Fe < 2 + >-containing edible gel as well as preparation method and application thereof

Abstract

The invention discloses edible gel containing Fe < 2 + > as well as a preparation method and application thereof, and relates to the technical field of biological medicines. The gel mainly comprises Fe < 2 + >, ascorbic acid and sodium alginate. Researches find that Fe < 2 + > can inhibit an NF-kappa B signal channel, reduce expression of proinflammatory factors and activate an antioxidant channel; ascorbic acid cooperates with Fe < 2 + > to remove active oxygen and enhance the anti-inflammatory effect; sodium alginate forms adhesive gel, so that the drug residence time is prolonged, and mucous membrane repair is promoted. Animal experiments show that the gel can effectively relieve intestinal inflammation, reduce the level of inflammatory markers and improve the expression of anti-inflammatory factors; meanwhile, the effect of oxidative stress regulation is remarkable, the activity of antioxidant enzymes in the intestinal tract can be improved, and the content of oxidative damage markers can be reduced. The gel is high in safety and small in side effect, can solve the problems that existing intestinal inflammation treatment drugs are insufficient in targeting, large in whole-body side effect and the like, and provides a new way for treatment of intestinal inflammation diseases.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine and specifically relates to a 2+ Edible gel and preparation method and application thereof. Background Art

[0002] Inflammatory bowel disease (IBD), primarily including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic, nonspecific inflammatory bowel disease whose etiology remains unclear. In recent years, the incidence and prevalence of IBD have continued to rise globally. Epidemiological surveys in my country show that the incidence of IBD has climbed from less than 1 in 100,000 patients 20 years ago to over 10 in 100,000 patients in some regions today, severely impacting patients' quality of life and physical and mental health.

[0003] The pathogenesis of IBD is complex, involving the interplay of multiple factors, including genetics, environment, immunity, and the intestinal flora. Its pathological characteristics are characterized by impaired intestinal mucosal barrier function, overactivation of the immune system, and imbalanced oxidative stress responses, which in turn lead to chronic inflammation, ulcers, and bleeding in the intestinal tissue, and may even lead to serious complications such as intestinal perforation and cancer. Patients often experience symptoms such as abdominal pain, diarrhea, bloody stools, and weight loss, and the disease is prone to recurring, making clinical treatment extremely difficult.

[0004] Currently, clinical treatments for IBD primarily include 5-aminosalicylic acid (5-AMSA), glucocorticoids, immunosuppressants, and biologics. While 5-AMSA can alleviate mild to moderate inflammation, they require long-term, high-dose use, and some patients develop drug resistance. While glucocorticoids offer significant anti-inflammatory effects, long-term use can lead to serious systemic side effects such as increased risk of infection, osteoporosis, and elevated blood sugar. Immunosuppressants can cause adverse reactions such as liver and kidney damage and leukopenia. Biologics, such as anti-tumor necrosis factor-α (TNF-α) antibodies, while highly targeted, are expensive and immunogenic, leading to poor efficacy or relapse after discontinuation in some patients. Furthermore, these traditional drugs, mostly administered orally or intravenously, struggle to form high concentrations at sites of intestinal inflammation, resulting in insufficient targeting and low bioavailability. Furthermore, they are unable to effectively improve the intestinal microenvironment or repair damaged intestinal mucosal barriers.

[0005] In recent years, new therapies based on natural products have gradually become a research hotspot. Sodium alginate, a natural polysaccharide extracted from brown algae, has shown great potential in the field of drug delivery due to its good biocompatibility, degradability and mucosal adhesion. However, it is difficult to achieve efficient inflammation suppression and tissue repair when used alone.2+ and Vc have important physiological functions in the body. Studies have shown that Fe 2+ Vc can regulate the function of immune cells and has a powerful antioxidant effect, but how to effectively apply it to the treatment of intestinal inflammation and solve the problems of stability and targeted delivery are still technical challenges that need to be overcome.

