CN111743881A - Acid-responsive hydrogen-releasing drugs, preparation method thereof and application thereof in treatment of glycometabolism disorders and/or lipid metabolism disorders - Google Patents
Acid-responsive hydrogen-releasing drugs, preparation method thereof and application thereof in treatment of glycometabolism disorders and/or lipid metabolism disorders Download PDFInfo
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- B22F9/24—Making metallic powder or suspensions thereof using chemical processes with reduction of metal compounds starting from liquid metal compounds, e.g. solutions
- B22F2009/245—Reduction reaction in an Ionic Liquid [IL]
Abstract
The invention discloses an acid-response hydrogen release medicine, a preparation method thereof and application thereof in treating glycometabolism disorder and/or lipometabolism disorder, and relates to the technical fields of biology, nanometer materials and medicine and pharmacology. The acid-responsive hydrogen-releasing drug comprises: an acid-responsive hydrogen-releasing material that reacts with an acid to release hydrogen gas; the auxiliary material, the mass ratio of the acid-responsive nano hydrogen release material to the auxiliary material is 1: 1 to 1: 5; the acid-response hydrogen release medicine is formed by extrusion after the acid-response hydrogen release material and the auxiliary material are uniformly mixed. The acid-response hydrogen release medicine provided by the invention can slowly release hydrogen in a gastric acid environment after being orally taken, so that long-acting and controlled release of the hydrogen is realized, and sugar metabolism disorder and/or lipid metabolism disorder can be effectively relieved.
Description
Technical Field
The invention relates to the technical fields of biology, nano materials and medicine, in particular to an acid-response hydrogen release medicine, a preparation method thereof and application thereof in treating glycometabolism disorder and/or lipometabolism disorder.
Background
The metabolic syndrome is a group of syndromes which are clinically developed under the combined action of genetic factors and environmental factors and cause metabolic disorders of substances such as protein, fat, carbohydrate and the like of a human body, and mainly comprise abdominal obesity, hyperlipidemia and insulin resistance. With the worldwide prevalence of obesity, glycolipid metabolic disorders are regarded as important features of metabolic diseases, which threaten human health quietly and silently, and the clinical incidence of metabolic disorders such as diabetes and hyperlipidemia tends to increase, which has become an important factor affecting human health.
Hydrogen is a small molecule that is colorless, odorless, and reducing. More and more studies have found that hydrogen has antioxidant stress effects on almost all organ tissues. Compared with the traditional antioxidant, the hydrogen has the advantages of small molecular weight, easy free diffusion in vivo, capability of reaching a focus beyond the human body barrier beyond which many medicines cannot pass, no obvious toxic or side effect and the like. The existing research shows that the disease course progress of a disease model with oxidative damage as a common property can be remarkably relieved by adopting hydrogen absorption or oral administration of hydrogen-rich water or hydrogen-rich normal saline and the like.
Although hydrogen is a novel selective antioxidant and ideal anti-inflammatory substance, hydrogen has low solubility and can be freely diffused in the body, so that hydrogen is directly inhaled, and hydrogen-rich water is injected or drunk, so that hydrogen molecules are difficult to effectively reach and accumulate in deep focal tissues in large quantities, and the treatment effect is often limited. How to realize long-acting and controlled release of hydrogen has important significance on improving the treatment effect of hydrogen, and the challenge is still filled at present.
Disclosure of Invention
The invention mainly aims to provide an acid-response hydrogen release medicament, a preparation method thereof and application thereof in treating glycometabolism disorder and/or lipid metabolism disorder, and aims to provide the acid-response hydrogen release medicament capable of releasing hydrogen gas controllably and releasing hydrogen gas for a long time.
In order to achieve the above object, the present invention provides an acid-responsive hydrogen-releasing drug comprising:
an acid-responsive hydrogen-releasing material that reacts with an acid to release hydrogen gas;
the auxiliary material, the mass ratio of the acid-responsive nano hydrogen release material to the auxiliary material is 1: 1 to 1: 5;
the acid-response hydrogen release medicine is formed by extrusion after the acid-response hydrogen release material and the auxiliary material are uniformly mixed.
Optionally, the outer surface of the acid-responsive hydrogen-releasing drug is coated with a coating.
Optionally, the acid-responsive hydrogen-releasing material comprises hollow mesoporous silica loaded with at least one of ammonia borane, nano-iron particles, magnesium diboride nanoplates, and calcium diboride nanoplates.
Optionally, the surface of the acid-responsive hydrogen-releasing material is modified with a protective agent.
