Composition with osteogenesis effect as well as preparation method and application thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a composition with an osteogenesis effect, which is prepared from the following raw materials in parts by weight: 15-45 parts of magnetic nanoparticles and 2-10 parts of aspartatide. According to the invention, the magnetic nanoparticles and the aspartatide are combined, and the nanoparticles magnetized in a magnetic field are coupled with the aspartatide, so that thickening of local alveolar bone can be promoted, and an excellent alveolar bone osteogenesis effect is achieved. The magnetic nanoparticles and the aspartatide are coupled and then act on the alveolar bone through hydrogel wrapping, the slow release effect can be achieved, the concentration of active ingredients in a treatment window is maintained, the curative effect is improved, the unstable curative effect caused by medicine concentration fluctuation is reduced, meanwhile, the administration frequency is reduced, the medication compliance of a patient is improved, and the treatment effect of the alveolar bone is improved. The practical popularization and application value is realized.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, in particular to a composition with osteogenesis effect and its preparation method and use. BACKGROUND

[0002] The jaw plays an important role in maintaining facial shape and performing mastication function. Jaw atrophy or defect caused by trauma, infection, cyst, tumor, radiation osteonecrosis, developmental defects, etc. not only directly leads to facial deformity, but also causes serious functional disorders, bringing physiological, psychological, social and other damages to patients. Jaw defect repair and reconstruction is a common and difficult problem in oral surgery and has been one of the hot research topics.

[0003] For clinical jaw atrophy or defect, only surgical method, i.e. bone grafting, can be taken. Although autologous bone grafts usually have good biocompatibility and bone integration ability, in the case of insufficient bone mass or limited bone mass in the donor area, it is often necessary to cause more surgical trauma to obtain sufficient autologous bone. Moreover, the integration process of autologous bone may be affected by the patient's overall condition (such as diabetes, smoking, etc.), thereby affecting bone healing and graft stability. Any type of bone graft surgery can cause postoperative complications, including infection, bleeding, hematoma, nerve injury (such as inferior alveolar nerve injury), excessive absorption, etc. Especially in the case of severe atrophy, the bone in the surgical area is relatively fragile, and postoperative healing may be relatively slow, and the risk of complications increases. Abaloparatide is a new type of parathyroid hormone-related peptide (PTHrP) developed by Radius Health Company, which is a powerful selective activator of PTH-I receptor, can increase bone mineral content, bone density and bone strength, promote bone formation, and has been approved for marketing by FDA, with the trade name Tymlos. Abaloparatide is injected subcutaneously and used for treating postmenopausal women at risk of bone fracture or ineffective to other treatment drugs for osteoporosis, which can effectively reduce the incidence of new vertebral and non-vertebral fractures.

[0004] Magnetic nanoparticles are nanoscale solid particles composed of magnetic materials (such as iron oxide, ferrite, metallic magnetic material, etc.), at least one dimension of which is in the nanometer range (0-100 nanometers). Due to its large specific surface area, relatively high saturation magnetic moment and easy functionalization on the surface, it is widely used in protein or enzyme immobilization, targeted drug delivery, cell separation, medical imaging, etc. Studies have shown that magnetic nanoparticles can significantly promote the proliferation of bone marrow mesenchymal stem cells, and under the action of an external magnetic field, these particles can promote bone tissue regeneration.

[0005] There is no research on the combination of magnetic nanoparticles and abaloparatide for the treatment of alveolar bone osteogenesis. SUMMARY

[0006] To solve the above problems, the present application provides a composition with osteogenesis, which is composed of raw materials in the following weight parts: magnetic nanoparticles 15-45 parts, abaloparatide 2-10 parts.

[0007] Further, it is composed of raw materials in the following weight parts: magnetic nanoparticles 15 parts, abaloparatide 2 parts.

[0008] Further, the magnetic nanoparticles are ferroferric oxide nanoparticles.

[0009] The present application also provides a use of the aforementioned composition in the preparation of a drug for promoting osteogenesis.

[0010] Further, the drug is a drug for promoting jaw bone osteogenesis; the jaw bone includes alveolar bone.

