Application of lurasidone or pharmaceutically acceptable salt thereof in preparation of medicine for preventing and / or treating diabetic individual bone injury healing disorder

Abstract

The invention provides an application of lurasidone or a pharmaceutically acceptable salt thereof in preparation of a medicine for preventing and / or treating diabetes individual bone injury healing disorder. The hyperglycemia environment causes excessive secretion of lipocalin-2 (LCN2) by activating a phosphopentose pathway of neutrophil, thereby inhibiting osteogenic differentiation of skeletal stem cells. According to the application of the lurasidone or the pharmaceutically acceptable salt thereof in the preparation of the medicine for preventing and / or treating the diabetic individual bone injury healing disorder, in the application provided by the invention, the lurasidone can specifically inhibit the metabolic pathway and the secretion of LCN2, remodel an immune microenvironment beneficial to repair, and promote the healing of the diabetic individual bone injury. The formation of callus under the condition of diabetes mellitus is obviously accelerated and the mineral density of bone is improved.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to the use of lurasidone or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention and / or treatment of impaired bone healing in diabetic individuals. Background Technology

[0002] Diabetes mellitus is a chronic metabolic disease characterized by high blood sugar and impaired insulin levels or function, and is one of the major global health challenges of the 21st century. Epidemiological data shows that approximately 589 million adults worldwide were affected by this disease in 2024, and the number is projected to reach 853 million by 2050. Clinical studies have shown that the incidence of fractures in diabetic patients is significantly higher than in healthy individuals, and their fracture healing process is often significantly delayed or impaired, easily leading to serious consequences such as nonunion and malunion. This not only increases the disability rate of patients but also places a heavy burden on the healthcare system.

[0003] Fracture healing is a complex and sophisticated biological process involving the high coordination of various cells, particularly immune cells. This process begins the instant of injury, with neutrophils, acting as the "vanguard" of the innate immune system, rapidly infiltrating the hematoma area within hours of the fracture. They not only clear necrotic tissue and pathogens, but more importantly, they recruit monocytes / macrophages to the injury site by secreting cytokines such as interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), and stromal cell-derived factor-1α (SDF-1α / CXCL12), thereby initiating a repair cascade. Subsequently, macrophages at the injury site transition from a pro-inflammatory M1 phenotype to an anti-inflammatory / repairing M2 phenotype, releasing factors such as TGF-β, VEGF, and IGF-1, directly regulating osteogenic differentiation and angiogenesis of skeletal stem cells / mesenchymal stem cells. In short, this sequential cascade of immune cell involvement—from neutrophil-initiated inflammation to macrophage phenotype transformation, and then to immune factors driving stem cell osteogenic formation—is an indispensable core link in bone regeneration.

[0004] However, in the pathological state of diabetes, this intricate "immune-bone" dialogue is profoundly and extensively disrupted. The persistently hyperglycemic environment directly impairs the initiation of the immune response—the function of neutrophils—including their impaired chemotaxis, phagocytosis, and extracellular trap formation. Simultaneously, metabolic disturbances (such as the accumulation of advanced glycation end products) hinder the functional phenotype of neutrophils and macrophages, causing them to remain in a pro-inflammatory state for extended periods, resulting in a chronic, persistent, low-grade inflammatory microenvironment at the site of injury. This toxic microenvironment severely inhibits the osteogenic activity and survival of bone stem cells and also severely impairs the formation of new blood vessels that provide nutrients for repair.

[0005] Currently, existing technical solutions for diabetic fracture healing disorders mainly include the following categories, but all of them have certain limitations: Blood glucose control and basic treatment: Although intensive insulin therapy is the cornerstone of management, it can improve the metabolic environment and partially promote bone healing. However, it often depends on long-term patient compliance and is difficult to completely reverse the damage to the local microenvironment that has already occurred. It has limited effect on existing healing obstacles.

