in a bone defect area, and on the other hand, side effects caused by opioid drugs can be relieved, and symptoms can be relieved; meanwhile, for relieving opioid addicts, long-time drug action can be maintained, relapse can be prevented or reduced, and the pharmaceutical composition has great application potential in promoting osteoblast differentiation or inhibiting relapse of opioid drugs.

Description

Technical Field

[0001] The present application relates to the technical field of medical materials, and in particular to a drug-loaded bone filling material, a preparation method thereof, and an application thereof in inhibiting relapse of opioid drug use. Background Art

[0002] As an emerging bone filling material, bone cement has a broad application space in the orthopedic market. At present, the commonly used bone filling materials on the market are polymethyl methacrylate bone cement, calcium phosphate bone cement and calcium sulfate bone cement. In the treatment of bone cavities or bone defects, degradable inorganic artificial bones have great application prospects.

[0003] Artificial bone is a bone repair material with powder and curing liquid as the main components. The powder is a high-purity inorganic calcium salt, and the curing liquid is sterile water for injection. The powder and curing liquid are mixed in a certain proportion to form an injectable paste, which is then cured. Calcium sulfate, calcium phosphate, and hydroxyapatite bone cement are biodegradable and biocompatible. They can be reabsorbed after implantation in the body and replaced by new bone during the healing process.

[0004] Opioids act on specific parts of the central nervous system, bind to opioid receptors, reduce the transmission of pain signals, and thus produce analgesic effects; they may have some adverse reactions when used in clinical treatment, causing certain side effects, aggravating symptoms, and even causing relapse when used for a long time. Naltrexone is an opioid receptor antagonist, which has similar efficacy to naloxone, significantly weakening or completely blocking the effects of opioid receptors, and even reversing the effects produced by intravenous opioids. In addition, according to literature reports, the inhibition of opioid growth factor signaling can promote the differentiation of mesenchymal stem cells into osteoblasts, prevent monocytes from differentiating into osteoclasts, promote bone formation or reduce bone damage. However, if the drug is directly applied to the damaged bone, its drug release effect is too fast to match the normal growth of the bone. Summary of the invention

[0005] Based on this, it is necessary to provide a drug-loaded bone filling material and a preparation method thereof and an application in inhibiting relapse of opioid drugs, which has drug sustained-release properties and can fill the bone defect area with artificial bone that promotes osteoblast differentiation.

[0006] The technical solution of this application is as follows:

[0007] In a first aspect of the present invention, there is provided a drug-loaded bone filling material, the raw materials for preparing the material include powder and solidifying liquid;

[0008] The powder includes a mixture of an opioid receptor antagonist and an inorganic calcium salt;

[0009] In the powder, the mass ratio of the opioid receptor antagonist to the inorganic calcium salt is 4% to 20%.

[0010] In one embodiment, the opioid receptor antagonist includes at least one of naltrexone or its hydrochloride powder, naloxone or its hydrochloride powder.

[0011] In one embodiment, the inorganic calcium salt includes one or more of calcium phosphate, calcium sulfate or hydroxyapatite.

[0012] In one embodiment, the calcium sulfate includes α-crystalline calcium sulfate hemihydrate; optionally, the particle size of the α-crystalline calcium sulfate hemihydrate is 0.1µm~200µm, and the average particle size D50 is 4µm~10µm.

[0013] In one embodiment, the calcium phosphate comprises β-tricalcium phosphate; optionally, the particle size of the β-tricalcium phosphate is 0.1µm~100µm, and the average particle size D50 is 3µm~6µm; and / or

[0014] The particle size of the hydroxyapatite is 0.1µm~100µm, and the average particle size D50 is 3µm~6um.

[0015] In one embodiment, the mass ratio of the solidifying liquid to the powder is (0.25-0.5):1; and / or

[0016] The solidifying liquid includes at least one of sterile water for injection or physiological saline.

[0017] A second aspect of the present invention provides a method for preparing the drug-loaded bone filling material as described above, comprising the following steps:

[0018] The opioid receptor antagonist and the inorganic calcium salt are mixed to prepare a powder;

[0019] The powder and the solidifying liquid are mixed and solidified to obtain the product.

