A sustained-release oral powder for treating osteoporosis and a preparation method thereof

Abstract

The application discloses a sustained-release oral powder for treating osteoporosis and a preparation method thereof, and comprises supermolecular metal organic framework material sMOF 2 parts, microcrystalline cellulose 0.8-1.0 parts and magnesium stearate 0.1-0.2 parts. 2+ The supermolecular metal organic framework material sMOF is formed by Sr 2+ , Mg and alendronate (ALN), 1,6-diphosphofructose sodium salt (FDP) and casein phosphopeptide (CPP) through coordination self-assembly. The powder has excellent treatment effect, biocompatibility and sustained-release characteristics, can effectively promote osteoblast differentiation, inhibit osteoclast activity and reverse bone density reduction, and is suitable for treating osteoporosis, bone fracture and other bone diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and specifically discloses a sustained-release oral powder for treating osteoporosis and its preparation method. Background Technology

[0002] Osteoporosis is a growing public health problem worldwide. With an aging population, the number of people suffering from osteoporosis continues to rise, affecting approximately 200 million people globally, with women accounting for as much as 80% of these cases. The annual incidence of osteoporotic fractures is approximately 18%, with a recurrence risk exceeding 40% within 5 years, seriously threatening patients' quality of life and survival rates.

[0003] Current treatments primarily revolve around two main strategies: "inhibiting bone resorption" and "promoting bone formation," but both have significant limitations. Among anti-resorption drugs, bisphosphonates (such as alendronate sodium) are the most widely used first-line drugs in clinical practice. They effectively slow bone loss by inhibiting osteoclast activity. However, the safety issues associated with their long-term use are becoming increasingly prominent: on the one hand, they may cause rare but serious side effects, such as osteonecrosis of the mandible and atypical femoral fractures, which are related to the drug's excessive inhibition of bone turnover and its impact on the bone's self-repair ability; on the other hand, oral bisphosphonates have extremely low bioavailability and are highly irritating to the gastrointestinal tract, requiring patients to take them under strict fasting, with plenty of water, and in an upright position, leading to poor long-term adherence due to the cumbersome medication process. Another class of anti-resorption drugs is RANKL inhibitors (such as denosumab). As a subcutaneously injected monoclonal antibody, it has a stronger inhibitory effect on osteoclast formation and is not limited by renal function. However, severe "bone turnover rebound" occurs after discontinuation, with bone density rapidly decreasing to or even below pre-treatment levels, and the risk of fracture increases dramatically. Therefore, patients must continue treatment and cannot arbitrarily interrupt it. In promoting bone formation, parathyroid hormone analogs (such as teriparatide) are currently the most effective osteogenic stimulants. They significantly stimulate osteoblast activity, increase bone density, and improve bone microstructure. However, their drawbacks are also prominent: they are extremely expensive and require daily subcutaneous injections, causing inconvenience and pain for patients, severely impacting the convenience and long-term adherence to medication; furthermore, due to safety concerns (an increased risk of osteosarcoma has been observed in animal studies), the course of treatment is usually limited to 18-24 months, limiting its long-term efficacy. In recent years, drugs with dual mechanisms of action (such as romosomab) have also been marketed, which promote bone formation while moderately inhibiting bone resorption, showing significant effects. However, due to the potential increase in cardiovascular event risk, their use is limited in patients with a relevant medical history, further highlighting the challenge of balancing efficacy and safety with existing drugs. Summary of the Invention

[0004] Purpose of the invention: The technical problem to be solved by the present invention is to address the shortcomings of the prior art by providing a sustained-release oral powder for the treatment of osteoporosis and its preparation method. The powder has excellent therapeutic effects, biocompatibility and sustained-release characteristics, and can effectively promote osteoblast differentiation, inhibit osteoclast activity, and reverse the decline in bone density. It is suitable for the treatment of osteoporosis, fractures and other bone diseases.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A sustained-release oral powder for the treatment of osteoporosis, comprising the following components in parts by weight:

[0007] Two portions of supramolecular metal-organic framework (sMOF) material;

[0008] 0.8-1.0 parts of microcrystalline cellulose;

[0009] Magnesium stearate 0.1-0.2;

[0010] Among them, the supramolecular metal-organic framework material sMOF is made of Sr 2+ Mg 2+ It is formed by coordination self-assembly with alendronate (ALN), fructose sodium 1,6-bisphosphate (FDP), and casein phosphopeptide (CPP).

