Acid-resistant gel as well as preparation method and application thereof

Abstract

The invention provides acid-resistant gel as well as a preparation method and application thereof. In order to solve the problems that the traditional weight-reducing medicine and the existing weight-reducing equipment permanently injure the body and endanger life health, and most of hydrogel cannot meet the acid tolerance and high expansion rate, the invention provides the edible acid-resistant gel with high expansion rate. The acid-resistant gel is composed of a core-shell structure, firstly, ionic cross-linking is carried out through electrostatic interaction to form a'core 'of an inner layer, and then secondary cross-linking is carried out outside to form a'shell'. The acid-resistant gel disclosed by the invention has the function of stably expanding in an acid environment on the premise of meeting the requirements of biocompatibility and biodegradability, can be used as a new material for replacing medicines and implantation equipment, and has a wide prospect.

Description

Technical Field

[0001] The invention belongs to the field of polymer materials, and in particular relates to an acid-resistant gel and a preparation method and application thereof. Background Art

[0002] Obesity has become a global "epidemic", with nearly two-thirds of adults and one-third of children being overweight or obese. The global obesity prevalence has nearly tripled between 1975 and 2016, and the obese group is still growing. Frost & Sullivan shows that the number of obese people in China will reach about 240 million in 2022, with an average annual compound growth rate of 4.66% in the past five years. Overweight and obesity, once considered a problem in high-income countries, are now also on the rise in low-income and middle-income countries. What's more serious is that overweight and obesity have seriously endangered health, ranking third among risk factors for death, second only to hypertension and tobacco, and are associated with many non-communicable diseases, including cardiovascular disease, type 2 diabetes and cancer. In addition, in terms of social impact, obesity may cause individuals to have negative psychology.

[0003] People have started to manage their weight since the last century, and traditional weight loss drugs were all the rage. Orlistat is currently the only drug approved for obesity treatment in China, and it is also an over-the-counter drug. Orlistat can selectively inhibit the activity of pancreatic lipase and reduce the decomposition and absorption of fat in the gastrointestinal tract. However, it can also cause adverse reactions to the gastrointestinal tract (such as oily stools and urgency of defecation). Users may also need to take multivitamin preparations daily to improve fat-soluble vitamin absorption disorders. In addition, at the end of 1997, sibutramine was approved by the US FDA as a weight loss drug, but since 2010, Europe, the United States and other countries have successively banned sibutramine. In October of the same year, the China Food and Drug Administration also requested to stop the production, sale and use of sibutramine in my country. This is because sibutramine not only failed to achieve significant weight loss effects, but also greatly increased the risk of cardiovascular disease. The disadvantages of traditional weight loss drugs cannot be ignored.

[0004] With the advancement of technology, new weight management devices have emerged. Maestro Rechargeable System is the first new weight loss device approved by the FDA. It can be used for some obese adult patients. It is also the first weight loss treatment device that targets the neural pathways between the brain and the stomach that control hunger and satiety. It can temporarily block the neural traffic between the brain and the stomach, thereby reducing hunger and increasing satiety. However, serious adverse events reported in clinical studies include nausea, pain, vomiting and surgical complications at the site of neuromodulation. Other adverse events include pain, heartburn, swallowing problems, belching, moderate nausea and chest pain. The second weight loss device approved by the FDA is the intragastric balloon Orbera, which occupies the space in the stomach with a silicone balloon filled with saline to assist in weight loss. However, about one-third of people will experience symptoms such as pain and nausea shortly after the intragastric water balloon is placed. Other adverse reactions include balloon displacement, gastric ulcers, intestinal obstruction, etc., which may require surgical repair in severe cases. A comprehensive analysis of the above-mentioned various weight management programs will not only increase the cost of weight loss sharply, but also have a great possibility of causing irreparable physical damage and endangering life and health.

[0005] Hydrogels are considered the safest alternative for gastric weight loss today because of their excellent biocompatibility. Plenity, an intragastric water-absorbing particle developed by Gelesis, is an oral weight management device used to assist in the treatment of chronic diseases such as overweight and obesity. It can absorb water and swell in the stomach without surgery and has low drug side effects. Although it has a relatively excellent expansion rate, its mechanical properties are poor and it is easily broken by gastric peristalsis and squeezing, losing the advantage of the gastric principle. This may be due to the fact that the cross-linked network is not dense enough.

