Preparation method of anthocyanin gastric floating tablet

Abstract

The invention discloses a preparation method of an anthocyanin gastric floating tablet, which comprises the following steps: firstly obtaining a solution containing a PCA-Fe < 3 + > complex, an anthocyanin solution and a chitosan-acetic acid-sodium alginate mixed solution, and adding the chitosan-acetic acid-sodium alginate mixed solution into the solution containing the PCA-Fe < 3 + > complex under stirring at room temperature to obtain a mixture 1; adding the obtained mixture 1 into an anthocyanin solution to obtain a mixture 2; adding the mixture 2 into a CaCl2 aqueous solution, fully hydrating the obtained mixture 3 in a tablet mold, and freeze-drying to obtain chitosan-sodium alginate gel tablets containing anthocyanin; preparing an HPMC aqueous solution, adding PEG 6000 and sodium bicarbonate to obtain a coating solution, carrying out spray coating on the gel sheet by using the coating solution, and drying to obtain a coated tablet; and carrying out spray coating on the coated tablet by using acrylic resin to obtain the anthocyanin gastric floating tablet. The gastric floating tablet prepared by the invention can realize continuous release of anthocyanin in the stomach.

Description

Technical Field

[0001] The invention belongs to the technical field of health food or pharmaceutical preparations, and particularly relates to a method for preparing anthocyanin gastric floating tablets. Technical Background

[0002] Anthocyanins are phenolic compounds glycosylated from anthocyanidins. Their physical and chemical properties give them antioxidant properties, which can effectively prevent neurological and cardiovascular diseases and inhibit cancer. However, anthocyanins are very sensitive to changes in temperature, light and pH. They are poorly lipophilic and highly hydrophilic. They are not easily absorbed by cells through the phospholipid bilayer. Only a small part of anthocyanins can be absorbed by the human body, resulting in low utilization. Among the different types of polyphenols, anthocyanidins are the only polyphenols that appear in different structures according to the environmental pH. Generally speaking, the main way for anthocyanins to enter the human body to exert their biological activity is through digestion and absorption in the stomach and small intestine. Anthocyanins have low bioavailability in the intestine. Anthocyanins that enter the small intestine mostly enter the human blood circulation and other tissues and organs in the form of degradation products. The stomach is an important absorption site for anthocyanins. Anthocyanins are stable in the stomach and can pass through the gastric mucosa. At the same time, they are quickly absorbed by the stomach in the form of glycosides. The absorption rate can reach 20%-25%, but the residence time of anthocyanins in the stomach is short, so the absorption is limited. Increasing the residence time of anthocyanins in the stomach can, to a certain extent, promote the absorption of anthocyanins in situ, thereby inhibiting Helicobacter pylori, improving gastric ulcers and resisting gastric cancer.

[0003] Metal-polyphenol networks (MPNs) are supramolecular framework materials formed by the coordination of metal ions and polyphenols, which have excellent drug loading performance, bioadhesion and biocompatibility. Without the help of any high temperature, electricity or other special solvents, polyphenols can quickly and stably chelate with metal ions to form MPNs. 3+ -Inspired by the mucus of catechol networks, MPNs are applied to the loading and delivery of anthocyanins while having tissue adhesion.

[0004] Hydrogels are ideal drug delivery systems because of their three-dimensional structure and ability to encapsulate small and large biomolecules, proteins, growth factors, and other components required for cell growth and differentiation. Gel carriers usually fix anthocyanin molecules inside the gel mesh structure, encapsulate anthocyanin molecules using non-chemical methods, and introduce MPNs through physical blending to improve the encapsulation rate, mechanical strength, and safety of delivery of anthocyanins. After drying and freezing, affected by the formation of ice crystals, the ice crystals in the gel are entangled into orderly and continuous lamellar crystals, thus forming a porous structure that is conducive to CO2 adsorption.