Optionally, when the acid-responsive hydrogen release material comprises hollow mesoporous silica supported ammonia borane, the protective agent of the hollow mesoporous silica supported ammonia borane is polyethylene glycol with a molecular weight of 2000-4000.
Optionally, the auxiliary material comprises at least one of polyethylene glycol, hydroxymethyl cellulose and polyvinylpyrrolidone, and the molecular weight of the polyethylene glycol is 2000-4000.
In order to achieve the above object, the present invention further provides a method for preparing an acid-responsive hydrogen-releasing drug, the method for preparing an acid-responsive hydrogen-releasing drug comprising:
and (3) mixing the acid response hydrogen release material and auxiliary materials according to the mass ratio of 1: 1 to 1: 5, uniformly mixing, and carrying out extrusion forming on the mixture to obtain the acid-response hydrogen release medicament.
Optionally, the acid-responsive hydrogen release material is a hollow mesoporous silica modified by polyethylene glycol loaded with ammonia borane, and the molecular weight of the polyethylene glycol is 2000-4000;
the acid response hydrogen release material and the auxiliary materials are mixed according to the mass ratio of 1: 1 to 1: 5, uniformly mixing, and performing extrusion forming on the mixture to obtain the acid-response hydrogen release medicament, wherein the step comprises the following steps:
dispersing the hollow mesoporous silica modified by polyethylene glycol as a nano carrier in absolute ethyl alcohol;
adding ammonia borane and polyethylene glycol with the molecular weight of 2000-4000 into absolute ethyl alcohol, and dissolving to obtain a mixed solution; wherein the mass ratio of the hollow mesoporous silica modified by polyethylene glycol to the ammonia borane is 1: 1 to 1: 2.5, the mass ratio of the hollow mesoporous silica modified by polyethylene glycol to the added polyethylene glycol with the molecular weight of 2000-4000 is 1: 0.5;
and drying the mixed solution in vacuum to obtain the hollow mesoporous silica modified by the polyethylene glycol loaded ammonia borane.
Optionally, the acid-responsive hydrogen-releasing material is a protective agent modified nano-iron particle;
the acid response hydrogen release material and the auxiliary materials are mixed according to the mass ratio of 1: 1 to 1: 5, uniformly mixing, and performing extrusion forming on the mixture to obtain the acid-response hydrogen release medicament, wherein the step comprises the following steps:
under the inert gas atmosphere, dissolving a protective agent in water to obtain a first solution, wherein the concentration of the protective agent in the first solution is 1-5 wt%;
adding water-soluble iron salt into the first solution to dissolve to obtain a second solution, wherein the concentration of iron ions in the second solution is 5-100 mM;
dissolving a reducing agent in water to obtain a reducing agent solution, adding the reducing agent solution into the second solution to obtain a third mixed solution, stirring the third mixed solution for 0.5-5 h, and separating to obtain a precipitate in the third mixed solution; wherein the concentration of the reducing agent is 10-500 mM, and the volume ratio of the reducing agent solution to the second solution is (1: 10) to (1000: 1);
and washing the precipitate with excessive water, and freeze-drying to obtain the nano-iron particles modified by the protective agent.
In addition, the invention also provides the application of the acid response hydrogen release medicament in treating glycometabolism disorder and/or lipid metabolism disorder.
In the technical scheme provided by the invention, the acid response hydrogen release medicine comprises: an acid-responsive hydrogen-releasing material that reacts with an acid to release hydrogen gas; the auxiliary material, the mass ratio of the acid-responsive nano hydrogen release material to the auxiliary material is 1: 1 to 1: 5; the acid-response hydrogen release medicine is formed by extrusion after the acid-response hydrogen release material and the auxiliary material are uniformly mixed. The acid-response hydrogen release medicine provided by the invention can slowly release hydrogen in a gastric acid environment after being orally taken, so that long-acting and controlled release of the hydrogen is realized, and sugar metabolism disorder and/or lipid metabolism disorder can be effectively relieved.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other related drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a schematic diagram of a preparation process of an acid-responsive hydrogen-releasing drug and a hydrogen releasing process when the acid-responsive hydrogen-releasing drug is a hollow mesoporous silica-loaded ammonia borane modified by polyethylene glycol and an auxiliary material is polyethylene glycol;
FIG. 2 is a structural characterization map of the hollow mesoporous silica-loaded ammonia borane modified by polyethylene glycol of the present invention;
FIG. 3 shows the long-acting hydrogen release performance of an acid-responsive hydrogen release material, which is an acid-responsive hydrogen release drug prepared by loading ammonia borane on hollow mesoporous silica modified by polyethylene glycol without adding auxiliary polyethylene glycol or adding auxiliary polyethylene glycol, at different pH values;
FIG. 4 is a schematic illustration of the effect of an acid-responsive hydrogen-releasing drug on lipid metabolism in mice;
FIG. 5 is a schematic illustration of the effect of an acid-responsive hydrogen-releasing drug on carbohydrate and lipid metabolism in mice;
fig. 6 shows the results of macrogenetic testing of feces collected before (week 3) and after (week 16) the C57 mice fed the acid-responsive hydrogen-releasing drug.