[0006] Therefore, developing a new preparation that is safe, efficient, highly targeted, and has anti-inflammatory, antioxidant, and mucosal repair functions is of great significance to improving the treatment status of IBD patients. Summary of the Invention

[0007] In order to overcome the above-mentioned shortcomings of the prior art, the present invention aims to provide a 2+ Edible gel and its preparation method and application, utilizing Fe 2+ The unique synergistic mechanism between ascorbic acid and sodium alginate has high-efficiency and broad-spectrum antibacterial ability, blocking bacteria from entering a "live non-culturable state", providing a new solution to the major challenges in the current food safety field.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions: The first object of the present invention is to provide an edible gel containing ferrous iron, comprising: Fe 2+ Compound, ascorbic acid, sodium alginate were used as raw materials to prepare Fe-containing 2+ Edible gel.

[0009] Preferably, the Fe 2+ The compound is selected from ferrous sulfate and / or ferrous lactate.

[0010] Preferably, the Fe-containing 2+ Fe in edible gel 2+ The concentration is 0.5~2wt%.

[0011] Preferably, the Fe 2+ The molar ratio of the compound to ascorbic acid was 1:1.

[0012] Preferably, the sodium alginate is in the Fe-containing 2+ The content in the edible gel is 2~5 wt%.

[0013] Preferably, the raw materials further include fructooligosaccharides and / or citric acid.

[0014] The second object of the present invention is to provide the above-mentioned Fe-containing 2+ The preparation method of edible gel comprises the following steps: Fe 2+ Compounds dissolve to form Fe2+ solution, in Fe 2+ Add ascorbic acid to the solution and stir evenly to obtain a stable Fe 2+ -Vc complex solution; Sodium alginate was slowly added to the stabilized Fe 2+ -Vc complex solution, stirring until a uniform and transparent colloid is formed; The colloid is homogenized and sterilized to obtain an edible gel.

[0015] Preferably, the sodium alginate is slowly added with stable Fe 2+ -Vc complex solution, specifically, sodium alginate is added to Fe at a temperature of 45±2℃ 2+ -Vc complex solution was stirred at a stirring speed of 125-175 rpm for 40-50 minutes.

[0016] Preferably, the colloid is homogenized by treating it at a pressure of 100-150 MPa for 2-3 times.

[0017] Preferably, the colloid is sterilized by sterilizing the gel by gamma ray sterilization.

[0018] The third object of the present invention is to disclose the above-mentioned Fe-containing 2+ The application of edible gel, the above Fe 2+ The edible gel is used for preparing a product for treating intestinal inflammation.

[0019] Compared with the prior art, the present invention has the following beneficial effects: The present invention proposes a Fe-containing 2+ The edible gel has high efficiency and broad spectrum antibacterial ability. 2+ The oxidative effect of sodium alginate and the synergistic effect of ascorbic acid show significant inhibitory effects on various foodborne pathogens; at the same time, the edible gel also has a unique VBNC blocking function, which solves the safety hazards caused by the "pseudo-death" of bacteria from the root; the edible gel is highly safe, and all ingredients are food-grade raw materials, meeting the most stringent food safety standards; finally, it has good process adaptability, the microcapsule form is convenient for transportation and storage, and the release characteristics can be adjusted according to different application requirements. The edible gel of the present invention is used as a gel carrier. The sodium alginate gel will swell and tightly adhere to the surface of the intestinal mucosa under the specific pH 5.5~7.5 environment of the intestine, forming a protective gel barrier. This barrier can increase the local concentration of the drug in the inflammatory area by 3~5 times compared to the free state, effectively reducing the scouring effect of gastrointestinal peristalsis on the drug, significantly prolonging the action time of the drug in the intestine, and creating a good environment for the repair of intestinal mucosa. Fe2+ It can inhibit the polarization of macrophages to pro-inflammatory type (M1), reduce the secretion of pro-inflammatory factors such as TNF-α and IL-1β, and reduce their levels by 40-60%. At the same time, it promotes the transformation of macrophages to anti-inflammatory type (M2), upregulates the expression of anti-inflammatory factor IL-10, thereby reducing intestinal inflammatory response and alleviating clinical symptoms of patients. 2+ The synergistic effect can significantly increase the activity of antioxidant enzymes in the intestine, such as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and reduce malondialdehyde (MDA) content by 50-70%. By enhancing the antioxidant capacity of the intestine, it can reduce the damage of oxidative stress to intestinal mucosal cells and promote the repair and regeneration of intestinal tissue.

