Nano-medicinal preparation capable of treating diabetes and preparation method of nano-medicinal preparation
By preparing strontium-vanadate organic framework nanoparticles and co-coating them with polydopamine and polylysine, a sustained-release nanomedicine formulation was formed, which solved the treatment problem of diabetic complications and achieved the effects of lowering blood sugar, improving osteoporosis and reducing oxidative stress.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-11-17
- Publication Date
- 2026-04-17
AI Technical Summary
Existing technologies are not effective in treating osteoporosis and oxidative stress associated with diabetes, and traditional vanadates have low bioavailability and certain toxic side effects.
Strontium-vanadate organic framework nanoparticles are formed using fructose-1,6-bisphosphate, vanadium pentoxide, and ergothionein. These nanoparticles are then co-encapsulated with polydopamine and polylysine to form a polylysine-polydopamine co-encapsulated nanomedicine formulation. This formulation slowly releases vanadium oxide complexes and strontium ions, thereby controlling blood sugar and improving diabetes symptoms.
It significantly lowers blood sugar, improves osteoporosis symptoms, reduces oxidative stress, prolongs drug action time, reduces toxic side effects, and improves drug stability and half-life.
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Figure CN121868244A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a nanomedicine formulation for treating diabetes and its preparation method. Background Technology
[0002] Osteoporosis complicating diabetes mellitus is a serious complication of diabetes affecting the skeletal system. It has a high incidence rate among various diabetic complications, currently ranging from 24% to 52%. Because osteoporosis easily leads to fractures, it is the disease with the highest rates of disability and mortality, and a major cause of long-term severe pain and functional impairment. Decreased bone density is closely related to chronically high blood sugar levels. Elevated urinary glucose concentration, along with osmotic diuresis, removes large amounts of calcium, phosphorus, and magnesium. Furthermore, high urinary glucose hinders the reabsorption of calcium, phosphorus, and magnesium by renal microvessels, exacerbating bone salt loss. Low serum calcium, phosphorus, and magnesium levels stimulate the parathyroid glands, leading to secondary parathyroid hyperfunction and increased secretion of parathyroid hormone, resulting in increased osteoclast activity. This promotes the mobilization of bone calcium and phosphorus to maintain normal serum calcium and phosphorus levels, thus increasing bone resorption. Accelerated bone resorption is also related to the excessive production of advanced glycation end products (AGEs) due to chronic hyperglycemia, which increases osteoclast activity.
[0003] Vanadates mimic the effects of insulin in vitro, exhibiting both "insulin-like" and "insulin-stimulating" effects, significantly improving insulin resistance and sensitivity. In vivo, they significantly restore the ability of peripheral tissues to metabolize glucose and respond to insulin, normalizing blood glucose levels in diabetic animal models. Vanadates do not increase the number or sensitivity of insulin receptors, nor do they increase tyrosine phosphorylation of receptors or their substrates, nor do they increase glucose transporters at low levels. However, inorganic vanadates have low gastrointestinal absorption, resulting in reduced bioavailability. Furthermore, vanadates are oxidizing, activating oxidative stress in vivo and causing harm. High doses of inorganic vanadates often cause diarrhea, lethargy, death, and other adverse reactions in experimental animals. Therefore, the synthesis of organovanadium compounds is crucial to improve the bioavailability of vanadium in vivo. Organovanadium compounds not only reduce the dosage and toxic side effects of metals but also increase the solubility of vanadium compounds, prolonging their duration of action and efficacy.
[0004] Furthermore, oxidative stress and the production of free radicals can cause insulin resistance. Oxidative stress is also considered a significant cause of diabetes and its complications. Most existing hypoglycemic drugs do not improve oxidative stress. Although the exact causes and pathogenesis of diabetes are still unclear, current research suggests that reducing oxidative stress in the body may be an effective way to prevent and treat diabetes and its complications. Summary of the Invention
[0005] In view of this, the purpose of the present invention is to provide a nanomedicine preparation for treating diabetes and a method for preparing the same. The nanomedicine preparation can slowly release vanadium oxide complex, ergothioneine and strontium ions, thereby controlling blood sugar, increasing blood strontium concentration and its half-life, improving diabetes symptoms, and improving diabetic complications such as osteoporosis and arteriosclerosis.
