Tea cheese-based gastric acid and body temperature dual-response hydrosol system, preparation method and application in preparing medicine for treating gastric ulcer

Abstract

The application discloses a kind of gastric acid and body temperature double-response hydrosol system based on tea cream, preparation method and application in preparation of treating gastric ulcer medicine, belong to biological medicine technical field.The application mixes tea cream, CaCl2 solution, Na2CO3 solution, and obtains calcium carbonate-coated tea cream by centrifugation;The hydrosol system is obtained by mixing calcium carbonate-coated tea cream and sodium alginate solution.The hydrosol system of the application can respond to gastric acid and precisely gel at gastric ulcer site, and has the advantages of oral delivery and precise targeting at gastric ulcer site, solves the problem that existing drugs need to be delivered by endoscope to achieve precise targeting at gastric ulcer site.The natural tea cream carried can be decomposed in response to body temperature, and the sustained-release factor continuously acts on gastric ulcer wound, plays the role of sustained-release drug continuous repair, promotes gastric ulcer repair while long-term resisting the risk of gastric ulcer recurrence, realizes the synergistic effect of "gastric acid response gelation, temperature response drug release".

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, and in particular to a gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt, its preparation method, and its application in the preparation of drugs for treating gastric ulcers. Background Technology

[0002] The incidence of gastric ulcers is increasing year by year, becoming a global "epidemic," and is often accompanied by recurrence. In severe cases, it can even develop into gastric perforation or even gastric cancer. Current clinical treatment mainly relies on acid-suppressing drugs such as proton pump inhibitors and H2 receptor antagonists, and gastric mucosal protectants such as colloidal bismuth and sucralfate. While these can effectively inhibit gastric acid secretion or temporarily protect the gastric mucosa, they cannot address the regenerative defects and complex inflammatory microenvironment of the ulcer wound, leading to high recurrence rates and the risk of complications. Furthermore, the dynamic acidic environment of the stomach and continuous gastric emptying make it difficult for local drug delivery systems to remain on the ulcer surface for an extended period, resulting in low drug utilization, short-lived protective effects, severely impacting healing and quality, and increasing the risk of gastric ulcer recurrence. Patients need to take medication multiple times daily or for long periods, leading to low patient compliance and a higher risk of side effects.

[0003] In recent years, the rise of the biomedical materials field, especially the increased research on hydrogel systems with both adhesion and sustained-release properties, has provided new options for the efficient treatment of gastric ulcers. However, the repair effects of most hydrogels on gastric ulcers require the support of equipment such as endoscopes or surgical procedures, causing secondary damage and greatly limiting their application scenarios. Therefore, there is an urgent need for a safe, efficient, and edible hydrogel system that can form in situ at the gastric ulcer site and release active substances sustainably for a long time, thus providing a lasting repair effect on the ulcer surface.

[0004] Tea has been widely reported to have preventive and therapeutic effects on gastric ulcers. However, its main functional component, theaflavins, suffers from poor structural stability and low absorption and utilization, severely limiting its activity and bioavailability. There is an urgent need to develop and construct theaflavins delivery technologies and platforms to overcome these application bottlenecks. Studies have shown that tea infusion becomes turbid upon cooling and further settles to form tea cream. Theaflavins preferentially distribute in the tea cream, exhibiting stronger antioxidant activity than in the tea infusion itself. However, complex non-covalent interactions exist between theaflavins and other components in the tea cream. These non-covalent interactions become unstable and may even break with increasing temperature. While this instability poses a challenge to the oral application of tea cream, it also provides an opportunity to achieve targeted release in the ulcer environment of 37°C.

[0005] Therefore, developing an oral medication that precisely gels at the site of a gastric ulcer in response to gastric acid and sustains repair by releasing the drug at body temperature, in order to promote gastric ulcer repair and resist the risk of gastric ulcer recurrence in the long term, has broad application prospects in biomedical fields such as gastric ulcer healing. Summary of the Invention

[0006] The main objective of this invention is to provide a gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt, its preparation method, and its application in the preparation of drugs for treating gastric ulcers, thereby solving the technical problem of providing a drug that can simultaneously achieve oral delivery and precise targeting of the gastric ulcer site for the treatment and repair of gastric ulcers.