[0020] The Fe-containing 2+ The edible gel is suitable for preparing products for a variety of intestinal inflammatory diseases, including but not limited to ulcerative colitis (UC), Crohn's disease (CD), radiation enteritis, and the recovery period of infectious bowel disease. DETAILED DESCRIPTION

[0021] In order to enable those skilled in the art to better understand the solutions of the present invention, the present invention will be clearly and completely described below in conjunction with the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0022] The present invention relates to a method based on Fe 2+ This invention, which combines vitamin C, sodium alginate, and an edible gel, as well as its preparation method and application, specifically addresses the control of foodborne pathogens in the food preservation field. Through the innovative combination of these three key ingredients, it achieves the dual efficacy of highly effective sterilization and blocking bacteria from entering a "viable non-culturable state" (VBNC), providing a novel solution to addressing current major challenges in food safety.

[0023] The core of the present invention is to discover and utilize Fe 2+ The unique synergistic mechanism among Fe, Vc and sodium alginate. 2+ As the main active ingredient, its effective concentration range is controlled between 10~200μM. This concentration range has been repeatedly verified by experiments and can ensure the bactericidal effect while avoiding the negative effects that may be caused by excessive iron ions. The amount of Vc added is precisely calculated and compared with Fe 2+ Maintain a molar ratio of 1:1 to 1:2, which can maintain Fe 2+It has excellent stability and can effectively inhibit the iron-dependent oxidative stress response in bacteria. Sodium alginate is used as a carrier material at a concentration of 1-3wt%, which can form an ideal microcapsule structure.

[0024] Fe 2+ :Fe 2+ It is derived from edible salts such as ferrous sulfate and ferrous lactate, and its concentration in the gel is controlled at 0.5~2 wt%. Its main mechanism of action is to accurately inhibit the activation of the NF-κB signaling pathway, effectively reduce the expression of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and activate the heme oxygenase-1 (HO-1) antioxidant pathway to promote the repair and regeneration of intestinal mucosal cells. In addition, Fe 2+ It is also involved in regulating the balance of iron metabolism in the intestine, affecting the composition and function of intestinal flora, and maintaining the stability of intestinal microecology.

[0025] Vc: As a powerful antioxidant, Vc and Fe 2+ The molar ratio of Vc is set to 1:1. It can effectively remove the excessive reactive oxygen species (ROS) produced in the intestine and reduce the damage of oxidative stress to intestinal mucosal cells. At the same time, Vc maintains Fe through redox reaction. 2+ reduced state, enhancing its stability and preventing Fe 2+ Oxidized to Fe 3+ The two work synergistically to inhibit the occurrence of inflammatory cascade reactions and further enhance the anti-inflammatory effect.

[0026] Sodium alginate: The content of sodium alginate in the gel is 2~5 wt%, which is the key component of the gel matrix. 2+ Ionic cross-linking occurs, creating a three-dimensional mesh gel structure. This structure exhibits excellent bioadhesion, tightly adhering to the intestinal mucosal surface and significantly prolonging drug retention in the intestine. Studies have shown that compared to free drugs, the retention time of drugs in gel form in the intestine can be increased by 3-5 times. Furthermore, sodium alginate can regulate the balance of intestinal flora, promote the repair of the intestinal mucus layer, and enhance the barrier function of the intestinal mucosa.

[0027] In order to optimize the performance of the gel, oligofructose (0.5~1%) can be selectively added according to actual needs to improve the palatability of the gel and make it easier for patients to take; or citric acid (0.1~0.3%) can be added to adjust the pH value of the gel to 3.8~4.2 to optimize the intestinal targeted release performance and ensure that the drug can be accurately released at the site of intestinal inflammation to achieve the best therapeutic effect.

[0028] Fe 2+Solution preparation: Accurately weigh ferrous sulfate or ferrous lactate and dissolve it in deionized water to prepare a solution with a concentration of 5~10 mg / mL. During the dissolution process, nitrogen is introduced for 10 minutes while stirring at a speed of 200~300 rpm and the solution temperature is controlled at 25~30℃ to effectively prevent Fe 2+ is oxidized, ensuring that Fe 2+ Stability of the solution.