The implementation, functional features and advantages of the objects of the present invention will be further explained with reference to the accompanying drawings.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments.
It should be noted that those whose specific conditions are not specified in the examples were performed according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially. In addition, the meaning of "and/or" appearing throughout includes three juxtapositions, exemplified by "A and/or B" including either A or B or both A and B. In addition, technical solutions between various embodiments may be combined with each other, but must be realized by a person skilled in the art, and when the technical solutions are contradictory or cannot be realized, such a combination should not be considered to exist, and is not within the protection scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Although hydrogen is a novel selective antioxidant and ideal anti-inflammatory substance, hydrogen has low solubility and can be freely diffused in the body, so that hydrogen is directly inhaled, and hydrogen-rich water is injected or drunk, so that hydrogen molecules are difficult to effectively reach and accumulate in deep focal tissues in large quantities, and the treatment effect is often limited. How to realize long-acting and controlled release of hydrogen has important significance on improving the treatment effect of hydrogen, and the challenge is still filled at present.
In view of the above, the present invention provides an acid-responsive hydrogen-releasing medicament, which comprises an acid-responsive hydrogen-releasing material and an auxiliary material, wherein the acid-responsive hydrogen-releasing material reacts with an acid to release hydrogen; the mass ratio of the acid-responsive nano hydrogen release material to the auxiliary material is 1: 1 to 1: 5; the acid-response hydrogen release medicine is formed by extrusion after the acid-response hydrogen release material and the auxiliary material are uniformly mixed.
In the technical scheme of the invention, the acid-response hydrogen release medicine is provided, the acid-response hydrogen release medicine comprises an acid-response hydrogen release material, the acid-response hydrogen release refers to that the medicine can react with acid to generate hydrogen under an acid environment (the acid environment in an organism is generally formed by gastric acid), and common reactions capable of generating hydrogen are generally violent, short in duration and high in hydrogen release speed, so that in order to slow down the reaction speed, the acid-response hydrogen release medicine also comprises auxiliary materials, and the auxiliary materials and the acid-response hydrogen release material are mixed according to the mass ratio of 1: 1 to 5: 1, and the auxiliary material can not react with acid, so that the speed of hydrogen generated by the reaction of the acid-response hydrogen release material and the acid can be greatly reduced by adding the auxiliary material into the acid-response hydrogen release material, thereby realizing the long-acting release and the controlled release of the hydrogen and improving the effect of hydrogen treatment.
Referring to fig. 3, the behavior of AB @ hMSN @ PEG in generating hydrogen under the condition of pH 1.2 is shown in (i); ② the behavior of AB @ hMSN generating hydrogen under the condition that pH is 1.2; ③ the action of AB @ hMSN generating hydrogen under the condition of pH 7.4; (iv) AB @ hMSN @ PEG at pH 7.4, hydrogen evolution behavior. As can be seen from fig. 3, both AB @ hMSN and AB @ hMSN @ PEG have almost no hydrogen generation in neutral environment (pH 7.4), while both are able to generate hydrogen in acidic environment, and release of hydrogen from AB @ hMSN occurs rapidly in a short time, with a relatively violent and non-persistent reaction; the AB @ hMSN @ PEG has stable hydrogen releasing speed, and the action of releasing hydrogen lasts for a long time, so that the speed of the hydrogen generated by the reaction of the acid response hydrogen releasing material and the acid can be reduced, the long-acting release and the controlled release of the hydrogen are realized, and the hydrogen treatment effect is improved.
Further, the acid-responsive hydrogen release material comprises at least one of Hollow Mesoporous Silica (HMSN) loaded ammonia borane, nano iron particles, magnesium diboride nanosheets and calcium diboride nanosheets, and the acid-responsive hydrogen release material can react with acid to generate hydrogen, and specifically, the ammonia borane in the hollow mesoporous silica loaded ammonia borane can react with the acid to generate hydrogen; the iron in the nano iron particles can react with acid to generate hydrogen; the magnesium diboride in the magnesium diboride nanosheets can react with acid to generate hydrogen; calcium diboride in the calcium diboride nanosheets can react with an acid to generate hydrogen.