[0006] Surgical and biomaterial interventions, such as bone grafting, bone cement filling, and bio-scaffolds, primarily provide mechanical support or passive filling. While attempting to provide a physical framework for bone regeneration, these methods suffer from low integration rates of implanted materials and pose a high risk of infection in the context of a deteriorating immune microenvironment and insufficient blood supply caused by diabetes.

[0007] Drug therapy includes the use of anti-osteoporosis drugs such as bisphosphonates and teriparatide. These drugs are not specifically designed for diabetic fractures; bisphosphonates may excessively inhibit bone remodeling, while teriparatide, although stimulating bone formation, cannot address upstream immune regulation issues. The application of recently developed growth factor patches for soft tissue healing in bone repair still requires further exploration.

[0008] Local cytokine therapy: such as the application of platelet-rich plasma (PRP) or bone morphogenetic proteins (BMPs). These strategies attempt to directly "force" activation of repair cells through high concentrations of factors to compensate for insufficient endogenous signaling. However, BMPs are expensive and carry the risk of ectopic ossification, and in the context of impaired core immune cell function, the responsiveness of repair cells to these factors is often reduced.

[0009] Stem cell therapy: Although theoretically it has the potential for multi-lineage differentiation and paracrine regulation, the function of autologous stem cells in diabetic patients is often impaired, while allogeneic stem cell transplantation faces challenges such as immune rejection, low survival rate and difficulty in homing, and the treatment cost is high.

[0010] In summary, existing technologies mostly focus on the mid-to-downstream stages of the repair process (such as directly stimulating osteogenic formation or providing a scaffold), failing to effectively address the root cause of diabetic fracture healing failure—namely, the imbalance in the initial repair microenvironment caused by dysfunction of immune cells such as neutrophils. Therefore, there is an urgent clinical need for innovative treatment options that restore the immune-skeletal axis function damaged in diabetic conditions, thereby restarting the fracture healing process. Summary of the Invention

[0011] To address the shortcomings of existing technologies, the present invention aims to provide the use of lurasidone or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention and / or treatment of impaired bone healing in diabetic individuals.

[0012] The first aspect of the present invention provides the use of lurasidone or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of impaired bone healing in diabetic individuals.

[0013] In one embodiment of the present invention, the bone injury healing disorder in diabetic individuals includes: delayed fracture healing, nonunion, pseudoarthrosis, poor repair of bone defects, osteoporotic fractures, and bone regeneration disorder after orthopedic surgery in the context of diabetes and hyperglycemia.

[0014] In one embodiment of the present invention, the drug has the following use: to promote bone injury healing by improving the local immune microenvironment of the injury site in diabetic individuals.

[0015] In one embodiment of the present invention, the improvement of the immune microenvironment specifically involves regulating the function of neutrophils, including: Inhibits the metabolic activity of the pentose phosphate pathway in neutrophils. And / or, It inhibits the secretion of lipid transporter protein-2 in neutrophils.

[0016] A second aspect of the present invention provides a pharmaceutical composition for promoting fracture healing in a diabetic environment, comprising the above-mentioned lurasidone or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0017] A third aspect of the present invention provides a bone repair material for promoting fracture healing in a diabetic environment, the bone repair material comprising a biocompatible scaffold and lurasidone or a pharmaceutically acceptable salt thereof loaded on the scaffold.

[0018] In one embodiment of the present invention, the biocompatible scaffold is selected from at least one of hydrogel, bone cement, collagen sponge, nanofiber scaffold, microspheres or 3D printed bone scaffold.

[0019] A fourth aspect of the present invention provides a method for screening candidate drugs for promoting fracture healing in a diabetic environment, comprising the following steps: Provides an in vitro neutrophil model under high glucose conditions; The candidate substances to be screened are brought into contact with the neutrophil model; The metabolic levels of the pentose phosphate pathway and / or the expression or secretion levels of lipid transporter-2 in the neutrophils were detected. Compared with the control group that was not exposed to the candidate substance, if the candidate substance can significantly reduce the metabolic level of PPP and / or reduce the expression or secretion level of lipid transport protein-2, then the candidate substance is determined to have the potential to promote fracture healing in the context of diabetes.