[0029] Vc synergistic dissolution: according to Fe 2+ The principle of equal molar ratio with Vc is to add Vc to the above Fe 2+ The solution was stirred for 15 minutes to allow Vc to fully dissolve and react with Fe 2+ Formation of stable Fe 2+ -Vc complex solution. This complex solution not only enhances the 2+ The stability of the product was further enhanced, and its antioxidant and anti-inflammatory activities were further improved.

[0030] Sodium alginate gelation: slowly add sodium alginate (molecular weight 50~100kDa) to the above mixed solution, stir at 125~175rpm for 40~50 minutes at 45±2℃, until a uniform and transparent colloid is formed. 2+ Through ionic bond cross-linking reaction, a stable three-dimensional network structure is formed, which makes the adhesion of the gel reach 150mN / cm 2 , which ensures the targeted delivery and sustained release of drugs in the intestine.

[0031] Homogenization and Sterilization: The prepared colloid is homogenized in a high-pressure homogenizer at a pressure of 100-150 MPa for 2-3 cycles to ensure a uniform particle size distribution (D90 < 50 μm), thereby improving the gel's stability and uniformity. Subsequently, the gel is sterilized by gamma irradiation (25 kGy) and aseptically filled into suitable containers for storage and use.

[0032] The methods of the present invention are further illustrated below with reference to the examples. The following examples utilize conventional instruments and equipment in the art. Unless otherwise specified, the various raw materials and reagents used are conventional commercially available products, with specifications conventional in the art, or can be prepared or formulated by known methods or reagent instructions. Experimental procedures in the following examples, where specific conditions are not specified, generally follow conventional conditions or the conditions recommended by the manufacturer.

[0033] Example 1: 1 mM ferrous lactate-hyaluronic acid hydrogel In this embodiment, ferrous lactate is used as Fe2+ Source, utilizing the hydrophilicity and mucosal adhesion properties of hyaluronic acid to prepare a gel dosage form suitable for oral administration.

[0034] First, 0.19g of ferrous lactate (molecular weight 288.04) was weighed and dissolved in 1L of sterile ultrapure water, and 0.176g of Vc was added. A stable mixed solution was formed under constant temperature and stirring at 50°C. Vc and ferrous lactate were added in a strict 1:1 molar ratio to maintain the Fe 2+ reduced state to prevent it from being oxidized to Fe 3+ and lose activity.

[0035] Then, 30g of hyaluronic acid powder (molecular weight 80kDa) was slowly sprinkled into the mixture and stirred at 150rpm for 30 minutes until a uniform and transparent colloid was formed. The amount of hyaluronic acid added was 3% of the mass of the mixed solution. The carboxyl groups on its molecular chain interacted with Fe 2+ Through ionic cross-linking, a three-dimensional network structure with weak elasticity is formed.

[0036] Finally, the gel was treated twice by a high-pressure homogenizer at a pressure of 100 MPa to make the gel particle size distribution uniform (D90 < 50 μm), and then sterilized for use.

[0037] This gel is suitable for daily treatment of patients with mild ulcerative colitis. After oral administration, the hyaluronic acid matrix swells in the presence of gastric acid to form an adhesive layer. After gastric emptying, it enters the intestine and further adheres to the intestinal mucosal surface in the intestinal pH range of 5.5-7.5, increasing the local drug concentration to more than three times that of the free drug. Clinical trials have shown that a twice-daily 5g dose significantly reduces levels of intestinal inflammatory markers (such as TNF-α) by 40% while increasing expression of the anti-inflammatory cytokine IL-10. The mild nature of ferrous lactate reduces irritation to the gastric mucosa, making it suitable for long-term use. Patient feedback indicates that after two weeks of continuous use, the abdominal pain and diarrhea symptom relief rate reached 75%, with no significant adverse reactions, demonstrating the balanced safety and efficacy of this dosage form.

[0038] Example 2: 3 mM ferrous sulfate-sodium alginate hydrogel (enema high concentration formula) In response to the need for treating left-sided colon inflammation, this example uses high-concentration ferrous sulfate (3 mM, corresponding to 0.49 g / L) and sodium alginate to prepare a gel specifically for enema.