Further, in order to further slow down the speed of hydrogen gas released by the reaction between the acid-responsive hydrogen releasing material and the acid, a protective agent can be modified on the surface of the acid-responsive hydrogen releasing material, and the protective agent cannot react with the acid. When the acid-responsive hydrogen release material is hollow mesoporous silica loaded ammonia borane, the protective agent can be polyethylene glycol with molecular weight of 2000-4000; when the acid-response hydrogen release material is a nano iron particle, the protective agent is a macromolecular compound capable of being in coordination complex with iron, and the protective agent comprises but is not limited to at least one of polyvinylpyrrolidone, sodium hydroxypropyl cellulose, sodium carboxyethyl cellulose, sodium carboxymethyl cellulose and sodium alginate; when the acid-response hydrogen release material is a magnesium diboride nanosheet, the protective agent is polyvinylpyrrolidone; when the acid-response hydrogen release material is calcium diboride nanosheets, the protective agent is polyvinylpyrrolidone.
Further, the auxiliary material comprises at least one of polyethylene glycol, hydroxymethyl cellulose and polyvinylpyrrolidone, and the molecular weight of the polyethylene glycol is 2000-4000.
Further, the outer surface of the acid-responsive hydrogen release medicament can be coated with a coating to further slow down the release rate of hydrogen. The coating may be at least one of polyvinyl alcohol, a blank pellet core, a hypertonic pellet core, a microcrystalline cellulose pellet core, a sugar pellet, and a high-strength starch pellet core, and certainly, the coating may also be at least one of polyethylene glycol having a molecular weight of 2000-4000, hydroxymethyl cellulose, and polyvinylpyrrolidone, which is not limited in this embodiment.
The acid-response hydrogen release medicament provided by the invention has the advantages of simple preparation process, low cytotoxicity and capability of slowly releasing hydrogen in a gastric acid environment, thereby realizing long-acting and controlled release of hydrogen.
Further, the invention also provides a preparation method of the acid-response hydrogen release medicine.
Taking the acid response hydrogen release material and auxiliary materials as raw materials, and mixing the raw materials according to the mass ratio of 1: 1 to 1: 5, uniformly mixing, and carrying out extrusion forming to obtain the acid-response hydrogen release medicament.
Further, if the acid-responsive hydrogen release material is polyethylene glycol modified hollow mesoporous silica supported ammonia borane, the molecular weight of the polyethylene glycol is 2000-4000, and the preparation method of the polyethylene glycol modified mesoporous silica supported ammonia borane comprises the following steps:
a1, dispersing the hollow mesoporous silica modified by polyethylene glycol as a nano carrier in absolute ethyl alcohol;
step A2, adding ammonia borane and polyethylene glycol with molecular weight of 2000-4000 into absolute ethyl alcohol, and dissolving to obtain a mixed solution; wherein the mass ratio of the hollow mesoporous silica modified by polyethylene glycol to the ammonia borane is 1: 1 to 1: 2.5, the mass ratio of the hollow mesoporous silica modified by polyethylene glycol to the added polyethylene glycol with the molecular weight of 2000-4000 is 1: 0.5;
and A3, drying the mixed solution in vacuum to obtain the hollow mesoporous silica modified by polyethylene glycol loaded ammonia borane.
It can be understood that, for the hollow mesoporous silica without the protection agent modification to load ammonia borane, the preparation method is similar to the preparation method of the mesoporous silica modified by polyethylene glycol to load ammonia borane.
Specifically, referring to fig. 1, in fig. 1, hMSN refers to polyethylene glycol modified hollow mesoporous silica, AB refers to ammonia borane, PEG refers to polyethylene glycol with a molecular weight of 2000-4000, AB @ hMSN refers to polyethylene glycol modified mesoporous silica loaded with ammonia borane, and AB @ hMSN @ PEG refers to an acid-responsive hydrogen-releasing drug prepared by uniformly mixing polyethylene glycol modified mesoporous silica loaded with ammonia borane and an auxiliary material PEG and then pressing the mixture.
In addition, referring to fig. 2, fig. 2(a) is a Transmission Electron Microscope (TEM) image of the polyethylene glycol-modified hollow mesoporous silica; FIG. 2(B) is a Scanning Electron Microscope (SEM) image of a hollow mesoporous silica modified by polyethylene glycol loaded with ammonia borane; fig. 2(C) is an element distribution diagram of the hollow mesoporous silica modified by polyethylene glycol loaded with ammonia borane.