[0020] The drug screening method established in this invention based on PPP metabolism and LCN2 expression in isolated neutrophils provides clear and quantifiable targets and standards for developing novel therapeutic drugs for diabetic fractures, overcoming the limitations of previous screening methods that relied solely on osteoblast phenotypes.

[0021] The fifth aspect of this invention provides the use of a lipid transporter-2 detection reagent in the preparation of a kit for assessing the prognosis of fracture healing in diabetic individuals.

[0022] The sixth aspect of the present invention provides the use of a lipid transporter-2 detection reagent in the preparation of a kit for screening patients for lurasidone treatment, wherein the patients are diabetic fracture patients with abnormally elevated lipid transporter-2 expression levels.

[0023] This invention clarifies the negative correlation between LCN2 levels and fracture healing outcomes in diabetic patients. Using LCN2 detection reagents, clinicians can assess the fracture healing risk in diabetic patients in advance (prognostic assessment) and identify patients with abnormally elevated LCN2 levels as the optimal candidate population for lurasidone treatment (companionship diagnosis), thereby achieving precision medicine and improving treatment success rates.

[0024] Compared with the prior art, the present invention has the following beneficial effects: 1. Existing technologies mostly focus on the mid-to-downstream stages of fracture healing (such as directly stimulating osteoblast activity or supplementing growth factors), often resulting in poor efficacy due to the inability to reverse the adverse microenvironment. In contrast, the application of lurasidone or its pharmaceutically acceptable salts in the preparation of drugs for the prevention and / or treatment of bone injury healing disorders in diabetic individuals, provided by this invention, establishes a "source regulation" treatment strategy based on innovative discoveries of the mechanism of diabetic fracture healing disorders. This invention reveals for the first time that the dysfunction of neutrophils—the earliest innate immune cells to reach the local area after injury—is the key reason why subsequent repair cascade reactions cannot be initiated. Specifically, the hyperglycemic environment specifically activates the pentose phosphate pathway (PPP) of neutrophils, leading to excessive secretion of lipid transport protein-2 (LCN2). It is LCN2 that directly inhibits the osteogenic differentiation ability of bone stem cells. This invention utilizes lurasidone to precisely target this "neutrophil PPP metabolism-LCN2 axis," and by preferentially correcting the metabolic abnormalities of immune cells, it eliminates the inhibition of fracture healing by the diabetic environment at its source. This strategy reshapes the initial immune microenvironment conducive to repair, indirectly but fundamentally restoring the normal function of bone stem cells. It overcomes the fundamental defects of existing technologies, such as delayed intervention targets and failure to address the imbalance of the initial microenvironment, thereby significantly accelerating callus formation and increasing bone mineral density.

[0025] 2. The application of lurasidone or its pharmaceutically acceptable salts in the preparation of drugs for the prevention and / or treatment of bone injury healing disorders in diabetic individuals, provided by this invention, achieves "drug repurposing," possessing both precise targeting and high safety potential. This invention discovers that lurasidone's application in orthopedics is not merely a simple one, but rather a precise therapeutic effect with a clearly defined molecular target. As an atypical antipsychotic drug already approved by the FDA, the pharmacokinetic characteristics and safety data of lurasidone are relatively well-established. Compared to developing entirely new compounds, this invention significantly reduces the risks, timelines, and costs of drug development. More importantly, this invention demonstrates its specific downregulation of the abnormal PPP metabolic pathway in neutrophils, providing a novel, safe, and reliable clinical intervention for the refractory disease of diabetic fractures.