[0011] Further, the drug is a preparation prepared by taking the aforementioned composition as an active ingredient and adding a pharmaceutically acceptable excipient; The preparation is a solution, a powder, a paste, a gel, an aerosol or a spray; The gel includes a hydrogel.

[0012] The present application is a hydrogel for promoting osteogenesis, which is prepared from raw materials in the following parts: magnetic nanoparticles 15-45 parts by weight, abaloparatide 2-10 parts by weight, carboxymethyl chitosan 90-270 parts by weight, aldehyde polyethylene glycol aldehyde group 60-180 parts by weight, water 1-5 parts by volume.

[0013] Further, it is prepared from raw materials in the following parts: magnetic nanoparticles 15 parts by weight, abaloparatide 2 parts by weight, carboxymethyl chitosan 90 parts by weight, aldehyde polyethylene glycol aldehyde group 60 parts by weight, water 1.3 parts by volume.

[0014] The present application also provides a preparation method of the aforementioned hydrogel, which comprises the following steps: 1) Take the raw materials according to the ratio, take the aldehyde polyethylene glycol aldehyde group, dissolve in water to get liquid A; take the magnetic nanoparticles and abaloparatide, dissolve in liquid A to get liquid B; 2) Take carboxymethyl chitosan, dissolve in water to get liquid C; 3) Mix liquid B and liquid C evenly, and get it.

[0015] The present application finally provides a use of the aforementioned hydrogel in the preparation of a drug for promoting osteogenesis, which is a drug for promoting osteogenesis of a jawbone; the jawbone includes alveolar bone.

[0016] The present application has the following beneficial effects: The present application combines magnetic nanoparticles and abaloparatide, and the nanoparticles magnetized in a magnetic field are coupled with abaloparatide, thereby promoting the thickening of local alveolar bone and achieving excellent effects of promoting alveolar bone osteogenesis. After the magnetic nanoparticles and abaloparatide are coupled, the hydrogel is used for alveolar bone through encapsulation, and the effect of sustained release can be achieved, the concentration of the active ingredient in the therapeutic window is maintained, the efficacy is improved, the efficacy instability caused by fluctuations in drug concentration is reduced, the frequency of drug administration is reduced, and the compliance of patients is improved.

[0017] Animal experiments prove that abaloparatide coupled with ferroferric oxide hydrogel produces qualitative changes in osteogenesis compared with either abaloparatide or ferroferric oxide alone, and further analysis of the bone trabecular structure parameters of the alveolar bone defect area determines that abaloparatide coupled with ferroferric oxide hydrogel produces a synergistic effect in repairing alveolar bone defects, and has practical popularization and application value.

[0018] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and conventional means in the art, other various forms of modifications, replacements or changes can be made without departing from the above basic technical ideas of the present application.

[0019] The above content of the present application will be further described in detail through the specific embodiments in the form of examples. However, this should not be understood as limiting the scope of the above subject matter of the present application to the following examples. Any technology achieved based on the above content of the present application belongs to the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 Micro-cT images of rat jawbone containing abaloparatide nanoparticle hydrogel; Figure 2 Bone structure in the region of interest; Figure 3 Tb.Th (trabecular thickness), BV / TV (bone volume fraction), and Tb.N (trabecular number) of each group in the region of interest. DETAILED DESCRIPTION

[0021] The raw materials, reagents and equipment used in the specific embodiments of the present application are all commercially available.

[0022] Example 1: Preparation of the hydrogel of the present application Formula: Aldehyde-based polyethylene glycol aldehyde (CHO-PEG-CHO) 60mg, iron oxide nanoparticles 15mg, abalopeptide 2mg, carboxymethyl chitosan 90mg, water 1.3mL; Preparation method: 1) Dissolve CHO-PEG-CHO in 1 mL of water to obtain liquid A; dissolve iron oxide nanoparticles and abalopeptide in liquid A to obtain liquid B; 2) Dissolve carboxymethyl chitosan in 0.3 mL of water to obtain liquid C; 3) Mix liquid B and liquid C thoroughly to obtain the final product.