Further, referring to fig. 3, the behavior of AB @ hMSN @ PEG in generating hydrogen at pH 1.2 is shown; ② the behavior of AB @ hMSN generating hydrogen under the condition that pH is 1.2; ③ the action of AB @ hMSN generating hydrogen under the condition of pH 7.4; (iv) AB @ hMSN @ PEG at pH 7.4, hydrogen evolution behavior. The above experiments show that no matter AB @ hMSN or AB @ hMSN @ PEG, almost no hydrogen is generated in a neutral environment (pH 7.4), both can generate hydrogen in an acidic environment, and the speed of releasing hydrogen from AB @ hMSN @ PEG is relatively stable, the action of releasing hydrogen is relatively long, and the action of releasing hydrogen from AB @ hMSN is rapid and takes place in a short time, the reaction is relatively violent and not durable, which indicates that the drug obtained by extrusion molding has a longer hydrogen release effect than the drug without the added adjuvant.
Further, if the acid-responsive hydrogen release material is a nano-iron particle modified by a protective agent, the preparation method of the nano-iron particle modified by the protective agent comprises the following steps:
the acid response hydrogen release material and the auxiliary materials are mixed according to the mass ratio of 1: 1 to 1: 5, uniformly mixing, and performing extrusion forming on the mixture to obtain the acid-response hydrogen release medicament, wherein the step comprises the following steps:
step B1, dissolving a protective agent in water under an inert gas atmosphere to obtain a first solution, wherein the concentration of the protective agent in the first solution is 1-5 wt%;
step B2, adding a water-soluble iron salt into the first solution to dissolve to obtain a second solution, wherein the concentration of iron ions in the second solution is 5-100 mM;
step B3, dissolving a reducing agent in water to obtain a reducing agent solution, adding the reducing agent solution into the second solution to obtain a third mixed solution, stirring the third mixed solution for 0.5-5 h, and separating to obtain a precipitate in the third mixed solution; wherein the concentration of the reducing agent in the reducing agent solution is 10-500 mM, and the volume ratio of the reducing agent solution to the second solution is (1: 10) to (1000: 1);
step B4, washing the precipitate with excessive water to remove free iron ions, and freeze-drying to obtain the nano-iron particles modified by the protective agent.
In specific implementation, the inert gas is at least one of nitrogen, argon and helium; the protective agent is a macromolecular compound capable of being in coordination complexation with iron, and comprises but is not limited to at least one of polyvinylpyrrolidone, sodium hydroxypropyl cellulose, sodium carboxyethyl cellulose, sodium carboxymethyl cellulose and sodium alginate; the water-soluble ferric salt comprises but is not limited to at least one of ferric chloride, ferrous chloride, ferric sulfate, ferrous sulfate, ferric nitrate and ferrous nitrate; the reducing agent includes but is not limited to at least one of potassium borohydride, sodium thiosulfate, sodium sulfite, sodium sulfide, and sodium hydrosulfide.
Of course, the acid-responsive hydrogen-releasing material may also be magnesium diboride nanosheets or calcium diboride nanosheets, and for the preparation methods of the magnesium diboride nanosheets and the calcium diboride nanosheets, reference may be made to the existing preparation methods, which are not described herein again.
Further, the invention also provides application of the acid response hydrogen release medicament in treating glycometabolism disorder and/or lipid metabolism disorder.
Referring to fig. 4, the animal model used in the experiment is C57/6N mice, the mice are divided into 5 groups, and the mice are fed with high-fat diet only (the fat caloric content is 45-60%) in the blank control group; the mice in the group II are fed after being doped with a certain proportion of medicines in high-fat feed, wherein the proportion is that 40mg of hollow mesoporous silica is added into 100g of high-fat feed; the mice in the third group are fed with medicines with a certain proportion after being mixed with high-fat feed, and the proportion is that 40mg of polyethylene glycol is added into 100g of high-fat feed; feeding mice in a group of ammonia borane groups after a certain proportion of medicines are mixed into high-fat feed, wherein the proportion is that 40mg of ammonia borane is added into 100g of high-fat feed; and feeding mice in the fifth group after the mice are doped with medicines with a certain proportion in high-fat feed, wherein the proportion is that 40mg of AB @ hMSN @ PEG is added into 100g of high-fat feed.
FIG. 4A is a graph showing the change in body weight of mice in each group during the feeding period of 16 weeks, wherein the abscissa represents the feeding time and the ordinate represents the body weight of the mice, and the body weight measurement results show that the body weight of the mice fed with the AB @ hMSN @ PEG hydrogen release drug group is significantly reduced.