[0026] 3. The present invention further develops bone repair materials containing lurasidone. This local administration method can achieve: (1) direct action of the drug on the neutrophils at the fracture site, establishing a high concentration of therapeutic microenvironment in the early stage of injury; (2) greatly reduce the amount of drug entering the blood circulation, avoid adverse effects on non-target organs (especially the central nervous system), and improve drug safety; (3) the bone repair material itself can provide physical support or scaffolding, which, together with the bioactive regulatory effect of lurasidone, further improves the quality of healing. Attached Figure Description

[0027] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings: Figure 1 The figure shows the inhibitory effect of lurasidone on high glucose-induced LCN2 secretion in neutrophils; among them, Figure 1 In Figure A, the cell viability results of neutrophils in each group were detected using the CCK-8 assay. Figure 1 Figure B shows the results of qPCR detection of Lcn2 gene expression levels in neutrophils from each group. Figure 1 In the middle, C represents the LCN2 expression level in the culture supernatant of neutrophils in each group as detected by ELISA; all data are expressed as mean ± standard error of the mean (mean ± sem); statistical significance was defined as *P ≤ 0.05, P ≤ 0.01, *P ≤ 0.005, ****P ≤ 0.001; one-way ANOVA combined with Bonferroni multiple comparison test was used for analysis; all data are expressed as mean ± standard error of the mean (mean ± sem); statistical significance was defined as *P ≤ 0.05, P ≤ 0.01, *P ≤ 0.005, ****P ≤ 0.001.

[0028] Figure 2 The effect of lurasidone pretreatment on osteogenic differentiation of bone marrow mesenchymal stem cells is shown in the figure. Figure 2 The image in center A shows the results of ALP staining (top left) and Alizarin Red staining (bottom left) to detect osteogenic differentiation of neutrophils in each group, as well as the results of ALP activity unit levels (right). Figure 2 Figure B shows the results of qPCR detection of osteogenic gene expression levels in bone marrow mesenchymal stem cells in each group. All data are expressed as mean ± standard error of the mean (mean ± sem). Statistical significance was defined as *P ≤ 0.05, P ≤ 0.01, *P ≤ 0.005, ****P ≤ 0.001. One-way ANOVA combined with Bonferroni multiple comparison test was used for analysis. Figure 3 The figure shows the therapeutic effects of lurasidone in a diabetic mouse fracture model; among which... Figure 3 Image A shows a schematic diagram of the construction of a diabetic mouse fracture model and lurasidone injection. Figure 3 Image B in the middle is a representative image of the fracture healing status in each group shown by Micro CT. Figure 3 In the middle, C represents the corresponding values ​​of BV / TV, BMD, Tb.N, and Tb.Th at the fracture site in each group as shown by Micro CT examination; Figure 3The images show bone healing at the site of bone injury in normal mice, diabetic mice, and diabetic mice treated with lurasidone (D-section) after HE staining. All data are expressed as mean ± standard error of the mean (mean ± sem). Statistical significance was defined as *P ≤ 0.05, P ≤ 0.01, *P ≤ 0.005, ****P ≤ 0.001. One-way ANOVA combined with Bonferroni multiple comparison test was used for analysis. Figure 4 The figure shows the results of the open field experiment. Detailed Implementation

[0029] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several changes and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0030] In the following embodiments, unless otherwise specified, the raw materials or processing techniques are conventional commercially available materials or conventional processing techniques in the art.

[0031] Existing technologies for treating diabetic fractures primarily focus on the mid- and downstream stages of the repair process, such as directly stimulating osteoblasts with growth factors or supplementing stem cells. However, this invention, based on a profound analysis of the shortcomings of existing technologies, uniquely points out that in the harsh pathological environment of diabetes, without first improving the local microenvironment of the injury, directly applying stem cells or growth factors is unlikely to achieve the desired therapeutic effect.

[0032] Therefore, the core concept of this invention lies in shifting the focus of treatment forward, establishing a novel treatment strategy to promote the healing of diabetic fractures by "prioritizing the correction of functional disorders of damaged neutrophils in diabetic states." This means indirectly but fundamentally creating favorable conditions for bone regeneration by regulating the initial immune microenvironment, moving from "direct bone promotion" to "immune microenvironment remodeling."