[0005] As a drug delivery system, gastric floating sustained-release preparations are generally made of one or more hydrophilic gel skeleton materials supplemented with other materials. The dosage forms include capsules, tablets and microcapsules. After oral administration, the outer gel of the preparation swells when it encounters gastric juice, making its density less than that of gastric contents and floating. At the same time, a gel barrier is formed on the surface of the preparation, which controls the diffusion rate of anthocyanins and solvents, thereby prolonging the retention time of anthocyanins in the stomach and achieving slow and lasting release of anthocyanins. It can increase the stability under acidic conditions and the residence time of bioactive compounds absorbed by the stomach, has the advantages of improving bioavailability and reducing the number of medications, and has become a hot spot for drug development at home and abroad. The factors affecting its floating performance and release rate are mainly the selection of skeleton materials, additives and preparation processes. The use of CO2 gas is conducive to shortening the floating time of gastric floating tablets and improving their floating performance. Therefore, a non-chemical method is used to encapsulate anthocyanins in a three-dimensional metal polyphenol network hydrogel, and the gas-forming layer and gas-intercepting membrane layer are coated in turn. Summary of the invention

[0006] The present invention aims at the problem of low absorption and utilization rate of anthocyanins and provides a method for preparing a stomach floating tablet loaded with anthocyanins. The stomach floating tablet can realize the sustained release of anthocyanins in the stomach.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] The present invention provides a method for preparing anthocyanin gastric floating tablets, which comprises the following steps:

[0009] (1) Disperse protocatechuic acid and FeCl3·6H2O in double distilled water to obtain clear protocatechuic acid solution with a concentration of 8 to 15 mg / mL and FeCl3·6H2O solution with a concentration of 8 to 15 mg / mL. 3+ Solution (the concentration is calculated as FeCl3·6H2O);

[0010] (2) Add protocatechuic acid solution and Fe 3+ solution, so that the mass ratio of protocatechuic acid to FeCl3·6H2O is 1:1 to 1:1.5; then add the same volume of deionized water as the obtained mixed solution to dilute the stock solution to obtain PCA-Fe 3+ The metal phenol network was prepared by adjusting the pH to 7 with 0.5-1 mol / L NaOH solution to obtain PCA-Fe 3+ A solution of the complex;

[0011] (3) dispersing anthocyanins in double distilled water to prepare an anthocyanin solution with a concentration of 7.0 to 7.5 mg / mL;

[0012] (4) adding 0.5-1% (v / v) acetic acid aqueous solution to 0.5-1% (w / v) chitosan aqueous solution to make the mass volume ratio of chitosan to acetic acid be 200:1-300:1; adding 0.5-1% (w / v) sodium alginate aqueous solution to the chitosan-acetic acid mixture after continuous stirring for 30-40 minutes, and stirring to obtain a chitosan-acetic acid-sodium alginate mixed solution, and controlling the mass ratio of chitosan to sodium alginate to be 3:2-4:3;

[0013] (5) Under stirring at room temperature, in a PCA-Fe 3+ A certain amount of chitosan-acetic acid-sodium alginate mixed solution was added to the complex solution to make the PCA-Fe 3+ The volume ratio of the complex solution to the chitosan-acetic acid-sodium alginate mixed solution is 1:80-1:85, to obtain a mixture 1;

[0014] (6) adding the obtained mixture 1 to the anthocyanin solution obtained in step (3) so that the volume ratio of the mixture 1 to the anthocyanin solution is 1.2:1 to 1:1, and magnetically stirring for 1 to 2 hours to obtain a mixture 2;

[0015] (7) slowly adding 3-5% (w / v) CaCl2 aqueous solution to mixture 2 under stirring, wherein the volume ratio of mixture 2 to CaCl2 aqueous solution is 30:1-50:1, and then placing the obtained mixture 3 in a round tablet mold at 2-4°C for 12-24 hours to fully hydrate, and then freeze-drying at -60--45°C and 0.2-1 mBar for 24-48 hours to obtain chitosan-sodium alginate gel tablets containing anthocyanins, which are stored in dark dry conditions;

[0016] (8) preparing an 8-10% HPMC aqueous solution, adding PEG 6000 as a filler, and then adding sodium bicarbonate to obtain a coating solution; wherein the mass amounts of PEG 6000 and sodium bicarbonate account for 10%-15% and 50%-80% of the mass of HPMC in the HPMC solution, respectively;

[0017] (9) using the coating solution obtained in step (8) to spray-coat the chitosan-sodium alginate gel tablet containing anthocyanins obtained in step (7), controlling the weight gain of the coating layer to be 10% to 12%, and further drying in a coating chamber to evaporate residual water to obtain coated tablets;

[0018] (10) Use acrylic resin RL 30D spray-coated the coated tablets, controlling the weight gain of the coating gas interception layer to 5% to 10%. After the spray coating was completed, the tablets were further dried in the coating room to evaporate the residual water in the coating to obtain anthocyanin gastric floating tablets.

