An acid-resistant gel and its preparation method and application

Abstract

The present invention provides an acid-resistant gel and a preparation method and application thereof. In order to overcome the problems that traditional weight-loss drugs and existing weight-loss devices permanently damage the body and endanger life and health, and that most hydrogels cannot meet the acid tolerance and high expansion rate, an edible, acid-resistant gel with a high expansion rate is provided. The acid-resistant gel is composed of a core-shell structure, which first undergoes ionic crosslinking through electrostatic interaction to form an inner layer "core", and then undergoes secondary crosslinking on the outside to form a "shell". The acid-resistant gel of the present invention not only meets the requirements of biocompatibility and biodegradability, but also has the function of stable expansion in an acidic environment. It can be used as a new material to replace drugs and implant devices, and has broad prospects.

Description

Technical Field

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

[0002] Obesity has become a global "epidemic". Nearly two-thirds of adults and one-third of children are overweight or obese. The global obesity prevalence has increased nearly threefold between 1975 and 2016, and the obese population is still growing. More seriously, overweight and obesity have seriously endangered health, ranking third among the risk factors for death, second only to hypertension and tobacco, and are associated with many non-communicable diseases, including cardiovascular diseases, type II diabetes, and cancer. In addition, in terms of social impact, obesity may lead to adverse psychology in individuals.

[0003] People began to manage their weight in the last century, and traditional weight-loss drugs were popular for a while. Orlistat is the only drug currently approved for obesity treatment in China and 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 also brings adverse reactions to the gastrointestinal tract (such as oily stools and a sense of urgency to defecate), and users may also need to take a compound vitamin preparation daily to improve the absorption disorder of fat-soluble vitamins. In addition, at the end of 1997, sibutramine was approved by the US FDA as a weight-loss drug. However, since 2010, countries in Europe and America have successively banned sibutramine. In October of the same year, the China Food and Drug Administration also required to stop the production, sales, and use of sibutramine in China because sibutramine not only did not achieve significant weight-loss effects but also greatly increased the risk of cardiovascular diseases. The drawbacks 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 devices permanently damage the body, endanger life and health, and most hydrogels cannot meet the requirements of acid tolerance and high swelling rate, the present invention provides an edible, acid-resistant and highly swelling 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 wide in source, and a more stable irreversible internal network system is constructed through the dual action of physical crosslinking and chemical crosslinking, so that the gel not only has excellent acid resistance and swelling properties, but also has a simple preparation process and low cost, and can meet the requirements of industrial mass production.

[0009] The technical solution adopted by the present invention is: an acid-resistant gel, the acid-resistant gel 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 less than 7, the absorption ratio of the acid-resistant gel is not less than 40 g / g; more preferably, in an environment with a pH less than 2, the absorption ratio of the acid-resistant gel is not less than 40 g / g. In one or more specific embodiments of the present invention, the acid-resistant gel has an absorption ratio of 50-65 g / g in simulated gastric juice with a pH of 1.2.

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

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

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

[0015] The present invention also provides a preparation method of the acid-resistant gel, including the following steps:

[0016] Mix polysaccharide A and polysaccharide B in an acidic solution and carry out a modification reaction to obtain solution I;

[0017] Extrude solution I into an alkaline solution through a microfluidic device to carry out a curing reaction to obtain a core structure;

[0018] Place the core structure in a polysaccharide C solution with a concentration of 0.1 - 3 wt% and conduct an outer shell wrapping reaction for 1 - 2 h;

[0019] The wrapped core structure is placed in a crosslinking agent solution to conduct a crosslinking reaction, and an acid-resistant gel with a core-shell structure is prepared.

[0020] In the present invention, a secondary crosslinking using another polysaccharide (polysaccharide C) as a raw material is further carried out on the outer side of the polysaccharide-crosslinked core structure to form an outer shell structure with a large number of filamentous networks outside the core, greatly increasing the contact area with water and providing more channels for water molecules to enter. Therefore, it will not be decomposed under strong acid, but instead, both the absorption ratio and the swelling performance are significantly improved. One or more specific embodiments of the present invention prove that the absorption ratio of the gel beads without secondary crosslinking and thus without an outer shell structure is significantly lower than that of the gel beads with secondary crosslinking and thus with an outer shell structure. Moreover, as the concentration of polysaccharide C used for wrapping increases, the absorption ratio of the gel beads with secondary crosslinking has been significantly improved, which indicates that the secondary crosslinking increases the crosslinking density and the gel beads have more hydrophilic groups, thus having excellent water absorption and swelling performance in strong acid solutions. The prepared gel with excellent acid resistance and expansibility can more fully occupy the gastric space, thereby achieving the effect of inhibiting weight gain.

[0021] Preferably, the method further includes: freeze-drying the prepared acid-resistant gel for 24 - 48 h, more preferably for 48 h.

[0022] Preferably, the acidic solution is a hydrochloric acid solution with a concentration of 0.1 - 2 mol / L.

[0023] Preferably, the temperature of the modification reaction is 25 - 35 °C, and the time of the modification reaction is 4 - 8 h.

[0024] Preferably, the alkaline solution is a sodium hydroxide solution with a concentration of 0.1 - 2 wt%.

[0025] Preferably, the time of the curing reaction is 1 - 3 h.

[0026] Preferably, the concentration of polysaccharide C in the polysaccharide C solution is 0.5 - 3 wt%.

[0027] Preferably, the concentration of the crosslinking agent in the crosslinking agent solution is 3 - 6 wt%.

[0028] Preferably, the time of the crosslinking reaction is 1 - 2 h.

