Polysaccharide-coated nano bismuth agent as well as preparation method and application thereof

Abstract

The preparation method comprises the following steps: mixing a maltodextrin aqueous solution with an oxidized terminal aldehyde group with a bismuth salt aqueous solution, adjusting the pH value by using alkali, carrying out a heat preservation reaction, precipitating and drying to obtain a product. The prepared nano bismuth agent has good antibacterial activity on streptococcus mutans, porphyromonas gingivalis, staphylococcus aureus, enterococcus faecalis and the like, and also has a good gastric ulcer repairing effect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a polysaccharide-coated bismuth nanoparticle, its preparation method, and its application in treating gastric and oral diseases. Background Technology

[0002] Bismuth is a "green" metal, virtually non-toxic to humans compared to its neighboring highly toxic elements arsenic (As) and antimony (Sb) on the periodic table. Bismuth-based drugs are primarily used clinically to treat Helicobacter pylori, gastritis, and gastric ulcers.

[0003] In the acidic environment of the stomach, bismuth preparations can bind to proteins (such as glycoproteins) at the site of damage to the mucosa, forming a strong protective film that covers the surface of ulcers or erosions, isolating them from attacking factors such as gastric acid, pepsin, and bile. It can also stimulate mucosal epithelial cells to secrete mucus and bicarbonate, enhancing their own defense capabilities and promoting prostaglandin synthesis, thus accelerating mucosal repair. Bismuth can penetrate the bacterial membrane of Helicobacter pylori, causing precipitation of intracellular substances and directly killing the bacteria. Commonly used bismuth drugs in clinical practice include bismuth potassium citrate and colloidal bismuth pectin.

[0004] Flores-Castañeda, M. et al. reported that bismuth salicylate nanoparticles ablated by pulsed laser exhibited certain antibacterial properties against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. BSS colloids with an average particle size of 20 nanometers showed the best antibacterial effect, achieving an inhibition rate of over 80%, comparable to or higher than that of ciprofloxacin. Summary of the Invention

[0005] One objective of this invention is to provide a polysaccharide-coated bismuth nanoparticle, the preparation method of which is as follows: Aqueous solutions of maltodextrin with terminal aldehyde group oxidation were mixed with aqueous solutions of bismuth salts. The pH was adjusted with alkali, the reaction was carried out under heat, precipitation was achieved, and the mixture was dried to obtain carboxymethylmaltobismuth.

[0006] In the above preparation method, the bismuth salt is bismuth nitrate, bismuth chloride, basic bismuth nitrate, bismuth carbonate, or bismuth phosphate.

[0007] In the above preparation method, the maltodextrin with terminal aldehyde group oxidation is obtained by oxidizing maltodextrin with sodium hypochlorite in an alkaline environment.

[0008] In the above preparation method, the DE value of the maltodextrin is 5~30.

[0009] In the above preparation method, the alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, or ammonia.

[0010] In the above preparation method, the pH value is 5~12.

[0011] In the above preparation method, the reaction temperature is 30~100℃.

[0012] In the above preparation method, the precipitation method involves adding ethanol, methanol, or acetone to precipitate a solid.

[0013] Another object of the present invention is to provide the application of the aforementioned carboxymethyl maltose bismuth in the preparation of oral disinfection and periodontal disease treatment drugs.

[0014] Another object of the present invention is to provide the application of the aforementioned carboxymethyl maltose bismuth in the preparation of drugs for treating Helicobacter pylori, gastritis, and gastric ulcers.

[0015] The nano-sized carboxylated maltose bismuth provided by this invention exhibits good antibacterial activity against Streptococcus mutans, Porphyromonas gingivalis, Staphylococcus aureus, and Enterococcus faecalis, showing promising application prospects in oral disinfection and periodontal disease treatment. Simultaneously, it demonstrates excellent gastric ulcer repair properties and can be used to treat Helicobacter pylori infection, gastritis, and gastric ulcers. Detailed Implementation

[0016] The present application will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present application.

[0017] Example 1: Preparation of carboxymethylmaltose bismuth Add 20 g of DE12 maltodextrin, 0.2 g of sodium bromide, and 50 mL of water to a reaction flask and stir to dissolve. Adjust the pH to 11 with 10% NaOH aqueous solution, control the temperature at 25-35℃, and add 7 g of 13% sodium hypochlorite dropwise. After the addition is complete, maintain the temperature for half an hour to obtain an aqueous solution of oxidized maltodextrin.