Fig. 4B is a comparison of adipose tissue weight of each group of mice fed for 16 weeks, wherein the abscissa is different adipose tissue, the ordinate is weight, eWAT is epididymal fat, iWAT is inguinal fat, rWAT is peritoneal fat, BAT is brown fat, and the results of the adipose tissue weight comparison show that the adipose tissues of the mice fed with AB @ hMSN @ PEG hydrogen release drug are all significantly lower than those of the control group.
Fig. 4C is a comparison of liver weights of mice in each group after 16 weeks of feeding, with the ordinate being liver weight, and the liver weight comparison results show that the liver weight of mice in the group fed AB @ hMSN @ PEG hydrogen release drug was significantly reduced compared to the control group.
FIG. 4D is a comparison of liver H & E (hematoxylin-eosin stained) and ORO (oil red stained) sections of mice in each group after 16 weeks of feeding, showing that liver fat was significantly reduced in mice fed with AB @ hMSN @ PEG hydrogen release drug.
The above results demonstrate that acid-responsive hydrogen-releasing drugs can improve lipid metabolism in mice.
Further, referring to fig. 5, the animal model used in the experiment is db/db mice (diabetes model mice), the mice are divided into 2 groups, namely, a blank control group, and the mice are fed with normal maintenance feed only (the fat caloric content accounts for 4-15%); the mice in the group II are fed after being doped with medicines with a certain proportion in the normal maintenance feed, wherein the proportion is that 40mg of AB @ hMSN @ PEG is added into 100g of the normal maintenance feed.
FIG. 5a is a graph showing the change in body weight of mice in each group during 6 weeks of feeding, wherein the abscissa is the feeding time and the ordinate is the difference in body weight of the mice (when the week weight is subtracted from the initial week weight), and the body weight measurements show that the body weight of the mice fed the AB @ hMSN @ PEG hydrogen release drug group is significantly reduced compared to the blank control group.
Fig. 5b is a comparison of adipose tissue weight of the groups of mice fed 6 weeks later, wherein the abscissa is different adipose tissues, the ordinate is weight, eWAT is epididymal fat, iWAT is inguinal fat, rWAT is peritoneal fat, BAT is brown fat, and the results of the adipose tissue weight comparison show that inguinal adipose tissue of the mice fed the AB @ hMSN @ PEG hydrogen release drug group is significantly lower than that of the blank control group.
Fig. 5c is a comparison of total cholesterol levels in blood of mice in each group after 6 weeks feeding, the ordinate is the cholesterol level in blood, and the comparison result of the cholesterol levels in blood shows that the cholesterol level in blood of mice fed with the AB @ hMSN @ PEG hydrogen release drug is significantly lower than that of the mice fed with the blank control group.
FIG. 5d is a comparison of liver H & E (hematoxylin-eosin stained) and ORO (oil red stained) sections of mice in each group after 6 weeks feeding, showing that the liver fat content of the mice fed with the AB @ hMSN @ PEG hydrogen release drug was significantly less than that of the blank control group.
Fig. 5e is the blood glucose concentration after fasting for 6 weeks in each group of mice, and the ordinate is the blood glucose concentration measured after 8h fasting, and the comparison shows that the blood glucose concentration of the group of mice fed with the AB @ hMSN @ PEG hydrogen release drug is significantly lower than that of the blank control group.
FIG. 5f is a graph of glucose tolerance after fasting for 6 weeks in each group of mice with the ordinate representing blood glucose concentration in the mice and the abscissa representing blood withdrawal time after glucose injection. The comparison result shows that the mice fed with the AB @ hMSN @ PEG hydrogen release drug group have more obvious glucose tolerance compared with the blank control group.
FIG. 5g is an insulin resistance test after fasting for 6 weeks in mice fed with AB @ hMSN @ PEG hydrogen release drug, and the ordinate is the insulin concentration in the blood of the mice.
The above results demonstrate that acid-responsive hydrogen-releasing drugs can improve carbohydrate metabolism and lipid metabolism in diabetic mice. .
Further, referring to fig. 6, fig. 6 is a graph showing the results of the macrogene test on feces collected before (week 3) and after (week 16) the C57 mice were fed the acid-responsive hydrogen-releasing drug, wherein the ordinate is the relative abundance, a is a blank control group to which only the feed was fed, and a03 is the macrogene test result of the feces of the mice of the blank control group at week 3; a16 refers to macrogenic test results of the feces at week 16 of mice in the placebo group; e is a group fed with the acid-responsive hydrogen-releasing drug, the group is fed after a certain proportion of the acid-responsive hydrogen-releasing material is added into the feed, the proportion is that 40mg AB @ hMSN @ PEG is added into 100g of the feed, and E03 refers to a macrogene test result of the feces of the mice fed with the group at the 3 rd week; e16 refers to macrogenetic test results of the feces at week 16 of mice fed the acid-responsive hydrogen-releasing drug group.
