CN112741821B - Sialic acid nano-particles and preparation method and application thereof - Google Patents
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Abstract
The invention relates to sialic acid nano particles and a preparation method and application thereof. The adhesion effect of the nasal spray prepared from the sialic acid nanoparticles on mucous membrane tissues can ensure that sialic acid is not easily cleared by nasal cilia, prolong the retention time of sialic acid in nasal cavities, block virus invasion of cell surface sialic acid serving as a receptor, such as influenza virus, parainfluenza virus, respiratory syncytial virus and the like, provide lasting protection for respiratory tracts, reduce virus infection risks, and the prepared nasal spray preparation is safe, free of toxic and side effects, free of peculiar smell and free of change of normal nasal mucus viscosity.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to sialic acid nano-particles and a preparation method and application thereof.
Background
Sialic Acid (SA) is a natural carbohydrate widely present in biological systems, and is a generic name of a family of derivatives having nine-carbon glycosylneuraminic acid as a basic structure, and the total number of the derivatives is over 50, and the sialic acid is widely present in cell membrane glycoproteins and lipoproteins in organisms, plays an important role in many important processes of the organisms, and participates in cell recognition, survival, reproduction, biofilm flow and endocytosis.
Respiratory viruses such as influenza invade the human body through the mouth and nose mainly through air transmission, and the adhesion and infection are carried out by using cell surface sialic acid as a ligand, so that the virus invasion can be blocked by blocking the combination of the virus and the cell surface sialic acid ligand, and the virus infection is reduced. Since sialic acid glycoconjugate-based drugs or free sialic acid can effectively prevent adhesion of viruses to cell surfaces and prevent influenza by competitively binding to viral Hemagglutinin (HA), nasal spray containing sialic acid as a main component is expected to be a new choice for influenza prevention.
However, the application of the sialic acid nasal spray is limited in dosage, and sialic acid has the defects of being easily cleared by mucus and nasal mucociliary. The sialic acid nasal cavity administration preparation of the Chinese patent application CN 11544379A combines sialic acid and phospholipid in a form of a 'complex', on one hand, the phospholipid is utilized to reduce the viscosity of nasal mucus, and further the clearance of the nasal mucus on the sialic acid is reduced; on the other hand, the amphiphilicity of the phospholipid is utilized, the hydrophobic end of the phospholipid is connected with fat-soluble nasal mucosa, and the hydrophilic end of the phospholipid is connected with free sialic acid in the medicine, so that the sialic acid is tightly attached to the cell surface of the nasal mucosa, and the retention time of the sialic acid on the nasal mucosa is prolonged.
Disclosure of Invention
The present invention is directed to solving, at least to some extent, one of the technical problems in the related art. Therefore, the invention aims to provide sialic acid nanoparticles, and a preparation method and application thereof. The sialic acid nanometer particles have adhesion effect on mucous membrane tissues, so that sialic acid is not easily cleared by cilia of a nasal cavity, the retention time of the sialic acid in the nasal cavity is prolonged, the bioavailability of the medicine is improved, and the prepared nasal cavity spray preparation is safe, free of toxic and side effects, free of peculiar smell and free of change of normal nasal mucus viscosity.
To this end, in a first aspect of the invention, there is provided a sialic acid nanoparticle having the following structural formula:
according to the sialic acid nano-particles provided by the embodiment of the invention, the average particle size is 95nm, and through tests, the adhesion effect of the sialic acid nano-particles on mucous membrane tissues enables sialic acid not to be easily cleared by cilia of a nasal cavity, so that the retention time of the sialic acid in the nasal cavity is prolonged, and the bioavailability of a medicament is improved; meanwhile, the sialic acid nanoparticle nasal spray preparation is safe, free of toxic and side effects and peculiar smell, has the osmotic pressure approximately equal to that of nasal secretion, and does not change the normal nasal mucus viscosity.
In a second aspect of the present invention, the present invention provides a method for preparing the sialic acid nanoparticle, comprising the following steps:
(1) Reacting the aminated sialic acid with an anhydride group of a polystyrene maleic anhydride copolymer to obtain a sialic acid high molecular compound;
(2) And carrying out ultrasonic treatment on the sialic acid high molecular compound in an aqueous solution for 1h to obtain the sialic acid nano-particles.