[0006] To address the aforementioned technical problems, this invention provides a nanomedicine formulation for treating diabetes and a method for preparing the same, comprising the following steps:
[0007] S1. Add fructose-1,6-bisphosphate, vanadium pentoxide, and ergothioneine to water, place them in a stainless steel reactor lined with polytetrafluoroethylene, seal, perform hydrothermal reaction, cool to room temperature, remove and centrifuge to obtain strontium-vanadate organic framework nanoparticles.
[0008] S2. The strontium-vanadate organic framework nanoparticles obtained in step S1, dopamine hydrochloride, and polylysine are added to a tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution and reacted under aerobic conditions at room temperature and pressure for 12-24 hours. After centrifugation, the precipitate is washed with water and freeze-dried to obtain polylysine-polydopamine co-encapsulated organic framework nanoparticles, which are nanomedicine formulations for the treatment of diabetes.
[0009] Preferably, in step S1, the feeding ratio of fructose-1,6-bisphosphate, vanadium pentoxide, ergothioneine and water is (70-130) mg:(80-150) mg:(100-200) mg:10 mL.
[0010] Preferably, in step S1, the hydrothermal reaction temperature is 175-200℃ and the reaction time is 48-72h.
[0011] Preferably, in step S1, the cooling rate is 5-10℃ / h.
[0012] Preferably, in step S2, the feeding ratio of the strontium-vanadate organic framework nanoparticles, dopamine hydrochloride, polylysine and tris(hydroxymethyl)aminomethane-hydrochloric acid buffer is (80-100) mg:(10-30) mg:(50-80) mg:100 mL.
[0013] Preferably, in step S2, the pH range of the tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution is 8.0-8.5, and the concentration is 0.10-0.12 mol / L.
[0014] The present invention also provides a nanomedicine formulation prepared by the above preparation method.
[0015] Beneficial effects:
[0016] 1) This invention utilizes vanadate and Sr2+ Ergothioneine plays a synergistic role in the antidiabetic effect. Nitrogen-containing vanadium-oxygen complexes in metal-organic frameworks can exert their insulin-like effect by stimulating insulin receptor kinase, thereby lowering blood glucose; Sr 2+ Able to interact with sodium in the body + Antagonistic, it has a softening effect on arteriosclerosis caused by metabolic disorders due to diabetes, while Sr 2+ It can promote bone development and osteoid formation, and may reverse osteoporosis caused by diabetes. Ergothionein is not easily oxidized in vitro and is relatively stable. In vivo, it can weaken the oxidative stress caused by diabetes and scavenge free radicals, an effect superior to endogenous glutathione. This study further improved the vanadate and Sr content by preparing composite metal-organic frameworks and using polydopamine and polylysine co-coating methods. 2+ Stability of the thiol structure in ergothioneine.
[0017] 2) Utilizing vanadate and Sr 2+ It forms a complex metal-organic framework with ergothioneine and fructose-1,6-bisphosphate through coordination and ionic bonds, which can increase vanadate and Sr 2+ The stability in systemic circulation is improved, and its half-life is prolonged. Furthermore, polydopamine, formed by dopamine polymerization, is co-coated with polylysine to form a composite metal-organic framework. Under physiological conditions, polydopamine carries a negative surface charge, which generates electrostatic repulsion with fructose-1,6-bisphosphate, affecting the coating of the composite metal-organic framework. Polylysine, with a positive surface charge, can act as a bridge connecting fructose-1,6-bisphosphate and polydopamine in the composite metal-organic framework, enabling coating. Simultaneously, the phenolic hydroxyl groups on the surface of polydopamine possess strong antioxidant properties, stabilizing ergothioneine in the composite metal-organic framework, maintaining its thiol configuration, and allowing it to exert its antioxidant and free radical scavenging activities in vivo. Attached Figure Description
[0018] Figure 1 This refers to the possible structural units and variations within the strontium-vanadate organic framework. Detailed implementation method:
[0019] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.