The content of Akkermansia muciniphila (muciniphila-Ackermansia) is represented by the grid in FIG. 6, and it can be seen that the Akkermansia muciniphila population is significantly increased after feeding the hydrogen-releasing agent for 16 weeks.
The above results indicate that the acid-responsive hydrogen release drug can significantly improve the structure of the intestinal flora, and is particularly beneficial to increase the content of Akkermansia muciniphila (muciniphila-Ackermansia) in the intestinal tract, thereby effectively regulating sugar metabolism and/or lipid metabolism disorder.
The above is only a preferred embodiment of the present invention, and it is not intended to limit the scope of the invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall be included in the scope of the present invention.
Claims (10)
1. An acid-responsive hydrogen-releasing drug, wherein the acid-responsive hydrogen-releasing drug comprises:
an acid-responsive hydrogen-releasing material that reacts with an acid to release hydrogen gas;
the auxiliary material, the mass ratio of the acid-responsive nano hydrogen release material to the auxiliary material is 1: 1 to 1: 5;
the acid-response hydrogen release medicine is formed by extrusion after the acid-response hydrogen release material and the auxiliary material are uniformly mixed.
2. The acid-responsive hydrogen-releasing drug of claim 1, wherein an outer surface of the acid-responsive hydrogen-releasing drug is coated with a coating.
3. The acid-responsive hydrogen-releasing drug of claim 1, wherein the acid-responsive hydrogen-releasing material comprises hollow mesoporous silica loaded with at least one of ammonia borane, nano-iron particles, magnesium diboride nanoplates, and calcium diboride nanoplates.
4. The acid-responsive hydrogen-releasing medicament of claim 3, wherein the surface of the acid-responsive hydrogen-releasing material is modified with a protecting agent.
5. The acid-responsive hydrogen-releasing medicament of claim 4, wherein when the acid-responsive hydrogen-releasing material comprises hollow mesoporous silica loaded with ammonia borane, the protective agent of the hollow mesoporous silica loaded with ammonia borane is polyethylene glycol with a molecular weight of 2000-4000.
6. The acid-responsive hydrogen-releasing medicament of any one of claims 1 to 5, wherein the adjuvant comprises at least one of polyethylene glycol, hydroxymethyl cellulose and polyvinylpyrrolidone, and the polyethylene glycol has a molecular weight of 2000 to 4000.
7. A preparation method of an acid-response hydrogen release medicine is characterized by comprising the following steps:
and (3) mixing the acid response hydrogen release material and auxiliary materials according to the mass ratio of 1: 1 to 1: 5, uniformly mixing, and carrying out extrusion forming on the mixture to obtain the acid-response hydrogen release medicament.
8. The preparation method of the acid-responsive hydrogen-releasing medicament of claim 7, wherein the acid-responsive hydrogen-releasing material is a hollow mesoporous silica modified by polyethylene glycol loaded ammonia borane, and the molecular weight of the polyethylene glycol is 2000-4000;
the acid response hydrogen release material and the auxiliary materials are mixed according to the mass ratio of 1: 1 to 1: 5, uniformly mixing, and performing extrusion forming on the mixture to obtain the acid-response hydrogen release medicament, wherein the step comprises the following steps:
dispersing the hollow mesoporous silica modified by polyethylene glycol as a nano carrier in absolute ethyl alcohol;
adding ammonia borane and polyethylene glycol with the molecular weight of 2000-4000 into absolute ethyl alcohol, and dissolving to obtain a mixed solution; wherein the mass ratio of the hollow mesoporous silica modified by polyethylene glycol to the ammonia borane is 1: 1 to 1: 2.5, the mass ratio of the hollow mesoporous silica modified by polyethylene glycol to the added polyethylene glycol with the molecular weight of 2000-4000 is 1: 0.5;
and drying the mixed solution in vacuum to obtain the hollow mesoporous silica modified by the polyethylene glycol loaded ammonia borane.