[0006] The current pH-responsive hydrogels can undergo shrinkage-swelling transitions in response to stimuli, which meets the requirement that oral weight management gels have a high absorption rate in a strong acid environment. However, the dynamic chemical bonds such as imine bonds and acylhydrazone bonds in the current pH-responsive hydrogels are easily hydrolyzed and broken under acidic conditions, resulting in extremely low gel expansion rates or even direct degradation. In terms of raw material selection, most hydrophilic polymers such as food-grade sodium polyacrylate are almost soluble at pH = 2.5, but other polymers with relatively stable structures such as polyacrylamide and polyacrylonitrile are not edible. In short, the acid stability and high expansion rate of most existing hydrogels have not yet been met, and these properties are indispensable for gastrointestinal devices.

[0007] Taking into account the various weight management programs mentioned above, from traditional weight loss drugs to hydrogel oral weight management gels, gels with acid resistance, high swelling rate and excellent mechanical properties have not yet been reported. Summary of the invention

[0008] In order to overcome the problems that traditional weight loss drugs and existing weight loss equipment permanently damage the body and endanger life and health, and that most hydrogels cannot meet the acid tolerance and high expansion rate, the present invention provides an edible, acid-resistant and high-expansion oral weight management gel material. The present invention prepares a natural gel polymer through a core-shell structure design. The selected natural polysaccharide raw materials are rich in variety and widely available, and a more stable non-reversible internal network system is constructed through the dual effects of physical cross-linking and chemical cross-linking, so that the gel not only has excellent acid resistance and expansion, but also has a simple preparation process and low cost, which can meet the needs of industrial mass production.

[0009] The technical scheme adopted by the present invention is: an acid-resistant gel, which has a core-shell structure; the core structure is formed by ionic crosslinking of polysaccharide A and polysaccharide B; the shell structure is formed by crosslinking of polysaccharide C with the surface groups of the core structure under the action of a crosslinking agent; wherein the polysaccharide A is a cationic polysaccharide, the polysaccharide B is an anionic polysaccharide, and the polysaccharide C is a neutral polysaccharide.

[0010] Preferably, in an environment with a pH value less than 7, the absorption rate of the acid-resistant gel is not less than 40 g / g; more preferably, in an environment with a pH value less than 2, the absorption rate of the acid-resistant gel is not less than 40 g / g. In one or more specific embodiments of the present invention, the absorption rate of the acid-resistant gel in simulated gastric fluid with a pH value of 1.2 is 50-65 g / g.

[0011] Preferably, the polysaccharide A is selected from one or more of chitosan, cationic guar gum, cationic hydroxypropyl methylcellulose, cationic starch powder, and cationic agarose, and more preferably chitosan.

[0012] Preferably, the polysaccharide B is selected from one or more of xanthan gum, pectin, hyaluronic acid, alginate, carrageenan and gellan gum, more preferably hyaluronic acid.

[0013] Preferably, the polysaccharide C is selected from one or more of locust bean gum, konjac gum and kojic gum, more preferably locust bean gum.

[0014] Preferably, the cross-linking agent is selected from one or both of water-soluble carbodiimide and N-hydroxysuccinimide, more preferably water-soluble carbodiimide.

[0015] The present invention also provides a method for preparing the acid-resistant gel, comprising the following steps: The polysaccharide A and the polysaccharide B are mixed in an acidic solution to perform a modification reaction to obtain a solution I; Extruding solution I into an alkaline solution through a microfluidic device to undergo a curing reaction to obtain a core structure; The core structure was placed in a 0.1-3wt% polysaccharide C solution for 1-2 h of shell coating reaction; The wrapped inner core structure is placed in a cross-linking agent solution to undergo a cross-linking reaction, thereby obtaining an acid-resistant gel having an inner core and outer shell structure.

[0016] The present invention continues to perform secondary crosslinking with another polysaccharide (polysaccharide C) as a raw material outside the core structure of the polysaccharide crosslinking, so as to wrap a layer of shell structure with a large number of filamentous networks outside the core, greatly increasing the area in contact with water and providing more channels for water molecules to enter. Therefore, it will not be decomposed under strong acid, but the absorption rate and expansion performance are significantly improved. One or more specific embodiments of the present invention prove that the absorption rate of gel beads without secondary crosslinking and thus without shell structure is significantly lower than that of gel beads with shell structure after secondary crosslinking, and with the increase of the concentration of polysaccharide C used for wrapping, the absorption rate of gel beads after secondary crosslinking has been significantly improved, which shows that secondary crosslinking increases the crosslinking density, and the gel beads have more hydrophilic groups, so that they have excellent water absorption and expansion performance in strong acid solution. The obtained gel with excellent acid resistance and expansion can occupy the stomach space more fully, thereby playing the effect of inhibiting weight gain.