[0019] Preferably, in step (1), the protocatechuic acid solution and Fe 3+ The concentration of the solutions was 10 mg / mL.

[0020] Preferably, in step (2), the protocatechuic acid solution and Fe 3+ solution so that the mass ratio of protocatechuic acid to FeCl3·6H2O is 1:1.

[0021] Preferably, in step (3), the concentration of the anthocyanin solution is 7.5 mg / mL.

[0022] Preferably, in step (4), the concentration of the chitosan aqueous solution is 1%, the concentration of the acetic acid aqueous solution is 1% (v / v), and the concentration of the sodium alginate solution is 1%.

[0023] Preferably, in step (4), the mass ratio of chitosan to sodium alginate is controlled to be 3:2.

[0024] Preferably, in step (7), the concentration of the CaCl2 aqueous solution is 5% (w / v).

[0025] Preferably, the coating conditions of step (9) are: preheating temperature 48-50°C, preheating time 30-32 min, inlet temperature 48-50°C, outlet temperature 39-41°C, atomization pressure 1.1 bar, spraying speed 7-9 mL / min, spray coating onto the chitosan-sodium alginate gel tablet containing anthocyanins.

[0026] Preferably, the coating conditions of step (10) are: preheating temperature 48-50°C, preheating time 30-32 min, inlet temperature 48-50°C, outlet temperature 39-41°C, atomization pressure 2.5 bar, and spraying speed 5-8 mL / min.

[0027] Compared with the prior art, the present invention has the following beneficial effects: the present invention uses physical blending to introduce metal polyphenol network into chitosan-sodium alginate hydrogel to load anthocyanins, thereby improving the cross-linking strength and stability of the gel; at the same time, the CS / PCA / Fe gel prepared by double-layer film coating is conducive to the floating of anthocyanins in the stomach, and has good application prospects in the delivery and absorption of anthocyanins in the human body. Specifically:

[0028] (1) The present invention utilizes a physical method of introducing a metal-polyphenol network to enhance the crosslinking strength of the gel to avoid the toxicity of the chemical modification method; at the same time, physical blending can avoid uneven gelation, and the preparation process is simple.

[0029] Specifically, although chemical modification generally improves the cross-linking degree of the gel, it also reduces the safety of the gel and the synthesis process is complex and difficult to control. Heat treatment will destroy the stability of heat-sensitive components.3+ It can rapidly form a multifunctional metal-polyphenol network coating or thin shell. Under low pH conditions, most phenolic hydroxyl groups on polyphenol molecules are protonated, resulting in competitive chelation between proton hydrogens and metal ions, leading to the instability or even disintegration of the MPNs structure. MPNs are stable in a neutral pH environment and have pH responsiveness with controllable release under lower pH conditions, making it a drug carrier with good application prospects. After the metal ions are coordinated with the polyphenol groups, most of the sites of the metal ions are bound, and then the ligand of the metal ions and polyphenols is mixed with chitosan and combined through hydrogen bonds and ionic bonds to avoid the direct binding of the binding sites of the metal ions to chitosan and rapid gelation, preventing uneven gelation. The formed triple dense network structure of the metal-polyphenol gel can enhance the stability of encapsulated bioactive molecules.

[0030] (2) The present invention uses chitosan gel to make gastric floating tablets, taking advantage of the good biocompatibility and safety and non-toxicity of the polysaccharide gel carrier material, and at the same time using the pH-responsive characteristics of the cationic hydrogel to better achieve the purpose of gastric suspension.

[0031] Specifically, hydrogels usually contain ionizable acidic or basic groups inside. When the pH changes, these groups will change accordingly, resulting in a change in the degree of swelling. Inspired by the opening and closing function of plant stomata, it is proposed that under different pH changes in the human body, the pore size inside the hydrogel will change with the change of pH. When the pH of the cationic hydrogel becomes smaller, the pores become larger and the swelling is enhanced, achieving the effect of gastric targeting.

[0032] The main representatives of cationic hydrogels are chitosan and polyvinylpyridine, which contain ionizable amino groups inside. When the pH increases, hydrogen bonds are formed between the internal amino groups, resulting in the shrinkage of the hydrogel network and a decrease in the degree of swelling; when the pH decreases, the amino groups are ionized, the hydrogen bonds are broken, and the electrostatic repulsion is enhanced, resulting in enhanced swelling. Pure chitosan gel has low functionality. Chitosan and sodium alginate have good biocompatibility and a large application range, so chitosan-sodium alginate gel is selected.