9. The method for preparing an acid-responsive hydrogen-releasing medicament according to claim 7, wherein the acid-responsive hydrogen-releasing material is a nano-iron particle modified by a protective agent;
the acid response hydrogen release material and the auxiliary materials are mixed according to the mass ratio of 1: 1 to 1: 5, uniformly mixing, and performing extrusion forming on the mixture to obtain the acid-response hydrogen release medicament, wherein the step comprises the following steps:
under the inert gas atmosphere, dissolving a protective agent in water to obtain a first solution, wherein the concentration of the protective agent in the first solution is 1-5 wt%;
adding water-soluble iron salt into the first solution to dissolve to obtain a second solution, wherein the concentration of iron ions in the second solution is 5-100 mM;
dissolving a reducing agent in water to obtain a reducing agent solution, adding the reducing agent solution into the second solution to obtain a third mixed solution, stirring the third mixed solution for 0.5-5 h, and separating to obtain a precipitate in the third mixed solution; wherein the concentration of the reducing agent is 10-500 mM, and the volume ratio of the reducing agent solution to the second solution is (1: 10) to (1000: 1);
and washing the precipitate with excessive water, and freeze-drying to obtain the nano-iron particles modified by the protective agent.
10. Use of an acid-responsive hydrogen-releasing medicament as claimed in any one of claims 1 to 6 for the treatment of disorders of carbohydrate metabolism and/or lipid metabolism.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130266878A1 (en) * | 2012-04-04 | 2013-10-10 | GM Global Technology Operations LLC | Hydrogen storage system including a lithium conductor |
| EP2695851A1 (en) * | 2012-08-08 | 2014-02-12 | EADS Deutschland GmbH | Hydrogen generation from ammonia borane |
| CN103949254A (en) * | 2014-05-06 | 2014-07-30 | 江西师范大学 | Cu@mSiO2 core-shell nano catalyst for preparing hydrogen from ammonia borane and hydrazine borane by hydrolysis and preparation method of catalyst |
| CN106109489A (en) * | 2016-06-28 | 2016-11-16 | 西安交通大学 | The application in the medicine of the fat associated metabolic inflammation of preparation preventing and treating of the hydrogen molecule solid-state carrier |
| CN108042810A (en) * | 2017-12-28 | 2018-05-18 | 深圳大学 | Hydrogen Nano medication and preparation method thereof is released in a kind of acid response |
| CN109718224A (en) * | 2019-03-05 | 2019-05-07 | 深圳大学 | A kind of iron-based Nano medication and preparation method thereof with sour responsiveness release hydrogen |
| CN109876008A (en) * | 2019-03-13 | 2019-06-14 | 深圳大学 | A kind of drug and its preparation method and application for oncotherapy |
-
2020
- 2020-07-07 CN CN202010655914.7A patent/CN111743881A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130266878A1 (en) * | 2012-04-04 | 2013-10-10 | GM Global Technology Operations LLC | Hydrogen storage system including a lithium conductor |
| EP2695851A1 (en) * | 2012-08-08 | 2014-02-12 | EADS Deutschland GmbH | Hydrogen generation from ammonia borane |
| CN103949254A (en) * | 2014-05-06 | 2014-07-30 | 江西师范大学 | Cu@mSiO2 core-shell nano catalyst for preparing hydrogen from ammonia borane and hydrazine borane by hydrolysis and preparation method of catalyst |
| CN106109489A (en) * | 2016-06-28 | 2016-11-16 | 西安交通大学 | The application in the medicine of the fat associated metabolic inflammation of preparation preventing and treating of the hydrogen molecule solid-state carrier |
| CN108042810A (en) * | 2017-12-28 | 2018-05-18 | 深圳大学 | Hydrogen Nano medication and preparation method thereof is released in a kind of acid response |
| CN109718224A (en) * | 2019-03-05 | 2019-05-07 | 深圳大学 | A kind of iron-based Nano medication and preparation method thereof with sour responsiveness release hydrogen |
| CN109876008A (en) * | 2019-03-13 | 2019-06-14 | 深圳大学 | A kind of drug and its preparation method and application for oncotherapy |
Non-Patent Citations (3)
| Title |
|---|
| TIAN YANG , 等: "Intratumoral high-payload delivery and acid-responsive release of H2 for efficient cancer therapy using the ammonia borane-loaded mesoporous silica nanomedicine", 《APPLIED MATERIALS TODAY》 * |
| ZHAOKUI JIN，等: "Nanocapsule-mediated sustained H2 release in the gut ameliorates metabolic dysfunction-associated fatty liver disease", 《BIOMATERIALS》 * |
| 袁点: "氢分子对高脂饮食C57BL/6小鼠肝脏氧化应激的影响及其分子机制研究", 《中国优秀硕士学位论文全文数据库 (医药卫生科技辑)》 * |
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