[0017] Preferably, the method further comprises: freeze-drying the prepared acid-resistant gel for 24-48 hours, more preferably freeze-drying for 48 hours.

[0018] Preferably, the acidic solution is a hydrochloric acid solution with a concentration of 0.1-2 mol / L.

[0019] Preferably, the temperature of the modification reaction is 25-35° C., and the time of the modification reaction is 4-8 h.

[0020] Preferably, the alkaline solution is a sodium hydroxide solution with a concentration of 0.1-2 wt%.

[0021] Preferably, the curing reaction time is 1-3 h.

[0022] Preferably, the concentration of polysaccharide C in the polysaccharide C solution is 0.5-3 wt %.

[0023] Preferably, the concentration of the crosslinking agent in the crosslinking agent solution is 3-6 wt %.

[0024] Preferably, the cross-linking reaction time is 1-2 h.

[0025] The present invention also provides application of the acid-resistant gel in preparing products for weight management.

[0026] The present invention also provides a weight management product, comprising the acid-resistant gel. The weight management product can be orally administered to humans or animals, expands after absorbing water, occupies stomach space, and thus inhibits weight gain.

[0027] Beneficial effects of the present invention: The acid-resistant gel provided by the present invention uses edible natural polysaccharides as raw materials, and through an innovative core-shell structure design, utilizes the dual effects of physical crosslinking and chemical crosslinking to construct a more stable non-reversible internal network system, achieving excellent acid resistance and high swelling properties, and can maintain stable water absorption performance even in a strong acid environment, so that it can fully absorb water and swell in the stomach, effectively occupying the stomach space, thereby suppressing appetite and controlling weight gain. In summary, the acid-resistant gel provided by the present invention not only meets the requirements of biocompatibility and biodegradability, but also has the function of stable swelling in an acidic environment, and can be used as a new material to replace drugs and implant devices, and has broad prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It is the absorption rate of Examples 1-5 and Comparative Example 1 in simulated gastric fluid.

[0029] Figure 2 The scanning electron microscope images of the gel beads prepared in Examples 1-5 and Comparative Example 1 are shown.

[0030] Figure 3 This is a graph showing changes in body weight growth rate in the rat experiment in Example 4. DETAILED DESCRIPTION

[0031] The following is an explanation of the embodiments of the present invention by specific specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied by other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention. It should be noted that, in the absence of conflict, the features in the following embodiments and embodiments can be combined with each other. In the embodiments of the present invention, the methods used are all conventional methods unless otherwise specified, and the reagents used can be obtained from commercial sources.

[0032] Example 1: Preparation of acid-resistant gel Accurately weigh 2.5 g of chitosan powder and 1.5 g of hyaluronic acid powder, slowly add them to a three-necked flask containing 100 mL of 0.1 mol / L dilute hydrochloric acid for reaction, react at 30°C for 6 h to obtain solution I; extrude the dispersed solution I into 1000 mL of 1wt% sodium hydroxide solution through a microfluidic device, solidify for 2 h, and wash three times with deionized water to obtain a core structure; pour the washed core structure into 500 mL of 0.1 wt% locust bean gum for 1 h, and wash three times with deionized water; pour the wrapped core structure into 500 mL of 3 wt% water-soluble carbodiimide solution for crosslinking for 1 h, and wash three times with deionized water to obtain an acid-resistant gel with a core-shell structure; freeze-dry the cross-linked acid-resistant gel beads for 48 h. Example 2-5 and Comparative Example 1: The difference between Example 2 and Example 3 and Example 1 is that the concentration of the locust bean gum coated in the outer layer in step 3 is different, see Table 1, and the rest of the processes are exactly the same.

[0033] The difference between Example 4 and Example 1 is that cationic starch is used to replace chitosan in step 1, see Table 1, and the rest of the processes are exactly the same.

[0034] The difference between Example 5 and Example 1 is that alginate is used to replace hyaluronic acid in step 1, see Table 1, and the rest of the processes are exactly the same.

[0035] The difference between Comparative Example 1 and Example 1 is that the freeze-drying is performed directly for 48 h after washing in step 2, and steps 3, 4 and 5 are removed, see Table 1, and the rest of the processes are exactly the same.