According to the preparation method of the sialic acid nano-particles, a high-molecular polystyrene maleic anhydride copolymer is used as a skeleton, aminated sialic acid is reacted with an anhydride group on the high-molecular skeleton, sialic acid is covalently connected to the high-molecular skeleton, and the modified high-molecular substance is subjected to ultrasonic treatment in an aqueous solution and can be self-assembled into the high-molecular nano-particles through the hydrophilic and hydrophobic effects of functional groups, namely the sialic acid nano-particles.
In addition, the preparation method of sialic acid nanoparticles according to the above embodiment of the present invention may further have the following additional technical features:
optionally, the sialic acid is N-acetylneuraminic acid.
Alternatively, the polystyrene maleic anhydride copolymer has a molecular weight of 2000 to 20000.
Optionally, the mass ratio of the aminated sialic acid to the polystyrene maleic anhydride copolymer is 1-2.
In a third aspect of the invention, the invention provides a nasal spray formulation comprising the above sialic acid nanoparticles, heparin, marine sulfated polysaccharide and physiological saline.
Optionally, the sialic acid nanoparticles are at a concentration of 1-10mg/mL, the heparin is at a concentration of 0.05-0.2mg/mL, and the marine sulfated polysaccharide is at a concentration of 0.1-0.5mg/mL.
Optionally, the marine sulfated polysaccharide is fucoidan or carrageenan.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Drawings
FIG. 1 is a graph showing a distribution of sizes of sialic acid nanoparticles prepared according to example 1 of the present invention, the average size being 95nm;
FIG. 2 is a graph of the distribution of the particle size of sialic acid nanoparticles prepared according to example 2 of the present invention, with an average particle size of 98nm;
FIG. 3 is a graph showing a distribution of sizes of sialic acid nanoparticles prepared according to example 3 of the present invention, the average size being 102nm;
FIG. 4 shows the results of the residence time measurement of the sialic acid nanoparticle nasal spray preparation for preventing viral respiratory tract infection in the nasal cavity of a rat, wherein the residence time of the nasal spray preparation prepared from free sialic acid in the nasal cavity of the rat is short, only about 10% of the nasal spray preparation is remained after 20 minutes of administration, and the nasal spray preparation is completely removed within 40 minutes; the residence time of the sialic acid nanoparticle nasal spray preparation prepared by the application in the nasal cavity of a rat is obviously prolonged compared with that of free sialic acid, the sialic acid nanoparticle nasal spray preparation is completely removed in about 2 hours after the application, and the residence time of experimental groups 2, 3 and 4 in the nasal cavity of the rat is approximately the same;
Detailed Description
The technical solution of the present invention is illustrated by specific examples below. It is to be understood that one or more method steps recited herein do not preclude the presence of additional method steps before or after the recited combining step or that additional method steps can be inserted between the explicitly recited steps; it should also be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Moreover, unless otherwise indicated, the numbering of the various method steps is merely a convenient tool for identifying the various method steps, and is not intended to limit the order in which the method steps are arranged or the scope of the invention in which the invention may be practiced, and changes or modifications in the relative relationship may be made without substantially changing the technical content.
In order to better understand the above technical solutions, exemplary embodiments of the present invention are described in more detail below. While exemplary embodiments of the invention have been shown, it should be understood that the invention may be embodied in various forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The test materials adopted by the invention are all common commercial products and can be purchased in the market.
Sialic acid nanoparticles according to embodiments of the present invention are prepared comprising:
1. dissolving 500-1000mg of polystyrene maleic anhydride copolymer (PMSA) with average molecular weight of 2000-20000 (purchased from sigma company www. Sigma aldrich. Com.) in 10mL of DMF, adding 200-500mg of aminated sialic acid (SA, x = 0-4), adding 0.5-1mL of triethylamine to the reaction solution, stirring at room temperature for reaction for about 12 hr, and adding 5-10mL of saturated NaHCO 3 Stirring the aqueous solution at room temperature for 0.5-1 hour, and collecting the reaction solution; dialyzing with dialysis bag with cut-off molecular weight of 2000-20000 for 24 hr while collecting reaction solution, wherein the dialysis solution is ultrapure water, and the intermediate solution is changed for 4-5 times. Finally, the solution in the dialysis bag is frozen and dried to obtain a solid substance, namely the sialic acid high molecular compound.