[0007] To achieve the above objectives, this invention provides a method for preparing a gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt, comprising the following steps: Mix tea cream, CaCl2 solution, and Na2CO3 solution, and centrifuge to obtain tea cream coated with calcium carbonate. The calcium carbonate-encapsulated tea cheese and sodium alginate solution were mixed to obtain a hydrosol system.

[0008] In some embodiments of the present invention, the particle size of the tea cream is in the micrometer and / or nanometer range; The mixing ratio of the tea cream and the CaCl2 solution is (5~10) mg / (10~20) ml; The mixing ratio of the tea cream and the Na2CO3 solution is (5~10) mg / (10~20) ml; And / or, the concentration of the CaCl2 solution is 5 mmol / L to 40 mmol / L; And / or, the concentration of the Na2CO3 solution is 5 mmol / L to 40 mmol / L; And / or, the volume ratio of the CaCl2 solution to the Na2CO3 solution is 1:0.5 to 1:5; And / or, the centrifugation speed is 5000 rpm / min to 9500 rpm / min, and the centrifugation time is 10 min to 30 min; And / or, the mass concentration of the sodium alginate solution is 1% to 5%; And / or, the mixing ratio of the calcium carbonate-coated tea cheese particles and the sodium alginate solution is (0.5~3) mg / ml.

[0009] In some embodiments of the present invention, the method for preparing the tea cream includes the following steps: mixing tea leaves and water to obtain a tea-water mixture, heating and extracting the tea-water mixture, filtering to obtain a supernatant, refrigerating the supernatant, and collecting it by a first centrifugation to obtain the tea cream.

[0010] In some embodiments of the present invention, the tea includes at least one of black tea, green tea, yellow tea, dark tea, white tea, oolong tea, and flower tea; And / or, the mass ratio of tea leaves to water is 1:10 to 1:50.

[0011] In some embodiments of the present invention, the temperature of the heating extraction is 60°C to 100°C, and the heating extraction time is 10 min to 30 min.

[0012] In some embodiments of the present invention, the filtration is performed using qualitative filter paper to obtain a supernatant.

[0013] In some embodiments of the present invention, the refrigeration temperature is 1°C to 15°C, and the refrigeration time is 12h to 72h.

[0014] In some embodiments of the present invention, the rotation speed of the first centrifugation is 5000 rpm / min to 9500 rpm / min, and the time of the first centrifugation is 10 min to 30 min.

[0015] The present invention also provides a hydrogel system, which is prepared by the method described above for preparing a hydrogel system based on tea yogurt that is responsive to both gastric acid and body temperature.

[0016] The present invention also provides the application of the above-described hydrosol system in the preparation of a drug for treating gastric ulcers.

[0017] The beneficial effects that this invention can achieve are: The hydrogel system constructed in this invention can precisely gel at the site of a gastric ulcer in response to gastric acid, combining the advantages of oral delivery and precise targeting of the gastric ulcer. This solves the problem that existing drugs require endoscopic delivery to achieve precise targeting of gastric ulcers. Furthermore, the natural tea yogurt incorporated within the system can decompose in response to body temperature, releasing functional factors that continuously act on the gastric ulcer wound, exerting a sustained-release drug effect to promote ulcer repair while providing long-term protection against the risk of recurrence. This achieves a synergistic effect of "gelation in response to gastric acid and drug release in response to body temperature." Attached Figure Description

[0018] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art are briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the structures shown in these drawings without creative effort.