[0011] Specifically, the supramolecular metal-organic framework material sMOF is prepared through the following steps:

[0012] S1. Preparation of organic ligand solution:

[0013] Alendronate (ALN) and fructose 1,6-bisphosphate sodium salt (FDP) were dissolved in N,N-dimethylformamide (DMF) to obtain ligand solution A; casein phosphopeptide (CPP) was dissolved in water to obtain ligand solution B.

[0014] S2. Preparation of metal salt solutions:

[0015] Soluble strontium salt and soluble magnesium salt are dissolved in water to obtain solution C;

[0016] Self-assembly synthesis of S3 and sMOF:

[0017] Under nitrogen protection, the ligand solution A obtained in step S1 is slowly added dropwise to the solution C obtained in step S2 while stirring. After the addition is complete, the ligand solution B is slowly added dropwise. After the reaction is complete, the precipitate is collected by centrifugation, washed and dried to obtain the final product.

[0018] Further, in step S1, the concentration of alendronic acid (ALN) in ligand solution A is 0.1-0.2 mol / L, and the concentration of fructose sodium 1,6-bisphosphate (FDP) is 0.05-0.1 mol / L.

[0019] Furthermore, in step S1, the concentration of casein phosphopeptide (CPP) in ligand solution B is 0.2-0.4 g / L.

[0020] Further, in step S2, the soluble strontium salt is preferably SrCl2·6H2O; the soluble magnesium salt is preferably MgCl2·6H2O.

[0021] The molar ratio of SrCl2·6H2O to MgCl2·6H2O is 1:1 to 1:3.

[0022] Furthermore, in step S2, the total concentration of soluble strontium salt and soluble magnesium salt in solution C is 0.05-0.20 mol / L.

[0023] Further, in step S3, the volume ratio of ligand solution A, ligand solution B and solution C is (5-10):(1-3):1.

[0024] Further, in step S3, ligand solution A is added to solution C at a dropping rate of 0.5-1% v / v / min, and the stirring speed is 240-300 rpm.

[0025] Furthermore, in step S3, after the ligand solution A is added dropwise, the pH of the system is adjusted to 7.0-8.0, and the reaction is carried out at 40-60℃ for 4-8 h; after the ligand solution B is added dropwise, the reaction is carried out for another 8-12 h.

[0026] Furthermore, in step S3, after the reaction is complete, the mixture is washed alternately with pure water and ethanol, and then vacuum dried at 60℃-70℃ for 14-16 h.

[0027] Furthermore, the present invention also claims a method for preparing a sustained-release oral powder for treating osteoporosis, wherein supramolecular metal-organic framework material sMOF, microcrystalline cellulose and magnesium stearate are mixed evenly in a mass ratio of 2:(0.8-1.0):(0.1-0.2) to obtain the powder.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] (1) Multi-component synergistic therapy and structural innovation: creatively combining osteoclast-inhibiting ALN with osteogenic-promoting Sr 2+ Mg 2+FDP and CPP are integrated into a single sMOF structure. This achieves "bidirectional regulation" of bone metabolism: it inhibits excessive bone resorption while simultaneously promoting new bone formation, overcoming the limitations of single-drug therapy (such as bisphosphonates that only inhibit resorption or parathyroid hormone that only promotes bone formation). Through synergistic effects across multiple pathways, it is expected to achieve better bone mineral density enhancement at lower doses, thereby significantly reducing the risk of osteonecrosis of the mandible and atypical femoral fractures caused by long-term, high-dose bisphosphonate use, providing a safer and more comprehensive strategy for osteoporosis treatment.

[0030] (2) sMOF framework enables intelligent sustained release and bone-targeted delivery: sMOF has a stable framework structure, and ALN and FDP are natural bone-targeting groups. This structure protects the active pharmaceutical ingredient from immediate and complete disintegration in the gastrointestinal tract. The CPP encapsulated on the sMOF is transformed into zwitterionic nanoparticles by intestinal proteases, which are then recognized and transported to cross the epithelial barrier. The ALN and FDP dual ligand Sr... 2+ Mg 2+ The dual-center physiologically active MOF is delivered into the bloodstream. Simultaneously, with the "dual navigation" effect of ALN and FDP, the MOF preferentially accumulates in bone tissue, achieving targeted drug delivery. This significantly improves the effective drug concentration in bone after oral administration, solving the problems of poor targeting and insufficient bone tissue concentration in traditional oral drugs, while reducing exposure to non-target organs and lowering systemic side effects.