[0033] This invention has identified and confirmed the underlying mechanism leading to impaired fracture healing in diabetic patients: Initiating phase: Neutrophils, which are the first cells to infiltrate the injury site after a fracture, are key. In the hyperglycemic environment of diabetes, neutrophils undergo metabolic reprogramming, with their pentose phosphate pathway (PPP) becoming abnormally active.

[0034] Effector molecules: Abnormally active PPP metabolism directly drives neutrophil high expression and secretion of lipid transporter protein-2 (LCN2).

[0035] Pathological consequences: As a key pathogenic factor, LCN2 strongly inhibits the survival, proliferation and osteogenic differentiation of bone stem cells, thereby disrupting the normal repair cascade.

[0036] Based on the above mechanism exploration, this invention unexpectedly discovered that the FDA-approved drug, lurasidone, can precisely target this newly discovered pathological axis. Lurasidone is not only an antipsychotic drug; in the application scenario of this invention, it can effectively downregulate the PPP metabolic level of neutrophils in a diabetic environment, thereby significantly reducing the expression and secretion of LCN2.

[0037] This mechanism of action has a "root cause" effect: by intervening in the initial acute inflammatory phase of healing, it relieves the inhibition of bone stem cells by LCN2, restores the normal dialogue of the "immune-bone" axis, thereby initiating and accelerating the subsequent bone healing process.

[0038] In summary, the technical approach of this invention can be summarized as follows: identifying the initial disruptive link in the healing of diabetic fractures—the "neutrophil PPP metabolism-LCN2 axis"—→ specific intervention using lurasidone → reshaping an immune microenvironment conducive to repair → ultimately promoting bone regeneration. This technical concept of "regulating immunity to facilitate regeneration" overcomes the limitations of existing technologies. Example 1

[0039] This embodiment verifies the inhibitory effect of lurasidone on high glucose-induced LCN2 secretion in neutrophils (in vitro verification). The purpose of this embodiment is to verify whether lurasidone can directly reverse neutrophil dysfunction caused by a high-glucose environment, namely, inhibiting the PPP metabolic pathway and excessive secretion of LCN2.

[0040] 1. Experimental Methods Neutrophil isolation and culture: Wild-type C57BL / 6N mouse bone marrow neutrophils were isolated using Percoll™ separation medium (Cytiva, 17089101) via density gradient centrifugation (800×g, 35 min, ascending speed 5, descending speed 0). The cells were resuspended in RPMI-1640 medium (Gibco, C11875500BT) and divided into the following four groups: (1) Normal glucose concentration group (NG): glucose concentration was 5.5 mM; (2) High glucose concentration group (HG): glucose concentration of 25 mM, simulating the hyperglycemic environment of diabetes; (3) High glucose + low-dose lurasidone group (HG + Lurasidone-L): 25 mM glucose + 1 μM lurasidone; (4) High glucose + high dose of lurasidone group (HG + Lurasidone-H): 25 mM glucose + 10 μM lurasidone.

[0041] Note: Lurasidone was pre-dissolved in DMSO, and the final concentration of DMSO was kept consistent and <0.1% in all groups. Cells were cultured in a constant temperature incubator at 37°C and 5% CO2 for 24 hours.

[0042] Detection indicators and methods: ① Cell viability assay: The effect of lurasidone at different concentrations on neutrophil viability was detected using a CCK-8 assay kit to eliminate interference from drug toxicity.

[0043] ② LCN2 gene expression detection: Collect cells from each group, extract total RNA, reverse transcribe and then use qPCR to detect the mRNA expression level of the Lcn2 gene.

[0044] ③ LCN2 protein expression detection: Collect cell culture supernatant from each group and use an enzyme-linked immunosorbent assay (ELISA) kit to quantitatively detect the level of secreted LCN2 protein.