[0019] Figure 1 In Example 1 of this invention, image a shows the morphology of the black tea cheese before and after being coated with calcium carbonate. Figure 1 Figure b shows the particle size distribution of the tea cream before and after being coated with calcium carbonate in Example 1 of this invention. Figure 2 Figure a shows the component analysis results of the tea cheese in Example 1 of this invention; Figure 2 Figure b is a graph showing the relationship between the release efficiency and temperature of the tea cream before and after it is encapsulated by calcium carbonate in Example 1 of the present invention. Figure 3 Figure a shows the state changes of the BTC@CaCO3 / NaAlg hydrosol in Example 1 of this invention at pH 6.7~7.2 and pH 0.9~1.5; Figure 3 Figure b is a viscosity comparison diagram of the BTC@CaCO3 / NaAlg hydrosol in Example 1 of the present invention under different pH conditions; Figure 3 In Figure c, there is a comparison of the release efficiency of BTC@CaCO3 / NaAlg hydrosol and tea cream in BTC / NaAlg and BTC@CaCO3M-Nps in a simulated gastric juice environment in Example 1 of the present invention. Figure 4 This is a schematic diagram of how BTC@CaCO3 / NaAlg hydrosol forms BTC@CaCO3 / CaAlg hydrogel and adheres to a rat gastric ulcer lesion in response to gastric acid in Example 1 of the present invention. Figure 5 The images show the microstructure of the surface of gastric ulcers in rats from different treatment groups in Example 1 of this invention, during the study of its effect on gastric ulcer repair. Figure 6 The images shown are H&E staining images of rat gastric ulcer tissues from different treatment groups in Example 1 of this invention, during the study of its effect on gastric ulcer repair. Figure 7 Immunohistochemical staining images of TNF-α and IL-10 in gastric ulcer tissues of rats in different treatment groups in Example 1 of this invention, during the study of its effect on gastric ulcer repair. Figure 8 The images shown are H&E staining images of recurrent gastric ulcer tissues from rats in the model group and the BTC@CaCO3 / NaAlg hydrosol treatment group, in Example 1 of this invention, during a study on the effect of preventing gastric ulcer recurrence.

[0020] The realization of the objective, functional features and advantages of the present invention will be further explained in conjunction with the embodiments and with reference to the accompanying drawings. Detailed Implementation

[0021] It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

[0022] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0023] In this invention, descriptions involving "first," "second," etc., are for descriptive purposes only and should not be construed as indicating or implying their relative importance or implicitly specifying the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include at least one of that feature. Furthermore, the technical solutions of the various embodiments can be combined with each other, but only on the basis of being achievable by those skilled in the art. If the combination of technical solutions is contradictory or impossible to implement, such a combination should be considered non-existent and not within the scope of protection claimed by this invention.

[0024] Definitions: 1. Hydrosol: A sol in which water is the dispersion medium. It is a colloidal dispersion system in which solid colloidal particles are uniformly dispersed in water to form a liquid with a uniform appearance and fluidity.

[0025] 2. Hydrogel: A hydrophilic three-dimensional cross-linked polymer network that exists in a solid state, has no fluidity, can maintain a certain shape and elasticity, and has the mechanical properties of a solid.

[0026] 3. Tea cream: During the cooling process of tea soup after high-temperature brewing, micro-nano precipitates are formed by the self-assembly of substances such as catechins, theaflavins, thearubigins, caffeine, proteins, soluble sugars, and metal ions through intermolecular forces such as hydrogen bonds, hydrophobic interactions, and electrostatic interactions.

[0027] 4. Tea cheese coated with calcium carbonate: The surface of the tea cheese is coated with calcium carbonate.

[0028] This invention provides a gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt and its preparation method. The preparation method includes the following steps: S20. Mix tea cream, CaCl2 solution, and Na2CO3 solution, and centrifuge to obtain tea cream coated with calcium carbonate. S30. A hydrosol system is obtained by mixing calcium carbonate-coated tea cream with sodium alginate solution.

[0029] In the hydrosol system of the present invention, the tea cream particles coated with calcium carbonate are uniformly dispersed in the sodium alginate solution, and the hydrosol system as a whole has a certain degree of fluidity.

[0030] The principle of the hydrosol system for treating gastric ulcers in this invention is as follows: The tea yogurt in the hydrosol is rich in functional factors such as theaflavins, and it can decompose and release these functional factors in response to body temperature, thus having a preventive, therapeutic, and repairing effect on gastric ulcers. The hydrosol system has a certain fluidity and moderate viscosity in the oral environment of pH 6.7-7.2, making it convenient for oral swallowing. The surface of the tea yogurt in the hydrosol system is coated with a calcium carbonate shell. This calcium carbonate shell does not easily dissolve in the oral environment of pH 6.7-7.2, preventing premature release of the tea yogurt in the mouth and ensuring precise targeting of the gastric ulcer wound. However, the calcium carbonate shell will dissolve under the action of gastric acid, releasing calcium carbonate. 2+ When stomach acid triggers the release of CaCO3, Ca 2+ Ca 2+ It reacts with sodium alginate to form CaAlg hydrogel, which can both anchor the tea cream to the ulcer surface and form a sustained-release reservoir, achieving the effect of sustained-release drug repair, promoting the repair of gastric ulcers while resisting the risk of gastric ulcer recurrence in the long term.