2. 10mg of the sialic acid polymer compound is dissolved in 10ml of ultrapure water, and 1mg/ml of sialic acid nanoparticles are obtained after ultrasonic treatment (40KHz, 25 ℃) for 1 h.
The reaction process is as follows:
wherein, the preparation process of the aminated sialic acid comprises the following steps:
taking x =2 as an example, the synthesis of the aminated sialic acid is as follows:
5g of acetylated sialic acid (1) was dissolved in 50mL of anhydrous dichloromethane, and BF3.OEt was added under zero-degree conditions 2 (6 equiv.), reactant 2 (2 equiv.), and finally the reaction was stirred at room temperature overnight. The reaction solution was then concentrated and purified to obtain 2.5g of the product (2). Dissolving the product (2) in 30mL of DMF, adding sodium azide (4 equivalents), reacting at 80 ℃ for 8-10 hours under stirring, extracting the reaction liquid with ethyl acetate and water, collecting the ethyl acetate phase, concentrating and purifying to obtain 2g of the product (3). Then, the product (3) was dissolved in 20mL of tetrahydrofuran, 10mL of water and sodium hydroxide (3 equivalents) were added, and the reaction mixture was reacted at room temperature for 3 hours, then the pH of the reaction mixture was adjusted to 6-7 with 2M hydrochloric acid, and the reaction mixture was concentrated and purified to obtain 1g of the product (4). Then, 20mL of methanol was added to dissolve (4), triphenylphosphine (6 equivalents) was added thereto, and the reaction mixture was reacted at room temperature for 12 hours, followed by extraction with ethyl acetate and water, collection of the aqueous phase, and concentration to obtain 0.8g of a product (5).
The invention will now be described with reference to specific examples, which are intended to be illustrative only and not to be limiting in any way.
Example 1 preparation of sialic acid nanoparticles
750mg of a polystyrene maleic anhydride copolymer (PMSA) with a molecular weight of 10000 were dissolved in 10mL of DMF, 350mg of aminated sialic acid (SA, x = 2) was then added,adding 0.8mL of triethylamine to the reaction solution, stirring the mixture at room temperature for reaction for 12 hours, and adding 8mL of saturated NaHCO 3 Stirring the aqueous solution at room temperature for 1 hour to collect a reaction solution; and dialyzing with a dialysis bag with molecular weight cutoff of 10000 for 24 hr while collecting the reaction solution, wherein the dialysis solution is ultrapure water, and the solution is changed for 4-5 times. Finally, the solution in the dialysis bag is frozen and dried to obtain a solid substance, namely the sialic acid high molecular compound.
10mg of the sialic acid polymer compound is dissolved in 10ml of ultrapure water, and 1mg/ml of sialic acid nano-particles are obtained after ultrasonic treatment for 1h (40KHz, 25 ℃).
The particle size distribution of the material was measured by dynamic light scattering, and the results are shown in FIG. 1, which shows that the average particle size of the obtained sialic acid nanoparticles was 95nm.
Example 2 preparation of sialic acid nanoparticles
1000mg of a polystyrene maleic anhydride copolymer (PMSA) having a molecular weight of 5000 was dissolved in 10mL of DMF, and then 500mg of aminated sialic acid (SA, x = 4) was added, and 0.5mL of triethylamine was added to the reaction solution, and the reaction mixture was stirred at room temperature for 12 hours, followed by addition of 10mL of saturated NaHCO 3 Stirring the aqueous solution at room temperature for 1 hour, and collecting the reaction solution; and dialyzing the reaction solution for 24 hours by using a dialysis bag with the molecular weight cutoff of 5000 when collecting the reaction solution, wherein the dialysis solution is ultrapure water, and the solution is changed for 4-5 times in the middle. Finally, the solution in the dialysis bag is frozen and dried to obtain a solid substance, namely the sialic acid high molecular compound.