[0033] (3) The present invention uses the cross-linked network to endow the hydrogel with good mechanical strength and tissue adhesion, and the addition of MPNs significantly enhances the strength of the gel.

[0034] Specifically, the gel contains an interwoven first network and second network. Generally speaking, under strong acid conditions (pH < 2.0), most of the -OH groups of PCA are hydrogenated and form a single complex with Fe 3+ Under weak acid conditions (3.0 < pH < 6.0), the -OH groups of PCA are gradually dehydrogenated and form a double complex with Fe 3+ When pH > 7.0, most of the -OH groups of PCA are dehydrogenated and form a complex with Fe3+ The CS / PCA / Fe gels showed different colors at different pH values, which may be related to the 3+ The different types of coordination bonds that are formed.

[0035] (4) The present invention utilizes double-layer coating technology to achieve sustained release of tablets. The RL 30 layer and the sodium bicarbonate layer play different roles.

[0036] Specifically, the outer The RL 30D film not only protects the activity of anthocyanins and reduces the effects of the outside world, but also, after contacting with gastric juice, the gastric juice penetrates into the inner layer of the sodium bicarbonate coating film. Sodium bicarbonate reacts with gastric juice to produce carbon dioxide, so the outer coating film plays a role in binding carbon dioxide and achieving rapid bleaching. At the same time, water penetrates through the channel, and the outer layer of the tablet forms a preliminary gel barrier layer, which controls the drug release rate. As water gradually penetrates inward, the hydration of the tablet core gel skeleton intensifies, and anthocyanins are released through the micropores of the gel layer until the coating film ruptures, the barrier effect weakens, and the dissolution effect dynamically increases. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The cross-sectional scanning electron micrographs of the gel tablets prepared in Examples 1-2 and Comparative Example 1 are shown. Specific implementation methods

[0039] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme will be further described clearly and completely by examples below. If no specific conditions are specified in the examples, the conditions are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0040] The protocatechuic acid used in the examples was purchased from Shanghai Bailingwei Chemical Reagent Co., Ltd., anthocyanin was purchased from Nanjing Yuanzhi Biotechnology Co., Ltd., ferric chloride hexahydrate was purchased from Sinopharm Chemical Reagent Co., Ltd., chitosan was purchased from Hangzhou Jigong Biotechnology Co., Ltd., RL 30D was purchased from Shanghai Dexiang Pharmaceutical Technology Co., Ltd.

[0041] Embodiment 1:

[0042] (1) Protocatechuic acid (10 mg / mL) and FeCl3·6H2O (10 mg / mL) were dispersed in double distilled water and ultrasonicated at 350 W for 5 min to obtain a clear solution of protocatechuic acid and FeCl3·6H2O. 3+ Solution;

[0043] (2) Add 15 μL of protocatechuic acid solution and 15 μL of Fe 3+ solution, and then add 30 μL of deionized water to dilute the stock solution to obtain PCA-Fe 3+ The metal phenol network was prepared by adjusting the pH to 7.0 with 1 mol / L NaOH solution. 3+ A solution of the complex;

[0044] (3) dispersing anthocyanins in double distilled water at a concentration of 7.5 mg / mL to prepare anthocyanin solution;

[0045] (4) 3 mL of 1% (w / v) chitosan aqueous solution was added with 15 μL of 1% (v / v) acetic acid aqueous solution, the chitosan-acetic acid mixture was stirred continuously for 30 min, and then 2 mL of 1% (w / v) sodium alginate aqueous solution was added and stirred to obtain a chitosan-acetic acid-sodium alginate solution;

[0046] (5) Under stirring at room temperature, in a PCA-Fe 3+ Chitosan-acetic acid-sodium alginate solution is added to the solution of the metal phenol network to obtain a mixture 1;

[0047] (6) Add 5 mL of anthocyanin solution to mixture 1 and stir magnetically for 2 h to obtain mixture 2;

[0048] (7) 300 μL of CaCl2 (5% w / v) solution was slowly added to the mixture 2 under stirring, and then the resulting mixture 3 was placed in a round tablet mold at 4°C for 24 h to fully hydrate, and then freeze-dried at -45°C and 0.2 mBar for 48 h and stored in dark dry conditions to obtain chitosan-sodium alginate gel tablets containing anthocyanins.