[0031] The hydrogel system constructed in this invention can precisely gel at the site of a gastric ulcer in response to gastric acid, combining the advantages of oral delivery and precise targeting of the gastric ulcer. This solves the problem that existing drugs require endoscopic delivery to achieve precise targeting of gastric ulcers. Furthermore, the natural tea yogurt incorporated within the system can decompose in response to body temperature, releasing functional factors that continuously act on the gastric ulcer wound, exerting a sustained-release drug effect to promote ulcer repair while providing long-term protection against the risk of recurrence. This achieves a synergistic effect of "gelation in response to gastric acid and drug release in response to body temperature."

[0032] In some embodiments, the tea cream has a particle size of micrometers and / or nanometers. Smaller particle size is beneficial for its efficient therapeutic and repair effects on gastric ulcers.

[0033] In some embodiments, the mixing ratio of tea cream and CaCl2 solution is (5~10) mg / (10~20) ml, which can be 5 mg / 10 ml, 5 mg / 15 ml, 5 mg / 20 ml, 10 mg / 10 ml, 10 mg / 15 ml, etc.

[0034] In some embodiments, the mixing ratio of tea cream and Na2CO3 solution is (5~10) mg / (10~20) ml, which can be 5 mg / 10 ml, 5 mg / 15 ml, 5 mg / 20 ml, 10 mg / 10 ml, 10 mg / 15 ml, etc.

[0035] In some embodiments, adding CaCl2 solution and Na2CO3 solution sequentially to the tea cheese helps to coat the surface of the tea cheese with a relatively complete calcium carbonate shell, achieving a gelling effect in response to gastric acid, and solving the problem of premature leakage of tea cheese and difficulty in accurately gelling on the gastric ulcer surface.

[0036] In some embodiments, the concentration of the CaCl2 solution is 5 mmol / L to 40 mmol / L, and can be 5 mmol / L, 10 mmol / L, 15 mmol / L, 20 mmol / L, 25 mmol / L, 30 mmol / L, 35 mmol / L, 40 mmol / L, etc.

[0037] In some embodiments, the concentration of the Na2CO3 solution is 5 mmol / L to 40 mmol / L, and can be 5 mmol / L, 10 mmol / L, 15 mmol / L, 20 mmol / L, 25 mmol / L, 30 mmol / L, 35 mmol / L, 40 mmol / L, etc.

[0038] In some embodiments, the volume ratio of CaCl2 solution to Na2CO3 solution is 1:0.5 to 1:5, which can be 1:0.5, 1:1, 1:1.5, 1:2, 1:3, 1:5, etc. This is beneficial for promoting the formation of the calcium carbonate shell on the surface of tea cheese, achieving the effect of gastric acid-responsive gelation, and solving the problem of premature leakage of black tea cheese nanoparticles, making it difficult to accurately gel on the gastric ulcer surface.

[0039] In some embodiments, mixing tea cheese, CaCl2 solution, and Na2CO3 solution and stirring for 10 to 30 minutes can promote the formation of a calcium carbonate shell on the surface of the tea cheese.

[0040] In some embodiments, the centrifugation speed is 5000 rpm / min to 9500 rpm / min, and the centrifugation time is 10 min to 30 min, which is beneficial for separating the tea cream coated with calcium carbonate.

[0041] In some embodiments, the mass concentration of sodium alginate solution is 1% to 5%, which can be 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, etc., which is beneficial for forming a hydrosol system that is easy to take orally, and also beneficial for precise gelation on the gastric ulcer wound in response to gastric acid.

[0042] In some embodiments, the method for preparing tea cream also includes the following steps: S10, mixing tea leaves and water to obtain a tea-water mixture, heating and extracting the tea-water mixture, filtering to obtain a supernatant, refrigerating the supernatant, and collecting the black tea cream nanoparticles by a first centrifugation.