[0020] In one embodiment, the step of mixing satisfies at least one of the following conditions:

[0021] (1) The mixing frequency is 10r / min~20r / min;

[0022] (2) The mixing time is 30 min to 50 min;

[0023] (3) The mixing temperature is room temperature.

[0024] In one embodiment, the curing time is 1 min to 3 min; and / or

[0025] The curing temperature is room temperature.

[0026] The third aspect of the present invention provides the use of the drug-loaded bone filling material as described above, or the drug-loaded bone filling material prepared according to the preparation method of the drug-loaded bone filling material as described above, in the preparation of drugs or materials for promoting osteoblast differentiation or inhibiting opioid relapse.

[0027] Compared with the prior art, this application has the following beneficial effects:

[0028] This application aims at the problems that arise in the clinical application of opioid drugs. By designing and preparing raw materials and rationally matching each component, a drug-loaded bone filling material is provided. The drug-loaded bone filling material has the advantages of suitable setting time, good compressive strength, and good drug sustained-release characteristics after performance testing. On the one hand, it can fill the bone defect area with artificial bone that promotes osteoblast differentiation; on the other hand, in the process of orthopedic surgery, in order to reduce the pain of patients, intravenous administration of opioid drugs is the main means of analgesia, but intravenous administration has the disadvantages of large dosage, insufficient analgesic effect, and severe nausea and vomiting after surgery. However, adding opioid receptor antagonists such as naltrexone during the implantation of artificial bones can significantly reduce reactions such as nausea and vomiting, constipation, itching, intestinal obstruction, and urinary retention without affecting the analgesic effect, which can reduce the side effects of opioid drugs and alleviate symptoms. At the same time, for those who are recovering from opioid addiction, the drug-loaded bone filling material has a sustained release effect after being implanted into the body, eliminating the need for daily oral medication. It can maintain a long-term opioid antagonist effect and prevent or reduce relapse, and has great application potential in promoting osteoblast differentiation or inhibiting opioid relapse. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1 This is the in vitro release curve of the bone filling material with different material compositions in this application.

[0031] Figure 2 This is a diagram showing the drug release effect of the naltrexone-loaded artificial bone prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0032] In order to make the above-mentioned purposes, features and advantages of the present application more obvious and easy to understand, the specific implementation methods of the present application are described in detail below. In the following description, many specific details are set forth to facilitate a full understanding of the present application. However, the present application can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present application, so the present application is not limited by the specific embodiments disclosed below.

[0033] 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 specific embodiments and are not intended to limit this application.

[0034] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0035] The percentage content involved in the present invention, unless otherwise specified, refers to mass percentage for solid-liquid mixing and solid-solid mixing, and refers to volume percentage for liquid-liquid mixing.

[0036] As used herein, "one or more" refers to any one, any two, or any two or more of the listed items.

[0037] Herein, the optional scope of "and / or", "or / and", and "and / or" includes any one of two or more relevant listed items, and also includes any and all combinations of the relevant listed items, wherein said any and all combinations include any two relevant listed items, any more relevant listed items, or a combination of all relevant 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 the present application, the technical solution undoubtedly includes technical solutions that are all connected by "logical AND", and also 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 another example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, technical solutions that are all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, a combination of any two or any three of A, B, C, and D, and also includes a combination of four items of A, B, C, and D (that is, a technical solution that is all connected by "logical AND").)

[0038] Herein, "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 this application.

[0039] Herein, "first aspect", "second aspect", "third aspect", "fourth aspect", etc. are used for descriptive purposes only 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. In addition, "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. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In the description of the present application, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of the present application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0040] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0041] Only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form an undefined range; and any lower limit can be combined with other lower limits to form an undefined range, and any upper limit can be combined with any other upper limit to form an undefined range. In addition, each separately disclosed point or single value itself can be combined with any other point or single value as a lower limit or upper limit or with other lower limits or upper limits to form an undefined range. The use of numerical ranges represented by endpoints includes all numbers within the range and any range within the range, for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4 and 5, etc.