[0049] Embodiment 2:

[0050] (1) Protocatechuic acid (10 mg / mL) and FeCl3·6H2O (10 mg / mL) were dispersed in double distilled water and ultrasonicated at 350 W for 5 min to obtain a clear solution of protocatechuic acid and FeCl3·6H2O. 3+ Solution;

[0051] (2) Add 15 μL of protocatechuic acid solution and 15 μL of Fe 3+ solution, and then add 30 μL of deionized water to dilute the stock solution to obtain PCA-Fe 3+ The metal phenol network was prepared by adjusting the pH to 7 with 1 mol / L NaOH solution. 3+ A solution of the complex;

[0052] (3) dispersing anthocyanins in double distilled water at a concentration of 7.5 mg / mL to prepare anthocyanin solution;

[0053] (4) 3 mL of 1% (w / v) chitosan aqueous solution was added with 15 μL of 1% (v / v) acetic acid aqueous solution, the chitosan-acetic acid mixture was stirred continuously for 30 min, and then 2 mL of 1% (w / v) sodium alginate solution was added and stirred to obtain a chitosan-acetic acid-sodium alginate mixed solution;

[0054] (5) Under stirring at room temperature, in a PCA-Fe 3+ Adding a chitosan-acetic acid-sodium alginate mixed solution into the complex solution to obtain a mixture 1;

[0055] (6) Add 5 mL of anthocyanin solution to mixture 1 and stir magnetically for 2 h to obtain mixture 2;

[0056] (7) 300 μL of CaCl2 (5% w / v) solution was slowly added to the mixture 2 under stirring, and then the resulting mixture 3 was placed in a round tablet mold at 4°C for 24 hours to fully hydrate, and then freeze-dried at -45°C and 0.2 mBar for 48 hours, and stored in dark dry conditions to obtain chitosan-sodium alginate gel tablets containing anthocyanins;

[0057] (8) preparing a certain amount of HPMC solution (10% w / w), adding PEG 6000 as a filler, and then adding sodium bicarbonate to obtain a coating solution, wherein the added amounts of PEG 6000 and sodium bicarbonate account for 10% and 60% of the mass of HPMC in the HPMC solution;

[0058] (9) Using the coating liquid obtained in step (8) to spray-coat the chitosan-sodium alginate gel tablets containing anthocyanins obtained in step (7), the coating conditions are: preheating temperature 50°C, preheating time 30 min, inlet temperature 48°C, outlet temperature 39°C, atomization pressure 1.1 bar, spray speed 8 mL / min, spray coating on the chitosan-sodium alginate gel containing anthocyanins, and control the coating gas layer weight gain to 10%. Drying in a coating chamber at 50°C for 30 min to evaporate residual water to obtain coated tablets.

[0059] (10) Use acrylic resin The coated tablets were spray coated by RL 30D, and the coating conditions were as follows: preheating temperature 50°C, preheating time 30 min, inlet temperature 48°C, outlet temperature 40°C, atomization pressure 2.5 bar, and spraying speed 6 mL / min. The weight gain of the coating gas interception layer was controlled to be 7%. After the spray coating was completed, the tablets were further dried in the coating chamber for 30 min to evaporate the residual water in the polymer coating before storage to obtain anthocyanin gastric floating tablets.

[0060] Comparative Example 1

[0061] (1) Protocatechuic acid (10 mg / mL) and FeCl3·6H2O (10 mg / mL) were dispersed in double distilled water and ultrasonicated at 350 W for 5 min to obtain a clear solution of protocatechuic acid and FeCl3·6H2O. 3+ Solution;

[0062] (2) Add 15 μL of protocatechuic acid solution and 15 μL of Fe 3+ solution, and then add 30 μL of deionized water to dilute the stock solution to obtain PCA-Fe 3+ The metal phenol network was prepared by adjusting the pH to 7 with 1 mol / L NaOH solution. 3+ A solution of the complex;

[0063] (3) dispersing anthocyanins in double distilled water at a concentration of 7.5 mg / mL to prepare anthocyanin solution;

[0064] (4) Under stirring at room temperature, in a PCA-Fe 3+ 5 mL of 1% sodium alginate aqueous solution and anthocyanin solution were added to the complex solution to obtain a mixture 1;

[0065] (5) 300 μL of CaCl2 (5% w / v) solution was slowly added to the mixture 1 under stirring, and the resulting mixture was then placed in a round tablet mold at 4°C for 24 h to fully hydrate, and then freeze-dried at -45°C and 0.2 mBar for 48 h and stored in dark dry conditions to obtain sodium alginate gel tablets containing anthocyanins.