10mg of the sialic acid polymer compound is dissolved in 10ml of ultrapure water, and 1mg/ml of sialic acid nano-particles are obtained after ultrasonic treatment for 1h (40KHz, 25 ℃).
The particle size distribution of the material was measured by dynamic light scattering, and the result is shown in fig. 2, which shows that the obtained sialic acid nanoparticles had an average particle size of 98nm.
Example 3 preparation of sialic acid nanoparticles
500mg of a polystyrene maleic anhydride copolymer (PMSA) with a molecular weight of 20000 are dissolved in 10mL of DMF, and 200mg of aminated sialic acid (SA, x = 4) are added, and 1mL of aminated sialic acid are addedTriethylamine was added to the reaction mixture, the mixture was stirred at room temperature for 12 hours, and 10mL of saturated NaHCO was added 3 Stirring the aqueous solution at room temperature for 1 hour to collect a reaction solution; and dialyzing with dialysis bag with molecular weight cutoff of 20000 for 24 hr while collecting reaction solution, wherein the dialysis solution is ultrapure water, and the intermediate solution is changed for 4-5 times. Finally, the solution in the dialysis bag is frozen and dried to obtain a solid substance, namely the sialic acid high molecular compound.
10mg of the sialic acid polymer compound is dissolved in 10ml of ultrapure water, and 1mg/ml of sialic acid nano-particles are obtained after ultrasonic treatment for 1h (40KHz, 25 ℃).
The particle size distribution of the material was measured by dynamic light scattering, and the results are shown in FIG. 3, which shows that the average particle size of the obtained sialic acid nanoparticles was 102nm.
EXAMPLE 4 preparation of nasal spray formulations
The sialic acid nano-particles 2mg/mL, heparin 0.08mg/mL and fucoidan 0.15mg/mL prepared in the example 1 are dissolved in 250mL of normal saline, and the pH is adjusted to 6.5-7.0, so that the nasal spray preparation for preventing viral respiratory tract infection is prepared.
EXAMPLE 5 preparation of nasal spray formulation
2mg/mL of the sialic acid nanoparticles prepared in the example 2, 0.08mg/mL of heparin and 0.15mg/mL of carrageenan are dissolved in 250mL of normal saline, and the pH is adjusted to 6.5-7.0, so that the nasal spray preparation for preventing viral respiratory tract infection is prepared.
EXAMPLE 6 preparation of nasal spray formulations
The sialic acid nano-particles 2mg/mL, heparin 0.08mg/mL and fucoidan 0.15mg/mL prepared in the example 3 are dissolved in 250mL of normal saline, and the pH is adjusted to 6.5-7.0, so that the nasal spray preparation for preventing viral respiratory tract infection is prepared.
Comparative example 1
Dissolving sialic acid 2mg/mL, heparin 0.08mg/mL, and fucoidan 0.15mg/mL in 250mL of normal saline, and adjusting pH to 6.5-7.0 to obtain nasal spray.
Test example 1 mouse challenge protection experiment
Collecting 12g of female140 sex Kunming mice are randomly divided into 7 groups, 20 mice/group, 5 experimental groups and 2 control groups. Experimental group 1 mice were administered 1 week continuously by nasal instillation of 50. Mu.L of the nasal spray preparation prepared in example 4 daily. Experimental group 2 mice were administered 2 weeks continuously with 50. Mu.L of the nasal spray preparation prepared in example 4 being nasally dropped daily. Experimental group 3 mice were administered 1 week continuously by nasal drop administration of 50. Mu.L of the nasal spray preparation prepared in example 5 daily. Experimental group 4 mice were administered 1 week continuously by nasal instillation of 50. Mu.L of the nasal spray preparation prepared in example 6 daily. Experimental group 5 mice were administered 1 week continuously by nasal instillation of 50. Mu.L of the nasal spray preparation prepared in comparative example 1 into the nasal cavity daily. Experimental groups 1-5 subsequently instilled 50 μ L LD from nasal cavity 50 The virus was challenged with the A/PR/8/34 dose and then administered with 50 μ L nasal spray formulation of the corresponding experimental group for 3 consecutive days. In control group 1, mice were administered 1 week continuously by nasal instillation of 50. Mu.L of physiological saline daily. In control group 2, mice were administered with 50. Mu.L of physiological saline by nasal drip every day for 2 weeks.