[0042] The percentage contents involved in this application, unless otherwise specified, refer to mass percentage for solid-liquid mixing and solid-solid mixing, and refer to volume percentage for liquid-liquid mixing.

[0043] The percentage concentrations mentioned in this application, unless otherwise specified, refer to the final concentration, which refers to the percentage of the added component in the system after the addition of the component.

[0044] The temperature parameters in this application, unless otherwise specified, allow both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±2°C, ±1°C, ±0.5°C, ±0.4°C, ±0.3°C, ±0.2°C, and ±0.1°C are allowed. Normal temperature or room temperature in this application refers to no temperature control operation, generally 4°C~35°C, preferably 20±5°C.

[0045] 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.

[0046] In a first aspect of the present invention, there is provided a drug-loaded bone filling material, the raw materials for preparing the material include powder and solidifying liquid;

[0047] The powder includes a mixture of an opioid receptor antagonist and an inorganic calcium salt;

[0048] In the powder, the mass ratio of the opioid receptor antagonist to the inorganic calcium salt is 4% to 20%.

[0049] In some examples, the opioid receptor antagonist includes at least one of naltrexone or its hydrochloride powder, and naloxone or its hydrochloride powder.

[0050] In one embodiment, the inorganic calcium salt includes one or more of calcium phosphate, calcium sulfate or hydroxyapatite.

[0051] In one embodiment, the calcium sulfate comprises α-crystalline calcium sulfate hemihydrate.

[0052] In some examples, the particle size of the α-crystalline calcium sulfate hemihydrate is 0.1µm to 200µm. It can be understood that the particle size of the α-crystalline calcium sulfate hemihydrate includes but is not limited to 0.1µm, 30µm, 60µm, 90µm, 120µm, 150µm, 180µm, and 200µm.

[0053] In some examples, the average particle size D50 of the α-crystalline calcium sulfate hemihydrate is 4µm to 10µm. It can be understood that the average particle size D50 of the α-crystalline calcium sulfate hemihydrate includes but is not limited to 4µm, 5µm, 6µm, 7µm, 8µm, 9µm, and 10µm.

[0054] In one embodiment, the calcium phosphate comprises β-tricalcium phosphate.

[0055] In some examples, the particle size of the β-tricalcium phosphate is 0.1µm to 100µm. It is understandable that the particle size of the β-tricalcium phosphate includes but is not limited to 0.1µm, 10µm, 20µm, 30µm, 40µm, 50µm, 60µm, 70µm, 80µm, 90µm, and 100µm.

[0056] In some examples, the average particle size D50 of the β-tricalcium phosphate is 3µm to 6µm. It is understandable that the average particle size D5 of the β-tricalcium phosphate includes but is not limited to 3µm, 3.5µm, 4µm, 4.5µm, 5µm, 5.5µm, and 6µm.

[0057] In some examples, the particle size of the hydroxyapatite is 0.1µm to 100µm. It is understandable that the particle size of the hydroxyapatite includes but is not limited to 0.1µm, 10µm, 20µm, 30µm, 40µm, 50µm, 60µm, 70µm, 80µm, 90µm, and 100µm.

[0058] In some examples, the average particle size D50 of the hydroxyapatite is 3µm~6um. It can be understood that the average particle size D50 of the hydroxyapatite includes but is not limited to 3µm, 3.5µm, 4µm, 4.5µm, 5µm, 5.5µm, and 6µm.

[0059] In some examples, the mass ratio of the solidifying liquid to the powder is (0.25-0.5): 1. It can be understood that the mass ratio of the solidifying liquid to the powder includes but is not limited to 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, and 0.5:1.

[0060] In some examples, the solidifying liquid includes at least one of sterile water for injection or physiological saline.

[0061] A second aspect of the present invention provides a method for preparing the drug-loaded bone filling material as described above, comprising the following steps:

[0062] The opioid receptor antagonist and the inorganic calcium salt are mixed to prepare a powder;

[0063] The powder and the solidifying liquid are mixed and solidified to obtain the product.