[0020] Example 1
[0021] A nanomedicine formulation for treating diabetes and its preparation method, comprising the following steps:
[0022] 1. Add 100 mg of fructose-1,6-bisphosphate, 120 mg of vanadium pentoxide, and 180 mg of ergothioneine to 10 mL of water, place the mixture in a stainless steel reactor lined with polytetrafluoroethylene, seal it, and carry out a hydrothermal reaction at 185 °C for 60 h. Then, cool the mixture to room temperature at a rate of 8 °C / h, remove it, and centrifuge to obtain strontium-vanadate organic framework nanoparticles.
[0023] 2. Add 95 mg of the strontium-vanadate organic framework nanoparticles obtained in step 1, 19 mg of dopamine hydrochloride, and 52 mg of polylysine to 100 mL of 0.11 mol / L pH 8.4 tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution. React for 18 h under aerobic conditions at room temperature and pressure. After centrifugation, take the precipitate, wash it with water, and freeze-dry it to obtain polylysine-polydopamine co-encapsulated organic framework nanoparticles, which are the nanomedicine formulation for the treatment of diabetes.
[0024] Example 2
[0025] A nanomedicine formulation for treating diabetes and its preparation method, comprising the following steps:
[0026] 1. Add 70 mg of fructose-1,6-bisphosphate, 80 mg of vanadium pentoxide, and 100 mg of ergothioneine to 10 mL of water, place the mixture in a stainless steel reactor lined with polytetrafluoroethylene, seal it, and carry out a hydrothermal reaction at 200 °C for 48 h. Then, cool the mixture to room temperature at a rate of 10 °C / h, remove it, and centrifuge to obtain strontium-vanadate organic framework nanoparticles.
[0027] 2. Add 80 mg of the strontium-vanadate organic framework nanoparticles obtained in step 1, 10 mg of dopamine hydrochloride, and 50 mg of polylysine to 100 mL of 0.1 mol / L pH 8 tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution. React for 24 h under aerobic conditions at room temperature and pressure. After centrifugation, take the precipitate, wash it with water, and freeze-dry it to obtain polylysine-polydopamine co-encapsulated organic framework nanoparticles, which are the nanomedicine formulation for the treatment of diabetes.
[0028] Example 3
[0029] A nanomedicine formulation for treating diabetes and its preparation method, comprising the following steps:
[0030] 1. Add 130 mg of fructose-1,6-bisphosphate, 150 mg of vanadium pentoxide, and 200 mg of ergothioneine to 10 mL of water, place the mixture in a stainless steel reactor lined with polytetrafluoroethylene, seal it, and carry out a hydrothermal reaction at 175 °C for 72 h. Then, cool the mixture to room temperature at a rate of 5 °C / h, remove it, and centrifuge to obtain strontium-vanadate organic framework nanoparticles.
[0031] 2. 100 mg of the strontium-vanadate organic framework nanoparticles obtained in step 1, 30 mg of dopamine hydrochloride, and 80 mg of polylysine were added to 100 mL of 0.12 mol / L pH 8.5 tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution. The mixture was reacted for 12 h under aerobic conditions at room temperature and pressure. After centrifugation, the precipitate was washed with water and lyophilized to obtain polylysine-polydopamine co-encapsulated organic framework nanoparticles, which are the nanomedicine formulation for the treatment of diabetes.
[0032] Comparative Example 1 (without vanadium pentoxide)
[0033] A nanomedicine formulation and its preparation method, comprising the following steps:
[0034] 1. Add 100 mg of fructose-1,6-bisphosphate and 180 mg of ergothioneine to 10 mL of water, place the mixture in a stainless steel reactor lined with polytetrafluoroethylene, seal it, and carry out a hydrothermal reaction at 185 °C for 60 h. Then, cool the mixture to room temperature at a rate of 8 °C / h, remove it, and centrifuge to obtain nanoparticles.