[0031] (3) The preparation process is simple, mild, green, and economical, with significant advantages for industrialization: It adopts aqueous coordination self-assembly technology, and the reaction conditions are mild and controllable. The entire synthesis process does not require complex equipment or harsh conditions, making it easy to achieve large-scale production and ensuring the stability and quality uniformity of product batches. The low production cost and stable product quality make this innovative therapy more economical and accessible, and it is expected to become a cost-effective clinical drug that benefits a large number of osteoporosis patients. Attached Figure Description

[0032] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0033] Figure 1 The image shows a scanning electron microscope (SEM) image of the sMOF powder prepared in Example 2.

[0034] Figure 2 The results show the effects of oral powders from Examples 1-3 and Comparative Examples 1-3 on osteoblast proliferation.

[0035] Figure 3The results of cytotoxicity experiments after treating Caco-2 cells, HepG2 cells, and NIH3T3 cells with oral powders of Examples 1-3 and Comparative Examples 1-3 are shown.

[0036] Figure 4 The results show the effects of oral powders from Examples 1-3 and Comparative Examples 1-3 on bone and serum calcium levels in mice.

[0037] Figure 5 The results show the effects of oral powders from Examples 1-3 and Comparative Examples 1-3 on bone P and serum P levels in mice.

[0038] Figure 6 The results show the effects of oral powders from Examples 1-3 and Comparative Examples 1-3 on bone Sr and serum Sr levels in mice.

[0039] Figure 7 The results show the effects of oral powders from Examples 1-3 and Comparative Examples 1-3 on bone Mg and serum Mg levels in mice. Detailed Implementation

[0040] The present invention can be better understood from the following embodiments.

[0041] Example 1

[0042] 1. Accurately weigh alendronic acid (ALN) and fructose 1,6-bisphosphate sodium salt (FDP), dissolve them in an appropriate amount of N,N-dimethylformamide (DMF) to make the ALN concentration 0.15 mol / L and the FDP concentration 0.075 mol / L, and stir until completely dissolved to obtain ligand solution A; accurately weigh casein phosphopeptide (CPP), dissolve it in ultrapure water to make the CPP concentration 0.3 g / L, and stir until completely dissolved to obtain ligand solution B; accurately weigh SrCl2·6H2O and MgCl2·6H2O, dissolve them in ultrapure water to make the SrCl2·6H2O concentration 0.05 mol / L and the MgCl2·6H2O concentration 0.10 mol / L, and stir until completely dissolved to obtain solution C.

[0043] 2. Under nitrogen protection and at 50°C, 80 mL of ligand solution A was added dropwise to 10 mL of solution C at a rate of 0.08 mL / min while stirring at 280 rpm. After the addition was complete, the pH was adjusted to 7.5, and the reaction continued for 6 hours. 20 mL of ligand solution B was then added dropwise to the above reaction solution at the same rate. After the addition was complete, the temperature and stirring were maintained, and the reaction continued for another 10 hours. After the reaction was complete, the precipitate was collected by centrifugation. The precipitate was washed alternately with ultrapure water and anhydrous ethanol. The washed precipitate was then vacuum-dried at 65°C for 15 hours to obtain sMOF powder.

[0044] 3. Mix sMOF powder with microcrystalline cellulose and magnesium stearate in a mass ratio of 2:0.9:0.15 to prepare sustained-release oral powder A for the treatment of osteoporosis.

[0045] Example 2

[0046] 1. Accurately weigh ALN and FDP, dissolve them in an appropriate amount of DMF to make the concentration of ALN 0.1 mol / L and the concentration of FDP 0.1 mol / L, and stir until completely dissolved to obtain ligand solution A; accurately weigh CPP, dissolve it in ultrapure water to make the concentration of CPP 0.2 g / L, and stir until completely dissolved to obtain ligand solution B; accurately weigh SrCl2·6H2O and MgCl2·6H2O, dissolve them in ultrapure water to make the concentration of SrCl2·6H2O 0.025 mol / L and the concentration of MgCl2·6H2O 0.025 mol / L, and stir until completely dissolved to obtain solution C.