The results are shown in table 1, and the sialic acid nanoparticle nasal spray preparation for preventing viral respiratory tract infection prepared by the application has good prevention and treatment effects on viral infection.
TABLE 1 survival Rate of mice
| Grouping | Survival rate |
| |
85 |
| Control group | |
| 1 | 55％ |
| Experimental group 2 | 90％ |
| Control group 2 | 45％ |
| Experimental group 3 | 90％ |
| Experimental group 4 | 80％ |
| Experimental group 5 | 90％ |
Test example 2 measurement of sialic acid content
Sialic acids in examples 4 to 6 and comparative example 1 were labeled with the fluorescent dye Cy5.5, and 24 SD rats were anesthetized and randomly divided into 4 groups and 6 groups. Experimental group 1 rat nasal cavity dropped 100. Mu.L of the nasal spray formulation prepared in comparative example 1, experimental group 2 rat nasal cavity dropped 100. Mu.L of the nasal spray formulation prepared in example 4, experimental group 3 rat nasal cavity dropped 100. Mu.L of the nasal spray formulation prepared in example 5, and Experimental group 4 rat nasal cavity dropped 100. Mu.L of the nasal spray formulation prepared in example 6. Immediately detecting the fluorescence intensity of the nasal cavity of the SD rat by using a small animal living body imaging system after nasal administration, and detecting once every 20min until no fluorescence is detected;
the results are shown in fig. 4, the nasal spray preparation prepared from free sialic acid has short retention time in the nasal cavity of the rat, only about 10% of the free sialic acid remained after 20 minutes of administration, and all the free sialic acid was removed within 40 minutes; the residence time of the sialic acid nanoparticle nasal spray preparation prepared by the application in the nasal cavity of the rat is obviously prolonged compared with that of free sialic acid, the sialic acid nanoparticle nasal spray preparation is completely removed in about 2 hours after the application, and the residence time of experimental groups 2, 3 and 4 in the nasal cavity of the rat is approximately the same.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above should not be understood to necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples described in this specification can be combined and combined by those skilled in the art.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (8)
1. A sialic acid nanoparticle, wherein the sialic acid nanoparticle is connected with sialic acid by using a polystyrene maleic anhydride copolymer as a skeleton, and the structural formula of the sialic acid nanoparticle is as follows:
2. a method of preparing sialic acid nanoparticles of claim 1, comprising the steps of:
(1) Reacting the aminated sialic acid with an anhydride group of a polystyrene maleic anhydride copolymer to obtain a sialic acid high molecular compound;
(2) And carrying out ultrasonic treatment on the sialic acid high molecular compound in an aqueous solution for 1h to obtain the sialic acid nano-particles.
3. The method of claim 2, wherein the sialic acid is N-acetylneuraminic acid.
4. The method of claim 2, wherein the polystyrene maleic anhydride copolymer has a molecular weight of 2000 to 20000.
5. The method according to claim 2, wherein the mass ratio of the aminated sialic acid to the polystyrene maleic anhydride copolymer is 1-2.
6. A nasal spray formulation comprising the sialic acid nanoparticles of claim 1, heparin, marine sulfated polysaccharide, and physiological saline.
7. The nasal spray formulation of claim 6, wherein the sialic acid nanoparticles are at a concentration of 1-10mg/mL, the heparin is at a concentration of 0.05-0.2mg/mL, and the marine sulfated polysaccharide is at a concentration of 0.1-0.5mg/mL.
8. The nasal spray formulation of claim 6, wherein the marine sulfated polysaccharide is fucoidan or carrageenan.
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| 壳聚糖-唾液酸寡糖离子复合物对流感病毒感染的抑制作用;吕玲等主编;《中国家禽》;20141231;第36卷(第10期);全文 * |
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