[0023] The following experimental examples further illustrate the beneficial effects of the present invention: Experimental Example 1: Study on the osteogenic hydrogel of the present invention 1. Investigational drug PBS buffer: Commercially available PBS buffer with a pH of 7.4; Abalopeptide-coupled ferric oxide hydrogel: prepared according to Example 1; Abalopeptide hydrogel: ① Dissolve 60 mg of CHO-PEG-CHO in 1 mL of water to obtain liquid A; dissolve 2 mg of abalopeptide in liquid A to obtain liquid B; ② Dissolve 90 mg of carboxymethyl chitosan in 0.3 mL of water to obtain liquid C; mix liquid B and liquid C to obtain the final product. Ferric oxide nanoparticle hydrogel: ① Dissolve 60 mg of CHO-PEG-CHO in 1 mL of water to obtain liquid A; dissolve 15 mg of ferric oxide nanoparticles in liquid A to obtain liquid B; ② Dissolve 90 mg of carboxymethyl chitosan in 0.3 mL of water to obtain liquid C; mix liquid B and liquid C to obtain the final product. 2. Osteogenic efficacy test 2.1 Test Methods Twenty healthy male SD rats aged 8 weeks were randomly divided into four groups with free access to water and food. The rats were placed under a static magnetic field: a control group (locally injected with PBS), a group locally injected with abalopeptide hydrogel, a group locally injected with iron oxide nanoparticle hydrogel, and a group locally injected with abalopeptide-coupled iron oxide hydrogel, with five rats in each group. 50 μl of the drug was injected into the edentulous region of the right mandible (the area between the incisor and the first molar), and the rats remained dormant for 14 days. The jawbones of each group were collected and fixed with 4% paraformaldehyde. Micro-CT scans were used to image the rat jawbones, and 3D images were reconstructed.

[0024] 2.2 Test Results For details, please see [link / details]. Figure 1 ,from Figure 1It can be seen that compared with the blank control group, obvious bulge appeared in the edentulous jaw region of the left rat in the local injection of abaloparatide coupled with ferroferric hydrogel group, and there was no obvious difference between the local injection of abaloparatide hydrogel group, the local injection of ferroferric nanoparticle hydrogel group and the blank control group. It shows that abaloparatide coupled with ferroferric produces qualitative changes in osteogenesis compared with either abaloparatide or ferroferric alone.

[0025] 3. Repair of alveolar bone defect efficacy test 3.1 Test method Take 20 8-week-old male SD rats free drinking water, diet, and pull out the right maxillary first molar. After two weeks of wound healing, use a fissure drill to make a defect with a diameter of 2 mm and a depth of 2 mm at the new bone formation site, and place it under a static magnetic field. Randomly divide into 4 groups, namely blank control group (local injection of PBS), local injection of abaloparatide hydrogel group (abbreviated as ABL+ magnetic field group), local injection of ferroferric nanoparticle hydrogel group (abbreviated as ferroferric nanoparticle+ magnetic field group), and local injection of abaloparatide coupled with ferroferric hydrogel group (abbreviated as ABL+ magnetic field group), 5 rats in each group. Inject 50 μl at the defect site every two weeks, a total of 2 times. Two weeks after the last injection, collect the jaw bones of rats in each group and fix them with 4% paraformaldehyde. Scan the rat jaw bones using Micro-CT and reconstruct 3D images. Take the second molar alveolar crest as the reference, reconstruct the interest domain with a diameter of 2 mm and a depth of 1 mm, and calculate the Tb.Th (trabecular thickness), BV / TV (bone volume fraction), and Tb.N (trabecular number) of the interest domain.

[0026] 3.2 Test results The interest domain reconstruction schematic diagram is shown in Figure 2 , and the Tb.Th, BV / TV, and Tb.N statistics of the interest domain are shown in Figure 3 .