[0047] 2. Under nitrogen protection and at 40°C, 100 mL of ligand solution A was added dropwise to 20 mL of solution C at a rate of 0.1 mL / min while stirring at 240 rpm. After the addition was complete, the pH was adjusted to 7.0, and the reaction continued for 8 hours. Then, 20 mL of ligand solution B was added dropwise to the above reaction solution at the same rate. After the addition was complete, the temperature and stirring were maintained, and the reaction continued for another 8 hours. After the reaction was complete, the precipitate was collected by centrifugation. The precipitate was washed alternately with ultrapure water and anhydrous ethanol. The washed precipitate was then vacuum-dried at 60°C for 14 hours to obtain sMOF powder. (See below) Figure 1 These are irregular particles with a particle size range of 50-400 nm.

[0048] 3. Mix sMOF powder with microcrystalline cellulose and magnesium stearate in a mass ratio of 2:1:0.1 to prepare sustained-release oral powder B for the treatment of osteoporosis.

[0049] Example 3

[0050] 1. Accurately weigh ALN and FDP, dissolve them in an appropriate amount of DMF to make the concentration of ALN 0.2 mol / L and the concentration of FDP 0.05 mol / L, and stir until completely dissolved to obtain ligand solution A; accurately weigh CPP, dissolve it in ultrapure water to make the concentration of CPP 0.4 g / L, and stir until completely dissolved to obtain ligand solution B; accurately weigh SrCl2·6H2O and MgCl2·6H2O, dissolve them in ultrapure water to make the concentration of SrCl2·6H2O 0.05 mol / L and the concentration of MgCl2·6H2O 0.15 mol / L, and stir until completely dissolved to obtain solution C.

[0051] 2. Under nitrogen protection and at 60°C, 150 mL of ligand solution A was added dropwise to 15 mL of solution C at a rate of 0.15 mL / min while stirring at 300 rpm. After the addition was complete, the pH was adjusted to 8.0, and the reaction continued for 4 h. 45 mL of ligand solution B was then added dropwise to the above reaction solution at the same rate. After the addition was complete, the temperature and stirring were maintained, and the reaction continued for another 12 h. After the reaction was complete, the precipitate was collected by centrifugation. The precipitate was washed alternately with ultrapure water and anhydrous ethanol. The washed precipitate was then vacuum-dried at 70°C for 16 h to obtain sMOF powder.

[0052] 3. Mix sMOF powder with microcrystalline cellulose and magnesium stearate in a mass ratio of 2:0.8:0.2 to prepare sustained-release oral powder C for the treatment of osteoporosis.

[0053] Comparative Example 1 (without CPP ligand)

[0054] 1. Accurately weigh ALN and FDP, dissolve them in an appropriate amount of DMF to make the concentration of ALN 0.15 mol / L and the concentration of FDP 0.075 mol / L, and stir until completely dissolved to obtain ligand solution A; accurately weigh SrCl2·6H2O and MgCl2·6H2O, dissolve them in ultrapure water to make the concentration of SrCl2·6H2O 0.05 mol / L and the concentration of MgCl2·6H2O 0.10 mol / L, and stir until completely dissolved to obtain solution C.

[0055] 2. Under nitrogen protection and at 50°C, 80 mL of ligand solution A was added dropwise to 10 mL of solution C at a rate of 0.08 mL / min while stirring at 280 rpm. After the addition was complete, the pH was adjusted to 7.5, and the reaction continued for 6 hours. 20 mL of water was then added dropwise to the reaction solution at the same rate. After the addition was complete, the temperature and stirring were maintained, and the reaction continued for another 10 hours. After the reaction was complete, the precipitate was collected by centrifugation. The precipitate was washed alternately with ultrapure water and anhydrous ethanol. The washed precipitate was then vacuum-dried at 65°C for 15 hours to obtain MOF powder.

[0056] 3. Mix MOF powder with microcrystalline cellulose and magnesium stearate in a mass ratio of 2:0.9:0.15 to prepare oral powder D.