[0066] The encapsulation rate of the chitosan-sodium alginate gel tablet containing anthocyanins obtained in Example 1, the anthocyanin gastric floating tablet obtained in Example 2, and the sodium alginate gel tablet containing anthocyanins obtained in Comparative Example 1 was tested. The test method was to add 0.1g of the ground tablet powder to 1mL of distilled water, and add 9mL of anhydrous ethanol and ultrasonically stir for 15min. The obtained solution was centrifuged at 15°C and 6000rmp for 5min, the supernatant was filtered, and the encapsulated anthocyanin content was determined by the pH differential method. At the same time, 0.1g of gel was added to 10mL of anhydrous ethanol and stirred for 10s. The obtained solution was centrifuged at 15°C and 6000rmp for 5min, the supernatant was filtered, and the anthocyanin content on the surface of the unencapsulated tablet was determined by the pH differential method. The encapsulation rate was calculated according to the following formula:

[0067]

[0068] The experimental results are shown in Table 1 below:

[0069] Table 1 Anthocyanin encapsulation rate in different groups

[0070] Group Packaging rate Comparative Example 1 <![CDATA[60.09±3.13 c ]]> Example 1 <![CDATA[82.15±3.49 b ]]> Example 2 <![CDATA[95.82±2.58 a ]]>

[0071] Note: Different lowercase letters indicate significant differences (P<0.05)

[0072] The encapsulation rate is an important indicator for evaluating the loading and delivery of nutrients. As shown in Table 1, the encapsulation rate of the simple metal phenol sodium alginate gel is about 60%, which is 13.67% and 22.06% lower than the encapsulation rate of the chitosan-sodium alginate hydrogel of the multi-network metal phenol network Example 1 and Example 2, which is about 80% to 90%, respectively. It can be seen that the addition of chitosan significantly enhances the encapsulation rate of the gel, which has a positive impact on improving the quality of the gastric suspension tablet.

[0073] The drug floating test was carried out on Example 1, Example 2 and Comparative Example 1. The test method was to put 0.1 mol·L of the drug at a temperature of (37±0.5)°C into a 1000 mL beaker. -1 900mL hydrochloric acid solution. Put the tablets into it, stir at 100r / min, record the floating time and continuous floating time of the tablets of different embodiments and comparative examples, repeat the experiment three times and take the average value. The results are shown in Table 2:

[0074] Table 2 The floating time and continuous floating time of anthocyanins in different groups in simulated gastric fluid

[0075] Group Drifting time (min) Continuous floating time (h) Comparative Example 1 <![CDATA[8.67±1.15 a ]]> <![CDATA[6.83±1.04 c ]]> Example 1 <![CDATA[4.50±0.50 b ]]> <![CDATA[15.67±3.25 b ]]> Example 2 <![CDATA[1.67±0.60 c ]]> <![CDATA[22.83±2.02 a ]]>

[0076] Note: Different lowercase letters indicate significant differences (P<0.05)

[0077] As shown in Table 2, the floating lag time of Example 2 is significantly shorter than that of Comparative Example 1 and Example 1, which may be due to the outer coating. The RL 30D membrane binds the CO2 gas produced by the simulated gastric fluid and calcium bicarbonate, causing the membrane to expand and the tablet volume to increase, so it floats quickly. Compared with the membrane-coated gastric suspension tablets in Example 2, the floating lag time of Comparative Example 1 and Example 1 slowed down by 7 minutes and 2.83 minutes. Example 1 is 4.17 minutes faster than Comparative Example 1 because of its highly cross-linked dense network structure that easily binds carbon dioxide. At the same time, the internal tablet swells after hydration after contacting with the simulated gastric fluid, and begins to slowly release anthocyanins outward, and maintains a relatively long ideal floating state of 22.83 hours. Comparative Example 1 has no The RL 30D film-coated tablets reacted directly with gastric acid and disintegrated 16 h faster than Example 2. The porous metal phenol sodium alginate chitosan gel structure of Example 1 floated 8.84 h longer than the simple metal phenol sodium alginate gel, but 7.16 h shorter than the film-coated tablets.