[0043] In some embodiments, tea includes at least one of black tea, green tea, yellow tea, dark tea, white tea, oolong tea, and flower tea.

[0044] In some embodiments, the mass ratio of tea leaves to water is 1:10 to 1:50.

[0045] In some embodiments, the heating extraction temperature is 60℃~100℃ and the heating extraction time is 10min~30min, which is conducive to the large-scale dissolution of active ingredients in tea leaves, and the various active ingredients self-assemble to obtain tea cream.

[0046] In some embodiments, heating extraction in a water bath has the advantage of uniform heating, which is beneficial for the dissolution of active ingredients in tea.

[0047] In some embodiments, a supernatant is obtained by filtration using qualitative filter paper, which can filter out impurities such as tea residue while effectively retaining the active ingredients that can be assembled into black tea cream.

[0048] This invention induces the formation of tea cream through refrigeration. Low temperature conditions are conducive to the formation and assembly of various active ingredients to form tea cream.

[0049] In some embodiments, the refrigeration temperature is 1℃~15℃, which can be 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, etc., and the refrigeration time is 12h~72h, which allows the active substances such as tea polyphenols, proteins, and polysaccharides in the supernatant to slowly self-assemble into nano-sized black tea cream.

[0050] In some embodiments, the first centrifugation speed is 5000 rpm / min to 9500 rpm / min, and the first centrifugation time is 10 min to 30 min, which is beneficial for separating and collecting micro-nano-sized tea cream particles.

[0051] The hydrosol of the present invention has certain therapeutic and repair effects on gastric ulcers. Therefore, the present invention further provides an application of the hydrosol system in the preparation of drugs for treating gastric ulcers.

[0052] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following specific embodiments are only used to explain the present invention and are not intended to limit the present invention.

[0053] Example 1 Example 1: The preparation method of the hydrogel system that responds to both gastric acid and body temperature is as follows: S10. Mix black tea and water at a mass ratio of 1:25 to obtain a tea-water mixture. Place the tea-water mixture in a water bath and extract at 100℃ for 30 min to obtain tea soup. Filter the tea soup with qualitative filter paper to obtain the supernatant. Refrigerate the obtained supernatant in a refrigerator at 4℃ for 24 h to induce the formation of black tea cream. Centrifuge the refrigerated tea soup at 9500 rpm / min for 10 min to separate the micro-nano-sized black tea cream micro-nanoparticles (BTC M-NPs). S20. Add 20 ml of 20 mmol / L CaCl2 solution and 20 ml of 20 mmol / L Na2CO3 solution to 10 mg of BTC M-NPs in sequence. After mixing well, centrifuge at 9500 rpm / min for 10 min to separate the calcium carbonate-encapsulated black tea cheese micro-nano particles (BTC@CaCO3M-NPs). S30. BTC@CaCO3M-NPs and sodium alginate solution with a mass concentration of 1.5% were mixed at a concentration of 1.5 mg / ml to obtain BTC@CaCO3M-NPs / NaAlg hydrosol.

[0054] Performance testing (1) Performance analysis of hydrosol system with dual response to gastric acid and body temperature Tea cheese properties: 1) Morphological observation The morphology of the micro- and nanoparticles was observed using scanning electron microscopy. The results are shown in the figure. Figure 1 , Figure 1 The left figure in a is a characterization diagram of BTC M-NPs. Figure 1 The right figure in a is a characterization diagram of BTC@CaCO3M-NPs after being encased in a CaCO3 shell.

[0055] Depend on Figure 1 As shown in Figure a, BTC M-NPs exhibit irregular spherical shapes with a particle size of approximately 153.89 ± 18.62 nm. After being coated with a CaCO3 shell, the particle size of BTC@CaCO3M-NPs increases to approximately 171.90 ± 21.97 nm. Both exhibit good dispersibility. (See reference for details.) Figure 1 a.

[0056] 2) Observation of particle size distribution BTC M-NPs and BTC@CaCO3M-NPs were analyzed using particle size analysis and dynamic light scattering method. Figure 1 b. It was found that the obtained BTC M-NPs and BTC@CaCO3M-NPs had a concentrated particle size distribution and uniform size.