[0057] Comparative Example 2 (without Mg) 2+ )

[0058] 1. Accurately weigh ALN and FDP, dissolve them in an appropriate amount of DMF to make the ALN concentration 0.15 mol / L and the FDP concentration 0.075 mol / L, and stir until completely dissolved to obtain ligand solution A; accurately weigh CPP, dissolve it in ultrapure water to make the CPP concentration 0.3 g / L, and stir until completely dissolved to obtain ligand solution B; accurately weigh SrCl2·6H2O, dissolve it in ultrapure water to make the SrCl2·6H2O concentration 0.15 mol / L, and stir until completely dissolved to obtain solution C.

[0059] 2. Under nitrogen protection and at 50°C, 80 mL of ligand solution A was added dropwise to 10 mL of solution C at a rate of 0.08 mL / min while stirring at 280 rpm. After the addition was complete, the pH was adjusted to 7.5, and the reaction continued for 6 hours. 20 mL of ligand solution B was then added dropwise to the above reaction solution at the same rate. After the addition was complete, the temperature and stirring were maintained, and the reaction continued for another 10 hours. After the reaction was complete, the precipitate was collected by centrifugation. The precipitate was washed alternately with ultrapure water and anhydrous ethanol. The washed precipitate was then vacuum-dried at 65°C for 15 hours to obtain sMOF powder.

[0060] 3. Mix sMOF powder with microcrystalline cellulose and magnesium stearate in a mass ratio of 2:0.9:0.15 to prepare oral powder E.

[0061] Comparative Example 3 (Physical Mixture)

[0062] Accurately weigh 29.77g ALN, 25.68g FDP, 0.06g CPP, 1.33g SrCl2·6H2O and 2.03g MgCl2·6H2O, then add 26.49g microcrystalline cellulose and 4.42g magnesium stearate, grind and mix thoroughly to prepare oral powder F.

[0063] Experimental Example 1: Osteoblast Proliferation Experiment

[0064] The oral powders from Examples 1-3 and Comparative Examples 1-3 were treated with artificial intestinal fluid and then used to treat MC3T3-E1 mouse embryonic osteoblasts. The proliferation of MC3T3-E1 cells was observed after 72 hours, and the results were as follows: Figure 2 As shown.

[0065] It can be seen that the sMOF oral powders prepared in Examples 1, 2, and 3 showed a significant effect in promoting the proliferation of MC3T3-E1 cells, while the comparative examples 1, 2, and 3 showed a slight improvement but no statistical difference. The core mechanism of this significant difference lies in the fact that the complete sMOF system constructed in this invention achieves multi-level functional integration of "efficient absorption - systemic circulation - bone-targeted enrichment - sustained-release synergy".

[0066] The complete sMOF structure is composed of Sr2+ Mg 2+ Formed through coordination self-assembly with ALN, FDP, and CPP, its stable framework protects active ingredients like ALN from premature degradation in a simulated intestinal environment. The outer CPP layer is converted into zwitterionic nanoparticles by proteases, significantly improving the efficiency of sMOFs in crossing the intestinal epithelial barrier and solving the fundamental problem of low oral bioavailability of ALN. Upon entering systemic circulation, the inherent ALN and FDP in the framework act as natural bone-targeting ligands, playing a "dual-navigation" role, guiding sMOFs to actively accumulate in the bone tissue microenvironment. Here, sMOFs slowly disintegrate, continuously and synergistically releasing Sr. 2 + Mg 2+ It directly promotes osteoblast differentiation and mineralization. The released ALN inhibits osteoclast activity to create a favorable osteogenic microenvironment, while FDP provides cellular energy metabolism support, thereby achieving multi-pathway synergistic stimulation of osteoblast proliferation.

[0067] In contrast, Comparative Example 1 lacked CPP, a key absorption-enhancing component, resulting in low intestinal absorption efficiency despite the formation of sMOF, preventing the active ingredients from effectively reaching target cells; Comparative Example 2 lacked Mg. 2+ This not only weakened its osteogenic promoting effect but may also affect the integrity of the sMOF structure, thereby impairing its sustained-release and delivery function. Comparative Example 3 was merely a physical mixture of the components and completely lacked the structural integration, absorption promotion, targeted delivery, and sustained-release characteristics of sMOF. The components were rapidly dispersed and metabolized in vivo, failing to form an effective concentration locally in cells. Therefore, the proliferative effects of the comparative examples were not significant.