[0035] 2. Add 95 mg of the nanoparticles obtained in step 1, 19 mg of dopamine hydrochloride, and 52 mg of polylysine to 100 mL of 0.11 mol / L pH 8.4 tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution. React for 18 h under aerobic conditions at room temperature and pressure. After centrifugation, take the precipitate, wash it with water, and freeze-dry it to obtain polylysine-polydopamine co-encapsulated nanoparticles, which are the nanomedicine formulation for the treatment of diabetes.
[0036] Comparative Example 2 (without ergothioneine)
[0037] A nanomedicine formulation and its preparation method, comprising the following steps:
[0038] 1. Add 100 mg of fructose-1,6-bisphosphate and 120 mg of vanadium pentoxide to 10 mL of water, place the mixture in a stainless steel reactor lined with polytetrafluoroethylene, seal it, and carry out a hydrothermal reaction at 185 °C for 60 h. Then, cool the mixture to room temperature at a rate of 8 °C / h, remove it, and centrifuge to obtain nanoparticles.
[0039] 2. Add 95 mg of the nanoparticles obtained in step 1, 19 mg of dopamine hydrochloride, and 52 mg of polylysine to 100 mL of 0.11 mol / L pH 8.4 tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution. React for 18 h under aerobic conditions at room temperature and pressure. After centrifugation, take the precipitate, wash it with water, and freeze-dry it to obtain polylysine-polydopamine co-encapsulated nanoparticles, which are the nanomedicine formulation for the treatment of diabetes.
[0040] Comparative Example 3 (fructose-1,6-bisphosphate strontium)
[0041] A nanomedicine formulation and its preparation method, comprising the following steps:
[0042] 1. Add 120 mg of vanadium pentoxide and 180 mg of ergothioneine to 10 mL of water, place them in a stainless steel reactor lined with polytetrafluoroethylene, seal the reactor, and carry out a hydrothermal reaction at 185 °C for 60 h. Then, cool the reactor to room temperature at a rate of 8 °C / h, remove the reactor and centrifuge to obtain nanoparticles.
[0043] 2. Add 95 mg of the nanoparticles obtained in step 1, 19 mg of dopamine hydrochloride, and 52 mg of polylysine to 100 mL of 0.11 mol / L pH 8.4 tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution. React for 18 h under aerobic conditions at room temperature and pressure. After centrifugation, take the precipitate, wash it with water, and freeze-dry it to obtain polylysine-polydopamine co-encapsulated nanoparticles, which are the nanomedicine formulation for the treatment of diabetes.
[0044] Comparative Example 4
[0045] A nanomedicine formulation and its preparation method include the following steps: 100 mg of fructose-1,6-bisphosphate, 120 mg of vanadium pentoxide, and 180 mg of ergothioneine are added to 10 mL of water, placed in a stainless steel reactor lined with polytetrafluoroethylene, sealed, and subjected to a hydrothermal reaction at 185 °C for 60 h. The mixture is then cooled to room temperature at a rate of 8 °C / h, removed, and centrifuged to obtain strontium-vanadate organic framework nanoparticles, which are the nanomedicine formulation for treating diabetes.
[0046] Hypoglycemic experiment in diabetic rats
[0047] Type II diabetes model SD rats were constructed: 8-week-old male SD rats were fed the same high-sugar and high-fat diet for 4 weeks. The model groups 1-6 were given streptozotocin (STZ) 25 mg / kg intraperitoneally for two consecutive days. Random blood glucose and fasting blood glucose were measured. Random blood glucose >11.1 mmol / L and fasting blood glucose >7 mmol / L were used as the model establishment criteria.
[0048] The nanomedicine formulations for treating diabetes described in Examples 1-3 and Comparative Examples 1-4 were administered to rats via tail vein injection at a dose of 4 mg / kg, once every 3 days. Random blood glucose and fasting blood glucose were measured on day 7, with untreated rats serving as controls. The results are shown in Table 1.