[0039] First, ferrous sulfate (0.49 g / L) and vitamin C (0.53 g / L) were dissolved in sterile water, heated to 55°C and stirred until completely dissolved to form an acidic aqueous phase (pH 3.8). Subsequently, 30 g of sodium alginate (molecular weight 50 kDa) was added and stirred at 150 rpm for 40 minutes. 2+Strong ionic cross-linking properties, forming an adhesion of 150mN / cm 2 of gel.

[0040] The edible gel disclosed in the present invention is mainly composed of ferrous ions, vitamin C and sodium alginate. Studies have found that ferrous ions can inhibit the NF-κB signaling pathway, reduce the expression of pro-inflammatory factors, and activate the antioxidant pathway; vitamin C cooperates with ferrous ions to scavenge reactive oxygen species and enhance the anti-inflammatory effect; sodium alginate forms an adhesive gel, prolongs the drug retention time, and promotes mucosal repair. Animal experiments have shown that the gel can effectively reduce intestinal inflammation, reduce the level of inflammatory markers, and increase the expression of anti-inflammatory factors; at the same time, it has a significant effect on the regulation of oxidative stress, can increase the activity of intestinal antioxidant enzymes, and reduce the content of oxidative damage markers. The gel has high safety and few side effects. It can solve the problems of insufficient targeting and large systemic side effects of existing intestinal inflammation treatment drugs, and provides a new approach for the treatment of intestinal inflammatory diseases.

[0041] The above content is only for explaining the technical idea of the present invention and cannot be used to limit the protection scope of the present invention. Any changes made on the basis of the technical solution in accordance with the technical idea proposed by the present invention shall fall within the protection scope of the claims of the present invention.

Claims

1. A kind of Fe-containing 2+ Edible gel, characterized in that include: Fe 2+ Compound, ascorbic acid, sodium alginate were used as raw materials to prepare Fe-containing 2+ Edible gel.

2. The Fe-containing compound according to claim 1 2+ Edible gel, characterized in that The Fe 2+ The compound is selected from ferrous sulfate and / or ferrous lactate.

3. The Fe-containing compound according to claim 1 2+ Edible gel, characterized in that The Fe-containing 2+ Fe in edible gel 2+ Concentration is 0.5~2wt%, Fe 2+ The molar ratio of the compound to ascorbic acid was 1:

1.

4. The Fe-containing compound according to claim 1 2+ Edible gel, characterized in that The raw materials further include oligofructose and / or citric acid, wherein the oligofructose is present in an amount of 0.5-1 wt % and the citric acid is present in an amount of 0.1-0.3 wt %.

5. The Fe-containing compound according to claim 1 2+ Edible gel, characterized in that The content of the sodium alginate is 2-5 wt %.

6. A kind of Fe-containing 2+ The preparation method of edible gel is characterized in that: The following steps are involved: Fe 2+ Compounds dissolve to form Fe 2+ solution, in Fe 2+ Add ascorbic acid to the solution and stir evenly to obtain a stable Fe 2 + -Vc complex solution; Sodium alginate was slowly added to the stabilized Fe 2+ -Vc complex solution, stirring until a uniform and transparent colloid is formed; The colloid is homogenized and sterilized to obtain an edible gel.

7. The Fe-containing compound according to claim 6 2+ The preparation method of edible gel is characterized in that: The sodium alginate is slowly added with stable Fe 2+ -Vc complex solution, specifically, sodium alginate is added to Fe at a temperature of 45±2℃ 2 + -Vc complex solution was stirred at a stirring speed of 125-175 rpm for 40-50 minutes.

8. The Fe-containing compound according to claim 6 2+ The preparation method of edible gel is characterized in that: The colloid is homogenized for 2 to 3 times under a pressure of 100 to 150 MPa.

9. The Fe-containing compound according to claim 6 2+ The preparation method of edible gel is characterized in that: The sterilization treatment of the colloid is specifically to sterilize the gel by gamma ray sterilization.

10. A kind of Fe-containing 2+ Application of edible gel, based on the Fe-containing gel according to any one of claims 1 to 5 2+ Edible gel, characterized in that Used in the preparation of products for treating intestinal inflammation.