[0045] 2. Experimental Results Cytotoxicity assessment: such as Figure 1 As shown in Figure A, the CCK-8 assay results indicated that, within the tested concentration ranges (1 μM and 10 μM), there was no significant difference in neutrophil viability between the lurasidone-treated group and the control group (P>0.05). This demonstrates that the subsequently observed effect was based on the drug's functional regulatory effects, rather than cell death caused by cytotoxicity.

[0046] Inhibition of LCN2 expression and secretion: For example Figure 1 B (genetic level) and Figure 1As shown in the C-square (protein level) diagram, compared with the NG group, the LCN2 mRNA expression level and LCN2 protein concentration in the supernatant of neutrophils in the HG group were significantly increased (P<0.001), confirming that the high glucose environment induced LCN2 overexpression. Compared with the HG group, the lurasidone treatment groups (HG + Lurasidone-L and HG + Lurasidone-H) showed a significant decrease in LCN2 levels, exhibiting a clear dose-dependent effect. In particular, the high-dose group (10 μM) almost reversed the LCN2 level to a level close to that of the NG group.

[0047] In summary, this embodiment demonstrates that lurasidone can effectively and safely inhibit neutrophil PPP metabolic activation induced by a high-glucose environment in vitro, thereby blocking the excessive secretion of the pathogenic factor LCN2 and correcting the abnormal immune cell function in a diabetic environment. Example 2

[0048] Effects of lurasidone pretreatment on osteogenic differentiation of bone marrow mesenchymal stem cells (in vitro co-culture validation) This embodiment uses a conditioned medium co-culture system to verify whether diabetic neutrophils whose function has been corrected by lurasidone relieved the inhibition of osteogenic differentiation of bone stem cells.

[0049] 1. Experimental Methods Preparation of conditioned medium (CM): After culturing neutrophils for 24 hours according to the method in Example 1, the culture supernatant of each group (NG, HG, HG+Lurasidone-L, HG+Lurasidone-H) was collected, and after centrifugation to remove cell debris, it was used as a conditioned medium for later use.

[0050] 2. Bone stem cell culture and osteogenic induction: Bone marrow tissue was collected from wild-type C57BL / 6N mice. Single-cell suspensions were obtained using a combination of bone marrow flushing and filtration. Bone marrow mesenchymal stem cells (BMSCs) were isolated and purified in vitro using an adherent selection method and seeded into culture plates. When the cell confluence reached approximately 80%, the medium was replaced with osteogenic induction medium. Experimental groups were as follows: (1) Control group: osteogenic induction medium + 50% normal neutrophil conditioned medium; (2) HG-neutrophil CM group: osteogenic induction medium + 50% HG group neutrophil conditioned medium; (3) HG+Lurasidone-neutrophil CM group: osteogenic induction medium + 50% (HG+Lurasidone-H) neutrophil conditioned medium. (Note: A low-dose group was also set up for parallel experiments).

[0051] All groups were replaced with fresh culture medium every 3 days and cultured for 21 days.

[0052] Detection indicators and methods: ① Alkaline phosphatase (ALP) detection: On day 7 of induction, ALP staining and quantitative detection of ALP activity were performed as a marker of early osteogenic development.

[0053] ② Alizarin Red staining: Alizarin Red staining was performed on days 14-21 of induction to observe and quantify calcium nodule formation and assess mineralization capacity.

[0054] ③ qRT-PCR detection: Detect the mRNA expression levels of key osteogenic genes (Alp, Col1a1, Opn, Runx2).

[0055] 3. Experimental Results like Figure 2 China A and Figure 2 As shown in Figure B, compared with the control group, BMSCs in the HG-neutrophil CM group exhibited significant osteogenic inhibition: ALP activity was significantly reduced, the area of ​​mineralized nodules shown by Alizarin Red staining was greatly reduced, and the expression of key osteogenic genes (Runx2, Opn, etc.) was downregulated. This confirms that neutrophil secretions (rich in LCN2) under high glucose stimulation have an osteoinhibitory effect.