[0029] The present invention also provides the application of the described acid-resistant gel in the preparation of products for weight management.

[0030] 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.

[0031] 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

[0032] Figure 1 It is the absorption rate of Examples 1-5 and Comparative Example 1 in simulated gastric fluid.

[0033] Figure 2 The scanning electron microscope images of the gel beads prepared in Examples 1-5 and Comparative Example 1 are shown.

[0034] Figure 3 This is a graph showing changes in body weight growth rate in the rat experiment in Example 4. DETAILED DESCRIPTION

[0035] 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.

[0036] Example 1: Preparation of acid-resistant gel

[0037] 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 well-dispersed Solution I through a microfluidic device into 1000 mL of 1 wt% sodium hydroxide solution, cure for 2 h, wash three times with deionized water to obtain the core structure; pour the washed core structure into 500 mL of 0.1 wt% locust bean gum to wrap for 1 h, 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, wash three times with deionized water to obtain an acid-resistant gel with a core-shell structure; freeze-dry the crosslinked acid-resistant gel beads for 48 h. Examples 2-5 and Comparative Example 1:

[0038] The differences between Example 2 and Example 3 and Example 1 are that the concentration of the outer-layer wrapped locust bean gum in Step 3 is different. See Table 1, and the rest of the processes are exactly the same.

[0039] 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.

[0040] 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.

[0041] The difference between Comparative Example 1 and Example 1 is that after washing in Step 2, it is directly freeze-dried for 48 h, and Steps 3, 4, and 5 are removed. See Table 1, and the rest of the processes are exactly the same.

[0042] Table 1 Formulations of Examples 1-5 and Comparative Example 1

[0043]

[0044]

Performance Test

[0045] Soak the gel beads prepared in Examples 1-5 and Comparative Example 1 in simulated gastric juice respectively, and sample and test the absorption ratio at time points. The results are as Figure 1As shown in the figure. The absorption capacity of the gel beads without secondary cross-linking is significantly lower than that of the gel beads with secondary cross-linking. Moreover, with the increase in the concentration of locust bean gum encapsulated, the absorption capacity of the gel beads with secondary cross-linking has been significantly improved. This indicates that secondary cross-linking increases the cross-linking density, and the gel beads have more hydrophilic groups, showing excellent water absorption and swelling performance in strong acid solutions. At the same locust bean gum concentration, the absorption capacity of Example 4 prepared with cationic starch and Example 5 prepared with alginate is slightly lower than that of Example 3, and the absorbency and swelling property are weakened. Under the same feeding ratio, the performance is lower than that of the examples prepared with chitosan and hyaluronic acid. Therefore, the performance of the gel beads prepared with chitosan and hyaluronic acid as raw materials will be mainly explored subsequently.

[0046] The gel beads prepared in Examples 1-3 and Comparative Example 1 were subjected to surface gold spraying treatment, and their surface microtopographies were observed under a scanning electron microscope. The SEM images are as Figure 2 shown. The surface of the gel beads without secondary cross-linking has a larger surface roughness. Although it can increase the hydrophilic area, there are no large pore structures to endow them with a more excellent absorption capacity in strong acid. However, after secondary cross-linking, filamentous networks are formed on the surface of the gel beads, greatly increasing the area in contact with water and providing more channels for water molecules to enter. Therefore, not only will they not be decomposed under strong acid, but their absorption capacity and swelling performance are significantly improved.

[0047] Example 4: Application of Acid-Resistant Gel

[0048] Based on the principle that a high water absorption capacity can occupy the gastric space more fully, the acid-resistant gel prepared in Example 2 was selected for rat experiments. Water and the acid-resistant gel prepared in Example 2 were fed into the stomach of rats through a feeding tube. The weight change rate of the rats at 14 days is as Figure 3 shown. The weight growth rate of female rats decreased by 22%, and that of male rats decreased by 31%. This indicates that the acid-resistant gel provided in the examples of the present invention has an inhibitory effect on the weight growth of rats, proving its potential for weight control.

[0049] The above-described examples are only used to describe the preferred embodiments of the present invention and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations and improvements made by those of ordinary skill in the art to the technical solutions of the present invention should 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 polysaccharide A and polysaccharide B undergoing a modification reaction in an acidic solution and then undergoing a curing reaction in an alkaline solution through ionic crosslinking; The outer shell structure is formed by cross-linking 0.5-3wt% of 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; The cationic polysaccharide is selected from one or more of chitosan and cationic starch; The anionic polysaccharide is selected from one or more of hyaluronic acid and alginate; The neutral polysaccharide is locust bean gum; The cross-linking agent is selected from one or both of water-soluble carbodiimide and N-hydroxysuccinimide.

2. 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.

3. The method for preparing the acid-resistant gel according to any one of claims 1 to 2, 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 0.5-3wt% 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.

4. The method according to claim 3, characterized in that Also includes: The obtained acid-resistant gel was freeze-dried for 24-48 h.

5. The method according to claim 3, 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.

6. The method according to claim 3, 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.

7. The method according to claim 3, 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.

8. Use of the acid-resistant gel as claimed in any one of claims 1 to 2 or the acid-resistant gel prepared by the preparation method of the acid-resistant gel as claimed in any one of claims 3 to 7 in preparing materials for weight loss.

9. A weight loss material, characterized in that: The acid-resistant gel comprises the acid-resistant gel according to any one of claims 1 to 2 or the acid-resistant gel prepared by the preparation method of the acid-resistant gel according to any one of claims 3 to 7.

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