[0049] Table 1. Blood glucose measurement results
[0050]
[0051] As shown in Table 1, the random blood glucose and fasting blood glucose levels of type 2 diabetic model mice treated with the nanomedicine formulations for treating diabetes in Examples 1-3 were significantly reduced, approaching those of the blank control group. Among Examples 1-3, the nanomedicine formulation prepared under the process parameters and preparation conditions of Example 1 was verified to have the most significant hypoglycemic effect. The reason for this is that in Example 1, strontium fructose-1,6-bisphosphate, vanadium pentoxide, and ergothione achieved the optimal ratio to obtain strontium-vanadate organic framework nanoparticles with the best structure and function. Figure 1 Furthermore, the optimal ratio of polylysine to dopamine achieves the best encapsulation effect and sustained-release function. This invention enhances the stability of strontium-vanadate organic framework nanoparticles by co-encapsulating them with polylysine and polydopamine, thereby controlling oxidative stress, eliminating free radicals, and improving their hypoglycemic effect.
[0052] In Comparative Example 1, no vanadium pentoxide was added during the preparation of the drug formulation; only Sr was present in the metal-organic framework. 2+ The first comparative example lacked vanadate, a key factor in blood sugar control in diabetes. Therefore, Comparative Example 1 showed the worst treatment, with no blood sugar-lowering effect. The second comparative example did not contain ergothioneine. In Comparative Example 2, the strontium-vanadate organic framework nanoparticles did not involve ergothioneine, failing to form complex nitrogen-oxyvanadate complexes. Consequently, it did not achieve optimal controlled-release in vivo, nor effectively scavenge free radicals or reduce the adverse effects of oxidative stress. Therefore, its blood sugar control effect on diabetes was inferior to the first example, and significant vanadate toxicity was observed in the experiment, with reduced food intake and weight loss in rats. The third comparative example did not contain strontium fructose-1,6-bisphosphate, an organic component connecting the core of a metal-organic framework that stabilizes vanadate and Sr. 2+ The core of the method was to achieve a better controlled-release effect and a longer half-life. Therefore, the hypoglycemic effect of Comparative Example 3 was also poor, and significant toxic side effects, including a significant decrease in weight, were also observed in the experiment. Comparative Example 4 did not use polydopamine and polylysine co-coating, which accelerated the metabolic rate of the strontium-vanadate organic framework nanoparticles in vivo, thus failing to achieve a significant sustained-release effect. Although the hypoglycemic effect was obvious, similar toxic side effects as Comparative Examples 2 and 3 were also observed.
[0053] This invention provides a nanomedicine formulation for treating diabetes and its preparation method. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. 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 method for preparing a nanomedicine formulation for treating diabetes, characterized in that, Includes the following steps: S1. Strontium fructose-1,6-bisphosphate, vanadium pentoxide, and ergothioneine were added to water, and after hydrothermal reaction, the mixture was cooled to room temperature and centrifuged to obtain strontium-vanadate organic framework nanoparticles. S2. Strontium-vanadate organic framework nanoparticles, dopamine hydrochloride, and polylysine were added to tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution and reacted under aerobic conditions at room temperature and pressure for 12-24 hours. After centrifugation, the precipitate was washed with water and freeze-dried to obtain polylysine-polydopamine co-encapsulated organic framework nanoparticles, which are nanomedicine formulations for the treatment of diabetes.
2. The preparation method according to claim 1, characterized in that, In step S1, the feeding ratio of fructose-1,6-bisphosphate, vanadium pentoxide, ergothioneine and water is (70-130) mg:(80-150) mg:(100-200) mg:10 mL.
3. The preparation method according to claim 1, characterized in that, In step S1, the hydrothermal reaction temperature is 175-200℃ and the reaction time is 48-72h.
4. The preparation method according to claim 1, characterized in that, In step S1, the cooling rate is 5-10℃ / h.
5. The preparation method according to claim 1, characterized in that, In step S2, the feeding ratio of the strontium-vanadate organic framework nanoparticles, dopamine hydrochloride, polylysine and tris(hydroxymethyl)aminomethane-hydrochloric acid buffer is (80-100) mg: (10-30) mg: (50-80) mg: 100 mL.
6. The preparation method according to claim 1, characterized in that, In step S2, the pH range of the tris(hydroxymethyl)aminomethane-hydrochloric acid buffer solution is 8.0-8.5, and the concentration is 0.10-0.12 mol / L.
7. The nanomedicine formulation prepared by the preparation method according to any one of claims 1 to 6.