[0027] From Figure 2 It can be seen that the blank control group has little bone growth at the defect site, while the other three groups have growth, and the abaloparatide coupled with ferroferric hydrogel injection group has the most new bone; from Figure 3It can be seen that the BV / TV, Tb.Th and Tb.N of the alveolar bone defect are increased most by the abaloparatide-coupled ferroferric oxide hydrogel, and the abaloparatide-coupled ferroferric oxide hydrogel has a statistical difference in the increase effect on BV / TV compared with the abaloparatide hydrogel and the ferroferric oxide hydrogel; although the abaloparatide-coupled ferroferric oxide hydrogel has no statistical difference in the increase effect on Tb.Th compared with the abaloparatide hydrogel, the abaloparatide-coupled ferroferric oxide hydrogel has an increase of 100 units on Tb.Th compared with the blank control group, while the abaloparatide hydrogel has an increase of less than 50 units compared with the blank control group, which indicates that the abaloparatide-coupled ferroferric oxide has a greater increase effect on Tb.Th than the abaloparatide and the ferroferric oxide. The effect of the abaloparatide-coupled ferroferric oxide hydrogel on the trabecular bone structure parameters further proves that the abaloparatide-coupled ferroferric oxide hydrogel has a synergistic effect in repairing the alveolar bone defect.

[0028] In conclusion, the abaloparatide-coupled ferroferric oxide hydrogel of the present application can promote the osteogenesis of the alveolar bone by magnetically coupling the ferroferric oxide and the abaloparatide in a specific ratio in a magnetic field and then wrapping the alveolar bone with the hydrogel. Animal experiments show that the abaloparatide-coupled ferroferric oxide hydrogel has a qualitative change in osteogenesis compared with the abaloparatide and the ferroferric oxide, and further analysis of the trabecular bone structure parameters of the alveolar bone defect area shows that the abaloparatide-coupled ferroferric oxide hydrogel has a synergistic effect in repairing the alveolar bone defect and has practical application value.

Claims

1. A composition having osteogenic activity, characterized in that: It is composed of raw materials in the following weight parts: magnetic nanoparticles 15~45 parts, abaloparatide 2~10 parts.

2. The composition of claim 1, wherein: It is composed of raw materials in the following weight parts: magnetic nanoparticles 15 parts, abaloparatide 2 parts.

3. The composition according to claim 1 or 2, characterized in that: The magnetic nanoparticles are ferroferric oxide nanoparticles.

4. Use of the composition of any one of claims 1~3 in the preparation of a drug for promoting osteogenesis.

5. Use according to claim 4, characterized in that; The drug is a drug for promoting osteogenesis of the jawbone; the jawbone includes alveolar bone.

6. Use according to claim 5, characterized in that: The drug is a preparation prepared by taking the composition of any one of claims 1~3 as an active ingredient, plus pharmaceutically acceptable adjuvants; The preparation is a solution, a powder, a paste, a gel, an aerosol or a spray; The gel includes a hydrogel.

7. An osteogenic-promoting hydrogel, characterized by: It is prepared from raw materials in the following parts: magnetic nanoparticles 15~45 parts by weight, abaloparatide 2~10 parts by weight, carboxymethyl chitosan 90-270 parts by weight, aldehyde polyethylene glycol aldehyde group 60-180 parts by weight, water 1~5 parts by volume.

8. The hydrogel of claim 7, wherein: It is prepared from raw materials in the following parts: magnetic nanoparticles 15 parts by weight, abaloparatide 2 parts by weight, carboxymethyl chitosan 90 parts by weight, aldehyde polyethylene glycol aldehyde group 60 parts by weight, water 1.3 parts by volume.

9. A method of preparing a hydrogel according to claim 7 or 8, characterized in that: It includes the following steps: 1) Take raw materials according to the ratio, take aldehyde polyethylene glycol aldehyde group, dissolve in water to get liquid A; take magnetic nanoparticles and abaloparatide and dissolve in liquid A to get liquid B; 2) Take carboxymethyl chitosan, dissolve in water to get liquid C; 3) Mix liquid B and liquid C, and you get it.

10. Use of the hydrogel according to claim 7 or 8 for the manufacture of a medicament for promoting osteogenesis, characterized in that: The drug is a drug for promoting osteogenesis of the jawbone; the jawbone includes alveolar bone.

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