[0018] Add 5 g of bismuth nitrate pentahydrate and 20 mL of water to the above-mentioned oxidized maltodextrin aqueous solution, and add 10% hydrochloric acid dropwise until the solution becomes clear. Maintain the temperature at approximately 25℃, and slowly add 10% NaOH aqueous solution dropwise until the pH reaches 10. Raise the temperature to 50℃ and maintain the reaction for 1 hour. Adjust the pH to 6.5-7.0 with 10% hydrochloric acid and stir for 0.5 hours. Add 80 mL of ethanol and stir for 0.5 hours. Filter, dry, and pulverize to obtain carboxymethyl maltodextrin (B-1). The bismuth content is 12.6%, and the particle size is 23 nm (DLS).

[0019] Example 2 Preparation of carboxymethylmaltose bismuth Add 20 g of DE19 maltodextrin, 0.2 g of sodium bromide, and 50 mL of water to a reaction flask and stir to dissolve. Adjust the pH to 10 with 10% NaOH aqueous solution, control the temperature at 25-35℃, and add 10 g of 13% sodium hypochlorite dropwise. After the addition is complete, maintain the temperature for half an hour to obtain an aqueous solution of oxidized maltodextrin.

[0020] Take 10 g of bismuth nitrate pentahydrate and 50 mL of water, add them to the above-mentioned oxidized maltodextrin aqueous solution, and add 10% hydrochloric acid dropwise until the solution becomes clear. Control the temperature at about 25℃, and slowly add 10% NaOH aqueous solution dropwise until the pH reaches 10. Raise the temperature to 80℃ and maintain the reaction for 1 hour. Adjust the pH to 6.5~7.0 with 10% hydrochloric acid and stir for 0.5 hours. Add 110 mL of ethanol and stir for 0.5 hours. Filter, dry, and pulverize to obtain carboxymethyl maltodextrin (B-2). The bismuth content is 21.5%, and the particle size is 61 nm (DLS).

[0021] Example 3 Preparation of carboxymethylmaltose bismuth Add 20 g of DE9 maltodextrin, 0.2 g of sodium bromide, and 50 mL of water to a reaction flask and stir to dissolve. Adjust the pH to 11 with 10% NaOH aqueous solution, control the temperature at 25-35℃, and add 7 g of 13% sodium hypochlorite dropwise. After the addition is complete, maintain the temperature for half an hour to obtain an aqueous solution of oxidized maltodextrin.

[0022] Add 5 g of bismuth nitrate pentahydrate and 20 mL of water to the above-mentioned oxidized maltodextrin aqueous solution, and add 10% hydrochloric acid dropwise until the solution becomes clear. Maintain the temperature at approximately 25℃, and slowly add 10% KOH aqueous solution dropwise until the pH reaches 8. Raise the temperature to 95℃ and maintain the reaction for 1 hour. Adjust the pH to 6.5–7.0 with 10% hydrochloric acid and stir for 0.5 hours. Add 100 mL of ethanol and stir for 0.5 hours. Filter, dry, and pulverize to obtain carboxymethyl maltodextrin (B-3). The bismuth content is 9.8%, and the particle size is 36 nm (DLS).

[0023] Example 4 Preparation of carboxymethylmaltose bismuth Add 20 g of DE14 maltodextrin, 0.2 g of sodium bromide, and 50 mL of water to a reaction flask and stir to dissolve. Adjust the pH to 11 with 10% NaOH aqueous solution, control the temperature at 25-35℃, and add 8 g of 13% sodium hypochlorite dropwise. After the addition is complete, maintain the temperature for half an hour to obtain an aqueous solution of oxidized maltodextrin.

[0024] Take 6 g of bismuth nitrate pentahydrate and 20 mL of water, add them to the above-mentioned oxidized maltodextrin aqueous solution, and add 10% hydrochloric acid dropwise until the solution becomes clear. Control the temperature at about 25℃, and slowly add 10% NaOH aqueous solution dropwise until the pH reaches 6. Raise the temperature to 80℃ and maintain the reaction for 1 hour. Adjust the pH to 6.5~7.0 with 10% hydrochloric acid and stir for 0.5 hours. Add 100 mL of methanol and stir for 0.5 hours. Filter, dry, and pulverize to obtain carboxymethyl maltodextrin (B-4). The bismuth content is 11.7%, and the particle size is 39 nm (DLS).