[0068] In summary, the osteoblast proliferation experimental data strongly confirm that the superior osteogenic activity of the sMOF oral powder of this invention does not originate from the simple sum of its components, but rather is highly dependent on the construction of a multifunctional integrated platform centered on sMOF. This platform successfully integrates CPP (promoting absorption), ALN / FDP (for bone-targeted delivery), and Sr (for synergistic osteogenic growth with metal ions). 2+ / Mg 2+ It has multiple advantages, such as intelligent sustained-release, thereby achieving a highly efficient and synergistic osteogenic effect at the cellular level.

[0069] Experimental Example 2: Cytotoxicity Experiment

[0070] Caco-2 cells, HepG2 cells, and NIH3T3 cells were treated with the oral powders of Examples 1-3 and Comparative Examples 1-3 at a concentration of 100 μg / ml, respectively, to verify whether the oral powders had cytotoxic effects on gastrointestinal epithelial cells, hepatocytes, etc. The results are as follows: Figure 3 As shown.

[0071] As can be seen, at a concentration of 100 μg / mL, after treating Caco-2 cells (human colon cancer cells, simulating intestinal epithelial cells), HepG2 cells (human liver cancer cells, simulating hepatocytes), and NIH3T3 cells (mouse fibroblasts, simulating normal tissue cells) with the oral powders of Examples 1-3 and Comparative Examples 1-3, the survival rate of each group of cells was not significantly different from that of the control group (p>0.05), no abnormal cell morphology was observed, and no obvious apoptosis or necrosis was observed.

[0072] This indicates that, within the experimental concentration range, none of the oral powder samples showed significant cytotoxicity to gastrointestinal epithelial cells, hepatocytes, or normal tissue cells, demonstrating good in vitro biocompatibility and safety.

[0073] Experiment Example 3: Animal Experiment

[0074] Osteoporosis model was created using 3-month-old female C57BL / 6 mice by surgically removing both ovaries. All mice were divided into eight groups: control group, model group (retinoic acid 150 mg / kg / day), Example 1 group (retinoic acid 150 mg / kg / day + oral powder A, 10 mg / kg / day), Example 2 group (retinoic acid 150 mg / kg / day + oral powder B, 10 mg / kg / day), Example 3 group (retinoic acid 150 mg / kg / day + oral powder C, 10 mg / kg / day), Comparative Example 1 group (retinoic acid 150 mg / kg / day + oral powder D, 10 mg / kg / day), Comparative Example 2 group (retinoic acid 150 mg / kg / day + oral powder E, 10 mg / kg / day), and Comparative Example 3 group (retinoic acid 150 mg / kg / day + oral powder F, 10 mg / kg / day). During the experiment, animals were given free access to food and water, and were weighed every 2 days to adjust the dosage. On day 30, animals were fasted for 12 hours, their eyeballs were enucleated to collect blood and separate serum. After euthanasia, the animals were dissected, and both femurs of the mice were harvested. After removing muscles and other soft tissues, the femurs were dried at 105℃ to constant weight. The dry weight of the bones was measured using an analytical balance, and the bone length was measured using calipers. The results are shown in Table 1. The bones (femurs) and serum were digested with a mixed acid (nitric acid:perchloric acid = 4:1), and the contents of Ca, P, Sr, and Mg were determined using ICP-OES. The results are as follows: Figures 4-7 .

[0075] Table 1: Measurement of femur length and mass in mice

[0076]

[0077] According to animal experimental data (Table 1), the sMOF oral powder prepared in Examples 1-3 of this invention can significantly restore femoral bone mass in osteoporosis model mice, bringing it close to or even exceeding that of the normal control group, indicating that it has a clear effect on improving bone density and protecting skeletal structure. This excellent therapeutic effect stems from the multi-component synergy and intelligent delivery mechanism of the sMOF system: among which Sr 2+ and Mg 2+ Synergistically promoting osteoblast differentiation, ALN effectively inhibits osteoclast activity; more importantly, the structural design of sMOF enables highly efficient "absorption-targeting" delivery: the outer CPP layer is acted upon by proteases in the intestine, transforming sMOF particles into zwitterionic nanoparticles that are easily recognized and transported, thereby significantly improving their ability to cross the intestinal epithelial barrier; after entering the circulatory system, ALN and FDP in the framework play a "dual navigation" role with their natural bone affinity, actively enriching the active ingredients in bone tissue.