[0064] In some examples, the mixing frequency is 10 r / min to 20 r / min. It is understandable that the mixing frequency includes but is not limited to 10 r / min, 11 r / min, 12 r / min, 13 r / min, 14 r / min, 15 r / min, 16 r / min, 17 r / min, 18 r / min, 19 r / min, and 20 r / min.

[0065] In some examples, the mixing time is 30 min to 50 min. It can be understood that the mixing time includes but is not limited to 30 min, 32 min, 34 min, 36 min, 38 min, 40 min, 42 min, 44 min, 46 min, 48 min, and 50 min.

[0066] In some of these examples, the mixing temperature is room temperature. It is understood that the mixing temperature includes but is not limited to 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, 32°C, 34°C, 35°C.

[0067] In some examples, the curing time is 1 min to 3 min. It is understandable that the curing time includes but is not limited to 1 min, 1.3 min, 1.2 min, 1.4 min, 1.5 min, 1.6 min, 1.7 min, 1.8 min, 1.9 min, 2 min, 2.1 min, 2.2 min, 2.3 min, 2.4 min, 2.5 min, 2.6 min, 2.7 min, 2.8 min, 2.9 min, 3 min.

[0068] In some of these examples, the curing temperature is room temperature. It is understood that the curing temperature includes but is not limited to 20°C, 22°C, 24°C, 26°C, 28°C, 30°C, 32°C, 34°C, 35°C.

[0069] The third aspect of the present invention provides the use of the drug-loaded bone filling material as described above, or the drug-loaded bone filling material prepared according to the preparation method of the drug-loaded bone filling material as described above, in the preparation of drugs or materials for promoting osteoblast differentiation or inhibiting opioid relapse.

[0070] Specifically, the drug-loaded bone filling material can be used as an implantable drug release carrier to reduce the side effects of using opioids during surgery and alleviate symptoms; and for those who are detoxified from opioids, it can maintain the long-term effect of naltrexone and prevent or reduce relapse.

[0071] In summary, the present application provides a bone filling material formed by hydration reaction and self-solidification of inorganic calcium salt powder doped with opioid receptor antagonists, which has the following advantages: on the one hand, it fills the bone defect area with artificial bone that promotes osteoblast differentiation; on the other hand, it reduces the side effects of opioid drugs and alleviates symptoms; for those who are detoxified from opioids, it can maintain the drug effect for a long time and prevent or reduce relapse.

[0072] The present application is further described in detail below in conjunction with specific examples. For experimental parameters not specified in the following specific examples, reference is made to the instructions given in the present application document, and reference may also be made to the experimental manual of the art or other experimental methods known in the art, or to the experimental conditions recommended by the manufacturer. It is understood that the instruments and raw materials used in the following examples are relatively specific, and may not be limited thereto in other specific examples.

[0073] Some of the raw materials used in the embodiment are as follows:

[0074] α-Calcium sulfate hemihydrate, β-tricalcium phosphate, and hydroxyapatite were homemade in the laboratory;

[0075] Naltrexone hydrochloride can be purchased from Beijing Huasu Pharmaceutical Co., Ltd.;

[0076] Naloxone hydrochloride can be purchased from Foshan Nanhai Beisha Pharmaceutical Co., Ltd.;

[0077] Physiological saline can be purchased from Sichuan Kelun Pharmaceutical Co., Ltd., with the national medicine approval number H20083400.

[0078] The following are specific embodiments.

[0079] Example 1

[0080] This embodiment provides a method for preparing a bone-filled artificial bone with sustained-release and drug addiction-relieving properties, as follows:

[0081] Preparation of powder components: weigh 1 kg of α-calcium sulfate hemihydrate (particle size 0.1 µm~60 µm, average particle size D50 7.2 µm) and 100 g of naltrexone hydrochloride, pour the two into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0082] The liquid component is physiological saline.

[0083] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0084] Example 2

[0085] Preparation of powder components: weigh 1 kg of β-tricalcium phosphate (particle size 0.1 µm~46 µm, average particle size D50 5.5 µm) and 100 g of naltrexone hydrochloride, pour them into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0086] The liquid component is physiological saline.