[0025] Example 5 Preparation of carboxymethylmaltose bismuth Add 20 g of DE12 maltodextrin, 0.2 g of sodium bromide, and 50 mL of water to a reaction flask and stir to dissolve. Adjust the pH to 11 with 10% NaOH aqueous solution, control the temperature at 25-35℃, and add 7 g of 13% sodium hypochlorite dropwise. After the addition is complete, maintain the temperature for half an hour to obtain an aqueous solution of oxidized maltodextrin.

[0026] Take 7 g of bismuth chloride and 30 mL of water, add them to the above-mentioned oxidized maltodextrin aqueous solution, and add 10% hydrochloric acid dropwise until the solution becomes clear. Maintain the temperature at approximately 25℃, and slowly add 5% ammonia water dropwise until the pH reaches 10. React at approximately 30℃ for 3 hours. Adjust the pH to 6.5-7.0 with 10% hydrochloric acid and stir for 0.5 hours. Add 100 mL of ethanol and stir for 0.5 hours. Filter, dry, and pulverize to obtain carboxymethyl maltodextrin (B-1) (B-5). The bismuth content is 14.8%, and the particle size is 52 nm (DLS).

[0027] Example 6 Antibacterial activity of carboxymethyl maltose bismuth The minimum inhibitory concentrations (MICs) of carboxylated bismuth maltose against Streptococcus mutans, Porphyromonas gingivalis, Staphylococcus aureus, and Enterococcus faecalis were determined using the MTT assay. The results showed that carboxylated bismuth maltose exhibits good antibacterial activity against these common oral bacteria.

[0028] Table 1 Antibacterial activity of carboxymethyl maltose bismuth ; Example 7: Protective effect of carboxymethyl maltose bismuth on gastric ulcers Thirty Wistar rats weighing 150-200 kg were used to establish a gastric ulcer model using the acetic acid cauterization method. They were randomly divided into a blank control group (purified water), a drug group (B-1, 100 mg / kg), and a positive control group (colloidal bismuth pectin, 100 mg / kg), with 10 doses in each group. Rats were administered the drug by gavage once daily for 10 consecutive days, after which they were sacrificed, their stomachs were dissected, and the size of the gastric ulcers was measured. The results showed that carboxylated bismuth maltose has a certain repairing effect on gastric ulcers.

[0029] Table 2. Protective effect of carboxymethyl maltose bismuth on gastric ulcers in rats. ; The above embodiments are intended to illustrate the essential content of the present invention, but are not intended to limit the scope of protection of the present invention. Those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of protection of the present invention.

Claims

1. A polysaccharide-coated bismuth nanoparticle, the preparation method of which is as follows: Aqueous solutions of maltodextrin with terminal aldehyde group oxidation were mixed with aqueous solutions of bismuth salts. The pH was adjusted with alkali, the reaction was carried out under heat, precipitation was achieved, and the mixture was dried to obtain carboxymethylmaltobismuth.

2. The preparation method according to claim 1, characterized in that, The bismuth salt is bismuth nitrate, bismuth chloride, basic bismuth nitrate, bismuth carbonate, or bismuth phosphate.

3. The preparation method according to claim 1, characterized in that, The maltodextrin with terminal aldehyde oxidation is obtained by oxidizing maltodextrin with sodium hypochlorite in an alkaline environment.

4. The preparation method according to claims 1 and 2, characterized in that, The DE value of the maltodextrin is 5~30.

5. The preparation method according to claim 1, characterized in that, The alkali is sodium hydroxide, potassium hydroxide, sodium carbonate, or ammonia.

6. The preparation method according to claims 1 and 5, characterized in that, The pH value is 5~12.

7. The preparation method according to claim 1, characterized in that, The reaction temperature is 30~100℃.

8. The preparation method according to claim 1, characterized in that, The precipitation method involves adding ethanol, methanol, or acetone to cause a solid precipitate to form.

9. The application of the compounds prepared according to claims 1 to 8 in the preparation of oral disinfection and periodontal disease treatment drugs.

10. The application of the compounds prepared according to claims 1 to 8 in the preparation of drugs for treating Helicobacter pylori, gastritis, and gastric ulcers.