[0057] 3) Material composition Analysis of the material composition of BTC M-NPs, results are shown in […]. Figure 2 .

[0058] Depend on Figure 2 As can be seen, BTC M-NPs are rich in tea functional factors such as theaflavins, flavonoids, polysaccharides, and proteins.

[0059] Depend on Figure 2 As can be seen from b, BTC M-NPs will decompose and release the above-mentioned functional factors under a body temperature of 37℃. However, by coating the surface with CaCO3 to obtain BTC@CaCO3M-NPs, the release of functional factors can be inhibited, preventing BTC NPs from decomposing prematurely in the oral cavity. At the same time, a sustained-release effect can be achieved on the gastric ulcer wound.

[0060] (2) Performance analysis of BTC@CaCO3M-NPs / NaAlg hydrosol The effects of the hydrogel on the simulated oral cavity (pH 6.7–7.2), the simulated stomach (pH 0.9–1.5), and the simulated gastric environment (heated at 37°C) were observed to investigate the release of functional factors from the hydrogel. Results were obtained from these observations. Figure 3 a, Figure 3 b and Figure 3 c. Figure 3 a represents the state and changes of BTC@CaCO3M-NPs / NaAlg hydrosol at different pH values; Figure 3 b represents the viscosity of BTC@CaCO3M-NPs / NaAlg hydrosol at different pH values; Figure 3 c represents the release rate of tea functional factors in a simulated gastric environment for BTC M-NPs / NaAlg hydrosol (a hydrosol obtained by mixing black tea cream micro / nanoparticles and sodium alginate solution), BTC@CaCO3M-NPs, and BTC@CaCO3M-NPs / NaAlg hydrosol.

[0061] Depend on Figure 3 a and Figure 3 As can be seen from b, BTC@CaCO3M-NPs / NaAlg hydrosol is a relatively viscous liquid. It remains fluid and has low viscosity in the simulated oral environment of pH 6.7~7.2, making it easy to swallow orally. In the simulated stomach environment of pH 0.9~1.5, BTC@CaCO3M-NPs / NaAlg hydrosol responds to gastric acid to form BTC@CaCO3M-NPs / CaAlg hydrogel, and the viscosity increases rapidly, which is conducive to adhesion to the gastric ulcer lesion.

[0062] Depend on Figure 3It can be seen that by simulating gastric juice and heating at 37°C to simulate the gastric environment in vitro, BTC M-NPs in BTC@CaCO3M-NPs / NaAlg hydrosol were found to decompose in response to body temperature and continuously release tea functional factors for nearly 20 days.

[0063] (2) Research on its effect on gastric ulcer repair A gastric ulcer model was established in SD rats using acetic acid: After the rats were anesthetized, the stomach was exposed through an abdominal incision. A small incision was made in the gastric fundus, and a tube with an inner diameter of 5 mm was inserted into the stomach. One end of the tube was pressed against the stomach wall, and 100% acetic acid was injected into the other end. After 2 minutes, the acetic acid was aspirated, and the residual acid was rinsed with Duchenne phosphate buffer (DPBS).

[0064] Rats were randomly divided into 5 groups. On days 1 and 5, they were administered water (model group), CaCO3 / NaAlg (a hydrosol of calcium carbonate and sodium alginate solution), BTC M-NPs / NaAlg (a hydrosol of black tea yogurt micro / nanoparticles and sodium alginate solution), BTC@CaCO3M-NPs, and BTC@CaCO3M-NPs / NaAlg via gavage at a dose of 7 mL / kg. A sham-operated group was also established, in which DPBS was used instead of 100% acetic acid during the modeling process, and water was administered via gavage at a dose of 7 mL / kg on days 1 and 5.

[0065] Results analysis: 1) Observe the gastric ulcer lesions of rats in the BTC@CaCO3M-NPs / NaAlg hydrosol group. The results are shown in the figure. Figure 4 We found that after oral administration of BTC@CaCO3M-NPs / NaAlg hydrosol, BTC@CaCO3M-NPs / CaAlg hydrogel was generated in response to gastric acid, and precise adhesion of BTC@CaCO3M-NPs / CaAlg hydrogel was observed at gastric ulcers in rats.