[0087] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0088] Example 3

[0089] Preparation of powder components: weigh 1 kg of hydroxyapatite (particle size of 0.1 µm to 50 µm, average particle size D50 of 4.0 µm) and 100 g of naltrexone hydrochloride, pour the two into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0090] The liquid component is physiological saline.

[0091] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0092] Example 4

[0093] Preparation of powder components: weigh 1 kg of α-calcium sulfate hemihydrate (particle size 0.1 µm~60 µm, average particle size D50 7.2 µm) and 100 g of naloxone hydrochloride, pour the two into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0094] The liquid component is physiological saline.

[0095] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0096] Example 5

[0097] Preparation of powder components: weigh 1 kg of β-tricalcium phosphate (particle size 0.1 µm~46 µm, average particle size D50 5.5 µm) and 100 g of naloxone hydrochloride, pour them into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0098] The liquid component is physiological saline.

[0099] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0100] Example 6

[0101] Preparation of powder components: weigh 1 kg of hydroxyapatite (particle size of 0.1 µm to 50 µm, average particle size D50 of 4.0 µm) and 100 g of naloxone hydrochloride, pour the two into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0102] The liquid component is physiological saline.

[0103] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0104] Comparative Example 1

[0105] Comparative Example 1 is basically the same as Example 1, except that the dosage of the opioid is reduced, as follows:

[0106] Preparation of powder components: weigh 1 kg of α-calcium sulfate hemihydrate (particle size 0.1 µm~60 µm, average particle size D50 7.2 µm) and 20 g of naltrexone hydrochloride, pour them into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0107] The liquid component is physiological saline.

[0108] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0109] Comparative Example 2

[0110] Comparative Example 2 is basically the same as Example 1, except that the dosage of the opioid is increased, as follows:

[0111] Preparation of powder components: weigh 1 kg of α-calcium sulfate hemihydrate (particle size 0.1 µm~60 µm, average particle size D50 7.2 µm) and 300 g of naltrexone hydrochloride, pour them into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0112] The liquid component is physiological saline.

[0113] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0114] Comparative Example 3

[0115] Comparative Example 3 is basically the same as Example 1, except that the amount of calcium salt is reduced, as follows:

[0116] Preparation of powder components: Weigh 400 g of α-calcium sulfate hemihydrate (particle size 0.1 µm~60 µm, average particle size D50 7.2 µm) and 100 g of naltrexone hydrochloride, pour them into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0117] The liquid component is physiological saline.

[0118] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0119] Comparative Example 4

[0120] Comparative Example 4 is basically the same as Example 1, except that the amount of calcium salt is increased, as follows:

[0121] Preparation of powder components: weigh 3 kg of α-calcium sulfate hemihydrate (particle size 0.1 µm~60 µm, average particle size D50 7.2 µm) and 100 g of naltrexone hydrochloride, pour them into a three-dimensional mixing device, set the mixing frequency to 12 r / min, and mix at room temperature for 40 min.

[0122] The liquid component is physiological saline.

[0123] Take 6 g of the powder component and 2 mL of normal saline, inject the normal saline into the powder component, stir quickly and evenly, mix at room temperature for 1 min, and then prepare a cylindrical sample for testing to test the coagulation time, compressive strength and in vitro release time.

[0124] The bone filling materials prepared in Examples 1 to 6 and Comparative Examples 1 to 4 were tested for properties such as coagulation time, compressive strength and in vitro release time. The test results are shown in Tables 1 and Figure 1-2 shown.

[0125] Among them, the test methods or test standards for each performance test item are as follows:

[0126] Setting time: Mix the powder component and the liquid component into a slurry, and the initial time is counted when stirring begins. After mixing into a slurry, transfer it to the mold as quickly as possible. Mold size: hollow cylinder inner diameter * height = 10mm * 40mm. Then use the Vicat instrument to test the setting time of the artificial bone. The final setting needle of the Vicat instrument contacts the upper surface of the bone cement mixture. After tightening the screw, release it for 1~2s. When the test needle can only sink into the solid mixture for no more than 0.5mm, that is, when the final setting needle cannot leave a mark on the solid, it is the final setting state of the bone cement, which is counted as the final time. The final setting time is the difference between the final time and the initial time.