[0078] In contrast, the effects of the control groups were significantly reduced. Control group 1 (without CPP) lacked the key absorption-enhancing effect mediated by CPP, resulting in decreased systemic bioavailability of sMOFs. Even with the bone-targeting potential of ALN and FDP, it could not achieve effective concentrations in bone tissue; Control group 2 (without Mg...) 2+ Due to the lack of Mg 2+ The nodal role of CPP in sMOF leads to structural instability, hindering subsequent effective delivery and weakening its bone-forming ability. Comparative Example 3 (physical mixture), due to its simple mixing of components, lacks both the structural absorption-promoting function of CPP and the integration and sustained-release protection of ALN / FDP within the sMOF framework, resulting in no significant difference in efficacy compared to the model group. These comparative results demonstrate that the absorption-promoting effect of CPP, the targeting of ALN / FDP to bone tissue, and the integration and sustained-release of multiple components within the sMOF framework are all indispensable, collectively constituting the core advantage of this invention for the highly effective treatment of osteoporosis.

[0079] according to Figures 4-7Based on animal experimental data, the sMOF oral powder prepared in Examples 1-3 of this invention exhibited a comprehensive and excellent regulatory effect on calcium (Ca), phosphorus (P), strontium (Sr), and magnesium (Mg) metabolism in bone and serum of osteoporosis model mice. Regarding bone mineralization, the bone Ca (295.87–320.13 mg / g) and bone P (180.14–184.67 mg / g) levels in the example groups were restored to levels close to or exceeding those of the normal control group. Simultaneously, serum Ca (1.98–2.27 mg / dL) and serum P (1.91–2.04 mg / dL) were significantly reduced and returned to normal ranges, indicating that sMOF can effectively inhibit osteoclast differentiation, thereby inhibiting mineral loss caused by bone resorption and promoting the redeposition of calcium and phosphorus in bone tissue. This effect is attributed to the multiple synergistic mechanisms of sMOF: ALN inhibits osteoclast activity and reduces bone salt breakdown; Sr… 2+ With Mg 2+ It directly stimulates osteoblast differentiation and mineralization; and the structural integrity of sMOF not only protects the active ingredients, but also allows the CPP on its surface to be converted into zwitterionic nanoparticles after action by intestinal proteases, significantly improving the efficiency of crossing the intestinal epithelial barrier. 2+ With Mg 2+ The high enrichment in bone also indicates that after sMOF enters the systemic circulation, ALN and FDP in the skeleton play a "dual navigation" role due to their high affinity for bone tissue, targeting and delivering active components to the bone site, thereby achieving enrichment of elements in bone and normalization of serum indicators.

[0080] Of particular note was the specific and significant increase in bone Sr (271.22–285.09 mg / g) and bone Mg (7.02–8.92 mg / g) levels in the example group, while serum Sr and Mg remained at reasonable levels. This confirms that Sr in sMOFs... 2+ With Mg 2+ Not only can it be effectively absorbed and enter the circulation, but it can also be precisely deposited in bone tissue through a targeted delivery system, exerting its physiological functions of promoting bone formation and increasing bone density. In contrast, the comparative groups showed a significant decrease in efficacy due to the absence of different links. Comparative Example 1 (without CPP) lacked the CPP-mediated intestinal absorption enhancement effect, resulting in decreased systemic bioavailability. Although it retained the bone-targeting potential of ALN and FDP, the bone Ca, P, Sr, and Mg contents were still significantly lower than those in the example group, while serum Ca and P were higher, indicating that the drug could not be effectively delivered to the target site. A large amount of Ca and P accumulated in the blood, which also shows that ALN did not show a good effect in inhibiting bone resorption, which is consistent with the poor oral bioavailability of ALN. Comparative Example 2 (without Mg 2+ Not only is Mg missing 2+The osteogenic promoting effect of sMOF may be affected by impaired structural stability, which may affect its overall delivery and release behavior. As a result, the bone Ca, P, and Mg contents were among the lowest in all groups, and the bone Sr enrichment was also significantly reduced. Comparative Example 3 (physical mixture) completely lacked the structural integration, sustained-release protection, and targeted delivery functions of sMOF. Its components were rapidly dispersed and metabolized in vivo, and the contents of each element in its bone were even lower than those in the model group. No improvement was observed in serum indicators, and the therapeutic effect was negligible.