[0078] The anthocyanin solubility test was performed on the products of Example 1, Example 2 and Comparative Example 1 according to the second method of the dissolution and release test method in Part IV of the 2020 edition of the Pharmacopoeia of the People's Republic of China. Dissolution medium: 0.1 mol·L -1 Hydrochloric acid solution 900mL, medium temperature: (37±0.5)℃, rotation speed: 100r·min -1 , sampling time 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24h. Take anthocyanin gastric suspension tablets and put them into 6 dissolution cups respectively, sample 5mL at the specified time point, and replenish 5mL of (37±0.5)℃ dissolution medium in time. The taken samples are filtered through a 0.45μm microporous filter membrane, and the sampling to filtration should be completed within 30s. The filtered samples are detected at a wavelength of 525nm using an ultraviolet spectrophotometer, and the anthocyanin solubility is calculated in combination with the anthocyanin standard curve. The results are shown in Table 3:

[0079] Table 3 Solubility of anthocyanins from different groups in simulated gastric fluid at pH 1.2

[0080] Comparative Example 1 Example 1 Example 2 Time / h Cumulative dissolution % Cumulative dissolution % Cumulative dissolution % 2 21.65 2.79 0.00 4 48.39 6.56 2.83 6 59.96 11.20 8.55 8 67.82 31.39 17.30 10 81.08 45.38 35.47 12 99.67 57.80 44.66 14 100.00 71.22 61.08 16 100.00 89.43 73.59 18 100.00 96.77 89.17 20 100.00 100.00 95.75 22 100.00 100.00 99.94 24 100.00 100.00 100.00

[0081] Note: Different lowercase letters indicate significant differences (P<0.05)

[0082] As shown in Table 3, different groups of gastric suspension tablets can maintain a floating state in simulated gastric juice. The anthocyanin release of comparative example 1 is very fast at the beginning, and it shows complete release at 12-14h; the anthocyanin release of example 1 is relatively stable, and it shows complete release at 18-20h; the anthocyanin release of example 2 is stable, and it shows complete release at 22-24h. Example 2 not only releases the drug steadily but also has a long release duration (>22h), anthocyanins are released slowly and at a constant rate, and show sustained release characteristics in in vitro tests. The metal phenol network sodium alginate chitosan double cross-linked network can protect the internal encapsulated anthocyanins to a certain extent and improve the stability of anthocyanins. The double-layer coating film restrains the carbon dioxide produced by simulated gastric juice and sodium bicarbonate, prolongs the gastric suspension time, and avoids direct contact between simulated gastric juice and anthocyanins. The gastric suspension tablets of the double-layer coating film metal phenol network chitosan gel have small drug release fluctuations and a long continuous floating time, which is conducive to promoting the absorption of anthocyanins in the stomach and improving the gastric bioavailability of anthocyanins.

[0083] Figure 1The scanning electron microscope images of different embodiments magnified 200 times and 500 times are compared. The crosslinking density of chitosan-sodium alginate gel with metal phenol network crosslinking is significantly greater than that of simple metal phenol sodium alginate gel. The dense pore structure is not only conducive to increasing the loading rate of anthocyanins, but also can improve the stability of active molecules encapsulated in the gel. This may be due to the crosslinking of sodium alginate and calcium ions, the crosslinking of sodium alginate and chitosan, the formation of hydrogen bonds between sodium alginate-COOH and -OH of PCA, and the bonding between PCA and Fe 3+ A multiple network structure formed by coordination bonds is formed between them.