[0127] Compressive strength: Mix the powder component and the 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.

[0128] 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.

[0129] In vitro release time: The powder component and the liquid component were blended into a slurry and made into a cylinder of fixed size (diameter*height=6mm*12mm). A certain proportion of PBS buffer (pH=7.4, containing 0.02% Tween 20) was then added as an extract.

[0130] The concentration of naltrexone hydrochloride or naloxone hydrochloride in the extract was detected by high performance liquid chromatography. The chromatographic conditions were as follows: octadecylsilane bonded silica gel as filler mobile phase, 0.02 mol / L potassium dihydrogen phosphate-methanol-acetonitrile (volume ratio of 75:15:10); flow rate: 1.0 mL / min; detection wavelength: 240 nm; column temperature: room temperature; injection volume: 20 μL.

[0131] Table 1

[0132]

[0133] As can be seen from Table 1 above, compared with Comparative Examples 1 to 4, the bone filling materials prepared in Examples 1 to 6 of the present application have better solidification time and compressive strength. Figure 1 It can be seen that, compared with Comparative Examples 1 to 4, the bone filling materials prepared in Examples 1 to 6 of the present application have better sustained-release properties in vitro.

[0134] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments 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.

[0135] The above-described embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be construed as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent application shall be subject to the attached claims, and the description may be used to interpret the content of the claims.

Claims

1. A drug-loaded bone filling material, characterized in that: The raw materials for its preparation include powder and solidifying liquid; The powder includes a mixture of an opioid receptor antagonist and an inorganic calcium salt; In the powder, the mass ratio of the opioid receptor antagonist to the inorganic calcium salt is 4% to 20%.

2. The drug-loaded bone filling material according to claim 1, characterized in that: The opioid receptor antagonist comprises at least one of naltrexone or its hydrochloride powder and naloxone or its hydrochloride powder.

3. The drug-loaded bone filling material according to claim 1, characterized in that: The inorganic calcium salt includes one or more of calcium phosphate, calcium sulfate or hydroxyapatite.

4. The drug-loaded bone filling material according to claim 3, characterized in that: The calcium sulfate includes α-crystalline calcium sulfate hemihydrate; optionally, the particle size of the α-crystalline calcium sulfate hemihydrate is 0.1µm~200µm, and the average particle size D50 is 4µm~10µm.

5. The drug-loaded bone filling material according to claim 3, characterized in that: The calcium phosphate includes β-tricalcium phosphate; optionally, the particle size of the β-tricalcium phosphate is 0.1µm~100µm, and the average particle size D50 is 3µm~6µm; and / or The particle size of the hydroxyapatite is 0.1µm~100µm, and the average particle size D50 is 3µm~6um.

6. The drug-loaded bone filling material according to claim 1, characterized in that: The mass ratio of the solidifying liquid to the powder is (0.25-0.5):1; and / or The solidifying liquid includes at least one of sterile water for injection or physiological saline.

7. A method for preparing the drug-loaded bone filling material according to any one of claims 1 to 6, characterized in that: The following steps are involved: The opioid receptor antagonist and the inorganic calcium salt are mixed to prepare a powder; The powder and the solidifying liquid are mixed and solidified to obtain the product.

8. The method for preparing the drug-loaded bone filling material according to claim 7, characterized in that: The mixing step satisfies at least one of the following conditions: (1) The mixing frequency is 10r / min~20r / min; (2) The mixing time is 30 min to 50 min; (3) The mixing temperature is room temperature.

9. The method for preparing the drug-loaded bone filling material according to claim 7, characterized in that: The curing time is 1min~3min; and / or The curing temperature is room temperature.

10. Use of the drug-loaded bone filling material according to any one of claims 1 to 6, or the drug-loaded bone filling material prepared by the preparation method of the drug-loaded bone filling material according to any one of claims 7 to 9, in the preparation of drugs or materials for promoting osteoblast differentiation or inhibiting opioid relapse.

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