[0081] In summary, the data on the distribution of the four elements in bone and serum fully demonstrate that the efficacy of the sMOF oral powder of this invention is highly dependent on the structural integrity and component synergy of its overall functional platform. CPP ensures efficient absorption, ALN and FDP achieve precise bone targeting, and Sr... 2+ With Mg 2+ The sMOF framework provides osteogenic activity and structural centers, and integrates these components in an orderly manner, achieving sustained release, protection, and synergistic delivery. The absence of any key component or structural feature will lead to the functional breakdown of this integrated system, significantly reducing its efficacy in regulating bone mineral metabolism and treating osteoporosis. This further highlights the innovation and superiority of the sMOF-based multi-component, multi-functional integrated strategy in overcoming the limitations of existing drugs.

[0082] This invention provides a sustained-release oral powder for treating osteoporosis and a method for preparing the same. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A sustained-release oral powder for treating osteoporosis, characterized in that, Includes the following components by parts by mass: Two portions of supramolecular metal-organic framework (sMOF) material; 0.8-1.0 parts of microcrystalline cellulose; Magnesium stearate 0.1-0.2; Among them, the supramolecular metal-organic framework material sMOF is made of Sr 2+ Mg 2+ It is formed by coordination self-assembly with alendronic acid, fructose 1,6-bisphosphate sodium salt and casein phosphopeptide; The supramolecular metal-organic framework (sMOF) material was prepared by the following steps: S1. Preparation of organic ligand solution: Alendronic acid and fructose 1,6-bisphosphate sodium salt were dissolved in N,N-dimethylformamide to obtain ligand solution A; casein phosphopeptide was dissolved in water to obtain ligand solution B. S2. Preparation of metal salt solutions: Soluble strontium salt and soluble magnesium salt are dissolved in water to obtain solution C; Self-assembly synthesis of S3 and sMOF: Under nitrogen protection, the ligand solution A obtained in step S1 is slowly added dropwise to the solution C obtained in step S2 while stirring. After the addition is complete, the ligand solution B is slowly added dropwise. After the reaction is complete, the precipitate is collected by centrifugation, washed, and dried to obtain the final product. In step S3, after ligand solution A is added dropwise, the pH of the system is adjusted to 7.0-8.0, and the reaction is carried out at 40-60℃ for 4-8 h; after ligand solution B is added dropwise, the reaction is carried out for another 8-12 h.

2. The sustained-release oral powder for treating osteoporosis according to claim 1, characterized in that, In step S1, the concentration of alendronate in ligand solution A is 0.1-0.2 mol / L, and the concentration of sodium fructose 1,6-bisphosphate is 0.05-0.1 mol / L; the concentration of casein phosphopeptide in ligand solution B is 0.2-0.4 g / L.

3. The sustained-release oral powder for treating osteoporosis according to claim 1, characterized in that, In step S2, the soluble strontium salt is SrCl2·6H2O; the soluble magnesium salt is MgCl2·6H2O. The molar ratio of SrCl2·6H2O to MgCl2·6H2O is 1:1 to 1:

3.

4. The sustained-release oral powder for treating osteoporosis according to claim 1, characterized in that, In step S2, the total concentration of soluble strontium salt and soluble magnesium salt in solution C is 0.05-0.20 mol / L.

5. The sustained-release oral powder for treating osteoporosis according to claim 1, characterized in that, In step S3, the volume ratio of ligand solution A, ligand solution B, and solution C is (5-10):(1-3):

1.

6. The sustained-release oral powder for treating osteoporosis according to claim 1, characterized in that, In step S3, ligand solution A is added to solution C at a dropping rate of 0.5-1% v / v / min, and the stirring speed is 240-300 rpm.

7. The sustained-release oral powder for treating osteoporosis according to claim 1, characterized in that, In step S3, after the reaction is complete, the mixture is washed alternately with pure water and ethanol, and then vacuum dried at 60℃-70℃ for 14-16 h.

8. The method for preparing the sustained-release oral powder for treating osteoporosis according to claim 1, characterized in that, The supramolecular metal-organic framework material (sMOF), microcrystalline cellulose, and magnesium stearate are mixed evenly in a mass ratio of 2:(0.8-1.0):(0.1-0.2) to obtain the final product.

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