[0066] 2) Observe the surface microstructure of gastric ulcer tissue in each group of rats, and see... Figure 5 The study found that the gastric mucosa of rats in the sham-operated group was smooth and intact, without edema or damage. The model group showed obvious gastric ulcers. The BTC@CaCO3M-NPs / NaAlg group generated BTC@CaCO3M-NPs / CaAlg hydrogels on the gastric ulcers, significantly promoting ulcer healing, reconstructing the gastric tissue surface structure with minimal defects, and all other treatment groups showed varying degrees of reduction in gastric ulcers. 3) H&E staining was performed on the gastric ulcer tissues of rats in each group, and the results are shown in the figure. Figure 6 .

[0067] Depend on Figure 6It was found that the BTC@CaCO3M-NPs / NaAlg group generated BTC@CaCO3M-NPs / CaAlg hydrogels on the gastric ulcer surface in response to gastric acid, significantly improving the histological abnormalities of the gastric ulcer. In the model group, the gastric ulcer site showed epithelial cell loss, basal granulation tissue development, and inflammatory cell infiltration, forming a relatively severe gastric ulcer surface with surrounding mucosal swelling, significant gastric gland dilation, and structural distortion. In contrast, the BTC@CaCO3M-NPs / NaAlg treatment group showed epithelial cell regeneration, restored gastric gland structure, repaired muscularis mucosae, and significantly reduced inflammatory cell infiltration.

[0068] 4) Immunohistochemical staining was used to detect the levels of pro-inflammatory cytokines TNF-α and anti-inflammatory cytokines IL-10 in the gastric ulcer tissues of rats in each group. The results are shown in [Figure number missing]. Figure 7 In the diagram, brownish-yellow represents positive, white represents negative, and blue represents the cell nucleus.

[0069] Depend on Figure 7 It can be seen that the TNF-α content in the model group is extremely high. The BTC@CaCO3M-NPs / NaAlg group significantly reduced the TNF-α content and increased the IL-10 level, which relieved local inflammation of gastric ulcer and promoted gastric ulcer repair.

[0070] (3) Research on its effect in preventing recurrence of gastric ulcers A gastric ulcer model was established in SD rats using acetic acid: After anesthetizing the rats, the stomach was exposed through an abdominal incision. A small incision was made in the gastric fundus, and a tube with an inner diameter of 5 mm was inserted into the stomach. One end of the tube was pressed against the gastric wall, and the other end was injected with 100% acetic acid. After 2 minutes, the acetic acid was aspirated, and residual acid was rinsed with DPBS.

[0071] Rats were randomly divided into two groups. On days 1 and 5, the rats were administered water and BTC@CaCO3M-NPs / NaAlg (7 mL / kg) by gavage. On day 15, gastric ulcer recurrence was induced by intraperitoneal injection of IL-1β (1 µg / kg) and gavage of 56% ethanol (2 mL / kg). Gastric tissue was collected 48 h after recurrence induction.

[0072] Results analysis: 1) H&E staining was performed on gastric tissues from each group, and the results are shown in the figure. Figure 8 .

[0073] Depend on Figure 8It was observed that the repaired ulcers in the model group recurred, with extensive damage to the mucosal layer, loss of normal tissue structures (such as gastric pits and glands), and abundant inflammatory cell infiltration accompanied by fibrous tissue hyperplasia at the ulcer base. More importantly, the recurrent lesions penetrated into the muscular layer, leading to muscle fiber rupture, indicating that the entire gastric wall was affected. Rats treated with BTC@CaCO3M-NPs / NaAlg hydrosol during the initial gastric ulcer treatment developed BTC@CaCO3M-NPs / CaAlg hydrogel at the gastric ulcer site, demonstrating strong anti-recurrence ability in the gastric tissue. Mucosal damage was significantly reduced, gastric pit and gland structures rapidly recovered, and inflammatory infiltration and fibrosis were inhibited. Importantly, the structure of the muscularis propria remained intact, indicating a significant improvement in both the severity and depth of the recurrent ulcers.

[0074] Example 2 Example 2 prepared a hydrosol system according to the preparation method of Example 1, except that green tea was used instead of black tea in Example 2.