[0036] Table 1 Formulas of Examples 1-5 and Comparative Example 1

[0037]

Performance test

[0038] The gel beads prepared in Examples 1-3 and Comparative Example 1 were subjected to surface gold spraying treatment, and their surface micromorphology was observed under a scanning electron microscope. The SEM images are shown in FIG. Figure 2 As shown in the figure, the surface roughness of the gel beads without secondary cross-linking is relatively large. Although it can increase the hydrophilic area, it does not have a large number of pore structures to make it have a better absorption rate in strong acid. After the secondary cross-linking, a filamentous network is generated on the surface of the gel beads, which greatly increases the area in contact with water and provides more channels for water molecules to enter. Therefore, it will not be decomposed under strong acid, but the absorption rate and expansion performance are significantly improved.

[0039] Example 4: Application of acid-resistant gel Based on the principle that high water absorption rate can make the stomach space more fully occupied, the acid-resistant gel prepared in Example 2 was selected for rat experiment exploration. Water and the acid-resistant gel prepared in Example 2 were fed into the stomach of the rats through a feeding tube, and the weight change rate of the rats at 14 days was obtained as follows: Figure 3 The weight growth rate of female rats decreased by 22%, and the weight growth rate of male rats decreased by 31%, which indicates that the acid-resistant gel provided in the embodiment of the present invention has an inhibitory effect on the weight growth of rats, proving that it has the potential to control body weight.

[0040] The embodiments described above are merely descriptions of preferred implementations of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope of the present invention.

Claims

1. An acid-resistant gel, characterized in that: The acid-resistant gel has a core-shell structure; The core structure is formed by ionic cross-linking of polysaccharide A and polysaccharide B; The outer shell structure is formed by cross-linking the polysaccharide C with the surface groups of the inner core structure under the action of a cross-linking agent; Wherein, the polysaccharide A is a cationic polysaccharide, the polysaccharide B is an anionic polysaccharide, and the polysaccharide C is a neutral polysaccharide.

2. The acid-resistant gel according to claim 1, characterized in that The polysaccharide A is selected from one or more of chitosan, cationic guar gum, cationic hydroxypropyl methylcellulose, cationic starch, and cationic agarose; and / or, The polysaccharide B is selected from one or more of xanthan gum, pectin, hyaluronic acid, alginate, carrageenan, and gellan gum; and / or, The polysaccharide C is selected from one or more of locust bean gum, konjac gum and konjac gum.

3. The acid-resistant gel according to claim 1, characterized in that The cross-linking agent is selected from one or both of water-soluble carbodiimide and N-hydroxysuccinimide.

4. The acid-resistant gel according to claim 1, characterized in that In an environment where the pH is less than 7, the absorption rate of the acid-resistant gel is not less than 40 g / g.

5. The method for preparing the acid-resistant gel according to any one of claims 1 to 4, characterized in that: The steps include: The polysaccharide A and the polysaccharide B are mixed in an acidic solution to perform a modification reaction to obtain a solution I; Extruding solution I into an alkaline solution through a microfluidic device to undergo a curing reaction to obtain a core structure; The core structure was placed in a 0.1-3wt% polysaccharide C solution for 1-2 h of shell coating reaction; The wrapped inner core structure is placed in a cross-linking agent solution to undergo a cross-linking reaction, thereby obtaining an acid-resistant gel having an inner core and outer shell structure.

6. The method according to claim 5, characterized in that Also includes: The obtained acid-resistant gel was freeze-dried for 24-48 h.

7. The method according to claim 5, characterized in that The acidic solution is a hydrochloric acid solution with a concentration of 0.1-2 mol / L; and / or, The temperature of the modification reaction is 25-35° C., and the time of the modification reaction is 4-8 h.

8. The method according to claim 5, characterized in that The alkaline solution is a sodium hydroxide solution with a concentration of 0.1-2 wt%; and / or, The curing reaction time is 1-3 h.

9. The method according to claim 5, characterized in that The concentration of the crosslinking agent in the crosslinking agent solution is 3-6 wt %; and / or, The cross-linking reaction time is 1-2 h.

10. Use of the acid-resistant gel according to any one of claims 1 to 4 or the acid-resistant gel prepared by the method for preparing the acid-resistant gel according to any one of claims 5 to 9 in preparing a weight management product.

11. A weight management product, characterized in that: The acid-resistant gel comprises the acid-resistant gel according to any one of claims 1 to 4 or the acid-resistant gel prepared by the preparation method of the acid-resistant gel according to any one of claims 5 to 9.

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