Claims

1. A method for preparing anthocyanin gastric floating tablets, characterized in that: The preparation method comprises the following steps: (1) Disperse protocatechuic acid and FeCl3·6H2O in double distilled water to obtain clear protocatechuic acid solution with a concentration of 8 to 15 mg / mL and FeCl3·6H2O solution with a concentration of 8 to 15 mg / mL. 3+ Solution; (2) Add protocatechuic acid solution and Fe 3+ solution, so that the mass ratio of protocatechuic acid to FeCl3·6H2O is 1:1 to 1:1.5; then add the same volume of deionized water as the obtained mixed solution to dilute the stock solution to obtain PCA-Fe 3+ The metal phenol network was prepared by adjusting the pH to 7 with 0.5-1 mol / L NaOH solution to obtain PCA-Fe 3+ A solution of the complex; (3) dispersing anthocyanins in double distilled water to prepare an anthocyanin solution with a concentration of 7.0 to 7.5 mg / mL; (4) adding 0.5-1% (v / v) acetic acid aqueous solution to 0.5-1% (w / v) chitosan aqueous solution to make the mass volume ratio of chitosan to acetic acid be 200:1-300:1; adding 0.5-1% (w / v) sodium alginate aqueous solution to the chitosan-acetic acid mixture after continuous stirring for 30-40 minutes, and stirring to obtain a chitosan-acetic acid-sodium alginate mixed solution, and controlling the mass ratio of chitosan to sodium alginate to be 3:2-4:3; (5) Under stirring at room temperature, in a PCA-Fe 3+ A certain amount of chitosan-acetic acid-sodium alginate mixed solution was added to the complex solution to make the PCA-Fe 3+ The volume ratio of the complex solution to the chitosan-acetic acid-sodium alginate mixed solution is 1:80-1:85, to obtain a mixture 1; (6) adding the obtained mixture 1 to the anthocyanin solution obtained in step (3) so that the volume ratio of the mixture 1 to the anthocyanin solution is 1.2:1 to 1:1, and magnetically stirring for 1 to 2 hours to obtain a mixture 2; (7) slowly adding 3-5% (w / v) CaCl2 aqueous solution to mixture 2 under stirring, wherein the volume ratio of mixture 2 to CaCl2 aqueous solution is 30:1-50:1, and then placing the obtained mixture 3 in a round tablet mold at 2-4°C for 12-24 hours to fully hydrate, and then freeze-drying at -60--45°C and 0.2-1 mBar for 24-48 hours to obtain chitosan-sodium alginate gel tablets containing anthocyanins, which are stored in dark dry conditions; (8) preparing an 8-10% HPMC aqueous solution, adding PEG 6000 as a filler, and then adding sodium bicarbonate to obtain a coating solution; wherein the mass amounts of PEG 6000 and sodium bicarbonate account for 10%-15% and 50%-80% of the mass of HPMC in the HPMC solution, respectively; (9) using the coating solution obtained in step (8) to spray-coat the chitosan-sodium alginate gel tablet containing anthocyanins obtained in step (7), controlling the weight gain of the coating layer to be 10% to 12%, and further drying in a coating chamber to evaporate residual water to obtain coated tablets; (10) Use acrylic resin RL 30D spray-coated the coated tablets, controlling the weight gain of the coating gas interception layer to 5% to 10%. After the spray coating was completed, the tablets were further dried in the coating room to evaporate the residual water in the coating to obtain anthocyanin gastric floating tablets.

2. The preparation method according to claim 1, characterized in that: In step (1), the protocatechuic acid solution and Fe 3+ The concentration of the solutions was 10 mg / mL.

3. The preparation method according to claim 1, characterized in that: In step (2), the protocatechuic acid solution and Fe 3+ solution so that the mass ratio of protocatechuic acid to FeCl3·6H2O is 1:

1.

4. The preparation method according to claim 1, characterized in that: In step (3), the concentration of the anthocyanin solution is 7.5 mg / mL.

5. The preparation method according to claim 1, characterized in that: In step (4), the concentration of the chitosan aqueous solution is 1% (w / v), the concentration of the acetic acid aqueous solution is 1% (v / v), and the concentration of the sodium alginate aqueous solution is 1% (w / v).

6. The preparation method according to claim 1, characterized in that: In step (4), the mass ratio of chitosan to sodium alginate is controlled to be 3:

2.

7. The preparation method according to claim 1, characterized in that: In step (7), the concentration of the CaCl2 aqueous solution is 5% (w / v).

8. The preparation method according to claim 1, characterized in that: The coating conditions of step (9) are as follows: preheating temperature 48-50°C, preheating time 30-32 min, inlet temperature 48-50°C, outlet temperature 39-41°C, atomization pressure 1.1 bar, spraying speed 7-9 mL / min, spray coating onto the chitosan-sodium alginate gel tablet containing anthocyanins.

9. The preparation method according to claim 1, characterized in that: The coating conditions of step (10) are: preheating temperature 48-50°C, preheating time 30-32min, inlet temperature 48-50°C, outlet temperature 39-41°C, atomization pressure 2.5bar, and spraying speed 5-8mL / min.

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