[0056] Importantly, compared with the HG-neutrophil CM group, the osteogenic capacity of BMSCs in the HG+lurasidone-neutrophil CM group was significantly restored. ALP activity, mineralized nodule formation, and osteogenic gene expression levels significantly increased, approaching the levels of the control group.

[0057] In summary, this embodiment demonstrates at the cell interaction level that lurasidone successfully relieves the inhibition of osteogenic differentiation of bone marrow mesenchymal stem cells by the harmful immune microenvironment by correcting the abnormal function of neutrophils (i.e., reducing LCN2 secretion), and reconstructs a microenvironment conducive to bone regeneration. Example 3

[0058] The therapeutic effect of lurasidone in a diabetic mouse model of fractures (in vivo validation) This embodiment verifies the actual efficacy of lurasidone in promoting the healing of diabetic fractures at the whole animal level.

[0059] 1. Experimental Methods Animal model establishment: Eight-week-old male db / db mice (a widely recognized model of type 2 diabetes with hyperglycemia and metabolic disorders) were selected. After anesthesia, all mice underwent open surgery to expose the midshaft of one femur, cut it, prepare a transverse fracture, fix it with an intramedullary nail, and close the wound layer by layer by suture.

[0060] Grouping and administration: Mice with successful modeling were randomly divided into two groups (n=10 / group): (1) Model control group (Vehicle): administered an equal volume of solvent (corn oil) daily; (2) Lurasidone treatment group (Lurasidone): administered lurasidone intraperitoneally every two days at a dose of 20 mg / kg body weight. Administration regimen: administration began on the day of fracture surgery (Day 0) and continued until the 14th day after surgery.

[0061] Detection indicators: ① Imaging assessment (Micro-CT): At 2 and 4 weeks post-fracture, the fracture site was scanned using Micro-CT (10 μm voxel resolution). Quantitative analysis of callus volume (BV / TV), bone mineral density (BMD), trabecular bone number (Tb.N), and separation (Tb.Sp) was performed after 3D reconstruction. ② Histological analysis: Some mice were sacrificed at 2 weeks post-fracture, and callus tissue specimens were collected. After decalcification and paraffin embedding, sections were prepared. Hematoxylin-eosin (H&E) staining was used to observe the overall structure, and Masson's trichrome staining was used to assess collagen deposition and maturation.

[0062] 2. Experimental Results Imaging results: such as Figure 3 China B and Figure 3 As shown in Figure C, Micro-CT results revealed that the model control group exhibited significant delayed bone healing at both 2 and 4 weeks post-surgery, with sparse callus and low mineralization. In contrast, the lurasidone treatment group showed a more rapid callus formation and remodeling process. Quantitative analysis indicated that the bone volume fraction (BV / TV) and bone mineral density (BMD) in the treatment group were significantly higher than those in the model control group (P<0.01).

[0063] Histological results: H&E (e.g.) Figure 3 As shown in Figure D) and Masson staining, the fracture ends in the lurasidone treatment group were more tightly connected, the cartilage callus transformed into hard callus more rapidly (with less cartilage residue), and the newly formed trabecular bone structure was thicker and more regularly arranged.

[0064] In summary, this embodiment provides conclusive in vivo evidence demonstrating that lurasidone can significantly improve fracture healing quality in diabetic mice, accelerate callus formation and mineralization, and has clear clinical translational potential. Example 4

[0065] Drug formulation and administration of lurasidone This embodiment describes in detail the preparation process of lurasidone oil solution for in vivo experiments, a formulation that ensures drug stability and bioavailability.

[0066] 1. Preparation process Raw material preparation: Prepare high-purity lurasidone powder (API) and pharmaceutical-grade corn oil (as solvent carrier).