[0075] Example 3 Example 3 prepared a hydrogel system according to the preparation method of Example 1, except that the concentrations of CaCl2 solution and Na2CO3 solution in Example 3 were both 40 mmol / L.

[0076] Example 4 Example 4 prepared a hydrogel system according to the preparation method of Example 1, except that the mass concentration of sodium alginate solution in Example 4 was 5%.

[0077] Example 5 Example 5 prepared a hydrosol system according to the preparation method of Example 1. The difference is that the mixing ratio of calcium carbonate-encapsulated black tea cheese micro-nano particles and sodium alginate solution in Example 5 is 3 mg / ml.

[0078] The hydrogel systems in Examples 2 to 5 above can all achieve the synergistic effect of "gel formation in response to gastric acid and drug release in response to body temperature", which can play a role in the continuous repair of sustained-release drugs, promote the repair of gastric ulcers and resist the risk of gastric ulcer recurrence in the long term.

[0079] The above are merely preferred embodiments of the present invention and do not limit the scope of the patent. Any equivalent structural or procedural transformations made based on the description and drawings of the present invention, or direct or indirect applications in other related technical fields, are similarly included within the scope of patent protection of the present invention.

Claims

1. A method for preparing a gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt, characterized in that, Includes the following steps: Mix tea cream, CaCl2 solution, and Na2CO3 solution, and centrifuge to obtain tea cream coated with calcium carbonate. The calcium carbonate-encapsulated tea cheese and sodium alginate solution were mixed to obtain a hydrosol system.

2. The preparation method of the gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt according to claim 1, characterized in that, The particle size of the tea cream is in the micrometer and / or nanometer range; The mixing ratio of the tea cream and the CaCl2 solution is (5~10) mg / (10~20) ml; The mixing ratio of the tea cream and the Na2CO3 solution is (5~10) mg / (10~20) ml; The concentration of the CaCl2 solution is 5 mmol / L to 40 mmol / L; The concentration of the Na2CO3 solution is 5 mmol / L to 40 mmol / L; The volume ratio of the CaCl2 solution to the Na2CO3 solution is 1:0.5 to 1:5; The centrifugation speed is 5000 rpm / min to 9500 rpm / min, and the centrifugation time is 10 min to 30 min; The sodium alginate solution has a mass concentration of 1% to 5%; The mixing ratio of the calcium carbonate-coated tea cheese particles and the sodium alginate solution is (0.5~3) mg / ml.

3. The method for preparing the gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt according to claim 1 or 2, characterized in that, The preparation method of the tea cream includes the following steps: mixing tea leaves and water to obtain a tea-water mixture, heating and extracting the tea-water mixture, filtering to obtain a supernatant, refrigerating the supernatant, and collecting it by a first centrifugation to obtain the tea cream.

4. The preparation method of the gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt according to claim 3, characterized in that, The tea mentioned includes at least one of black tea, green tea, yellow tea, dark tea, white tea, oolong tea, and scented tea; The mass ratio of tea leaves to water is 1:10 to 1:

50.

5. The preparation method of the gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt according to claim 3, characterized in that, The temperature for the heating extraction is 60℃~100℃, and the heating extraction time is 10min~30min.

6. The preparation method of the gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt according to claim 3, characterized in that, The filtration was performed using qualitative filter paper to obtain the supernatant.

7. The preparation method of the gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt according to claim 3, characterized in that, The refrigeration temperature is 1℃~15℃, and the refrigeration time is 12h~72h.

8. The preparation method of the gastric acid and body temperature dual-responsive hydrosol system based on tea yogurt according to claim 3, characterized in that, The first centrifugation is performed at a speed of 5000 rpm / min to 9500 rpm / min, and the first centrifugation time is 10 min to 30 min.

9. A hydrosol system based on tea yogurt that responds to both gastric acid and body temperature, characterized in that, The gastric acid and body temperature dual-responsive hydrogel system based on tea cheese is prepared by the preparation method of the gastric acid and body temperature dual-responsive hydrogel system based on tea cheese as described in any one of claims 1 to 8.

10. The use of the tea yogurt-based gastric acid and body temperature dual-responsive hydrosol system of claim 9 in the preparation of a drug for treating gastric ulcers.

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