[0067] Preparation steps: (1) Calculation and weighing: Accurately weigh lurasidone powder according to the target concentration of 4 mg / mL. For example, to prepare 10 mL of solution, weigh 40 mg of powder. (2) Dissolution and dispersion: Place the powder in a sterile glass bottle and add the predetermined volume of corn oil. (3) Physical dissolution: First, use a vortex shaker to vigorously shake for 5 minutes to initially disperse the powder; then place the container in an ultrasonic cleaner (power 300W, frequency 40kHz) and ultrasonically treat in a water bath for 30 minutes until the solution is uniform, transparent or slightly milky white and free of visible particles. (4) Sterilization and storage: Filter the solution using a 0.22 μm organic phase microporous membrane in a sterile operating table, dispense into brown vials, seal with nitrogen, and store at 4°C protected from light. Before use, remove and allow to return to room temperature and shake gently.

[0068] 2. Dosing regimen Route of administration: Intraperitoneal injection (ip).

[0069] Dosage calculation: Calculated based on 20 mg / kg body weight. For example, the injection volume for a 25 g mouse is: (25 g × 20 mg / kg) / 4 mg / mL = 0.125 mL.

[0070] Treatment course: The first dose is administered on the day of the fracture (Day 0), followed by injections every two days (i.e., Day 2, 4, 6...) until the critical period for fracture healing ends (e.g., Day 14).

[0071] 3. Safety observation Throughout the administration period, the mice's body weight and behavioral activity were monitored daily. Considering that lurasidone's own pharmacological effects might induce anxiety-like behavior in mice, open field tests were used to assess relevant behavioral indicators. The results showed that the weight gain curve in the lurasidone-treated group was not significantly different from that in the control group, and no obvious irritability, lethargy, or other acute toxic reactions were observed. Figure 4 As shown, the open field test indicators also showed no significant abnormalities, indicating that the dose and formulation were well tolerated.

[0072] It should be noted that although this embodiment uses intraperitoneal injection as a systemic drug delivery method to verify efficacy, based on the technical concept of this invention, lurasidone can also be prepared into a local drug delivery system (such as drug-loaded hydrogel, bone cement or sustained-release microspheres) to achieve targeted release at the fracture site, further increase the local drug concentration and reduce the risk of systemic exposure. This is also one of the embodiments protected by this invention.

[0073] Specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various changes or modifications within the scope of the claims, which do not affect the essence of the present invention. Unless otherwise specified, the embodiments and features described in this application can be arbitrarily combined with each other.

Claims

1. Use of lurasidone or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention and / or treatment of impaired bone healing in diabetic individuals.

2. The application according to claim 1, characterized in that, The bone injury healing disorders in diabetic individuals include: delayed fracture healing, nonunion, pseudoarthrosis, poor repair of bone defects, osteoporotic fractures, and bone regeneration disorders after orthopedic surgery in the context of diabetes and hyperglycemia.

3. The application according to claim 1, characterized in that, The drug has the following uses: promoting bone injury healing by improving the local immune microenvironment of the injury site in diabetic individuals.

4. The application according to claim 3, characterized in that, The improvement of the immune microenvironment specifically involves regulating the function of neutrophils, including: Inhibits the metabolic activity of the pentose phosphate pathway in neutrophils. And / or, It inhibits the secretion of lipid transporter protein-2 in neutrophils.

5. A pharmaceutical composition for promoting fracture healing in diabetic settings, characterized in that, Includes lurasidone or a pharmaceutically acceptable salt thereof as described in any one of claims 1-4, and a pharmaceutically acceptable carrier.

6. A bone repair material that promotes fracture healing in diabetic patients, characterized in that, The bone repair material comprises a biocompatible scaffold and lurasidone or a pharmaceutically acceptable salt thereof loaded on the scaffold.

7. The bone repair material according to claim 6, characterized in that, The biocompatible scaffold is selected from at least one of hydrogel, bone cement, collagen sponge, nanofiber scaffold, microsphere or 3D printed bone scaffold.

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