Tripterygium glycosides tablet and preparation method thereof

Abstract

The application relates to the field of biological medicine, and discloses a tripterygium glycosides tablet and a preparation method thereof; the preparation method comprises the following operation steps: uniformly mixing tripterygium glycosides, corn starch, pregelatinized starch and low-substitution hydroxypropyl cellulose, adding a binder to mix and granulate, integrating the granules, mixing the granules with magnesium stearate and silicon dioxide, pressing the granules to obtain a tablet core; step 2: (1) spraying a pregelatinized starch aqueous solution on the surface of the tablet core through a bottom-spraying type fluidized bed to form a wet adhesion layer, and then spraying probiotic microcapsules to form a probiotic microcapsule inlaid layer, so as to obtain a probiotic tablet core; (2) spraying a gastric-soluble coating liquid to form a coating layer, and obtaining the tripterygium glycosides tablet.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a Tripterygium wilfordii polyglycoside tablet and its preparation method. Background Technology

[0002] Tripterygium wilfordii glycosides are fat-soluble active ingredients extracted from Tripterygium wilfordii, a plant in the Celastraceae family. They have significant pharmacological effects such as anti-inflammatory and immunosuppressive effects and are widely used clinically in the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. They have definite efficacy and broad application prospects. However, traditional Tripterygium wilfordii glycoside preparations are highly irritating to the gastrointestinal mucosa, and long-term use can easily cause adverse reactions such as nausea and diarrhea, leading to decreased patient compliance.

[0003] In existing technologies, although coating technology can reduce gastrointestinal irritation, it is difficult to balance drug controlled release and bioavailability. However, the lack of synergistic regulation of probiotic protection and drug release rate in formulation preparation results in limited toxicity reduction effects.

[0004] In summary, the preparation of a Tripterygium wilfordii polyglycoside tablet is of great significance in order to solve the above problems. Summary of the Invention

[0005] The purpose of this invention is to provide a Tripterygium wilfordii polyglycoside tablet and its preparation method to solve the problems raised in the prior art.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A method for preparing Tripterygium wilfordii polyglycoside tablets includes the following steps:

[0008] Step 1: Mix Tripterygium wilfordii polyglycosides, corn starch, pregelatinized starch, and low-substituted hydroxypropyl cellulose evenly, add binder, mix and granulate, granulate, mix with magnesium stearate and silicon dioxide, compress into tablets to obtain tablet cores;

[0009] Step 2: (1) Spray a pregelatinized starch aqueous solution onto the surface of the tablet core through a bottom spray fluidized bed to form a moist adhesive layer, and then spray probiotic microcapsules together to form an embedded layer of probiotic microcapsules to obtain an embedded probiotic tablet core; (2) Spray a gastric coating solution to form a coating layer to obtain Tripterygium wilfordii polyglycoside tablets.

[0010] In a more optimized form, the raw materials of the core include the following components: by mass parts, 1-2 parts of Tripterygium wilfordii polyglycosides, 3-5 parts of corn starch, 1-3 parts of pregelatinized starch, 1-3 parts of low-substituted hydroxypropyl cellulose, 1-2 parts of binder, 0.1-0.4 parts of magnesium stearate, and 0.3-0.5 parts of silicon dioxide.

[0011] In a more optimized configuration, the thickness of the moist adhesive layer is 10-15 μm; the thickness of the coating layer is 15-20 μm; and the probiotic intercalation layer accounts for 30%-50% of the total surface area of ​​the Tripterygium wilfordii polyglycoside tablets.

[0012] In the scheme, in the fluidized bed, the temperature of the pregelatinized starch aqueous solution sprayed is 28~35℃, the atomization pressure is 0.25~0.3MPa, the spraying rate is 3~4mL / min, the temperature of the probiotic microcapsules is 28~32℃, and the feeding rate of the probiotic microcapsules is 0.5~1.0g / min; the inlet air temperature during the drying stage after spraying is 30~33℃, and the outlet air temperature is 27~29℃ to improve the survival of probiotics; when spraying the gastric coating solution, the temperature of the fluidized bed is 35~45℃.

[0013] A more optimized method for preparing the probiotic microcapsules is as follows: (1) Add whey protein to distilled water, denature it at 75~85℃, cool and let it stand, add sodium alginate aqueous solution and stir evenly, add poly-L-lysine and continue stirring to obtain a composite colloid; (2) Wash the probiotics with physiological saline, resuspend them in distilled water, add the composite colloid and mix to obtain an aqueous phase; use corn oil containing Tween 80 as an oil phase, mix the aqueous phase and oil phase, inject calcium chloride solution from the bottom to form microbeads, collect by centrifugation, freeze dry to obtain probiotic microcapsules.

[0014] In a more optimized form, the raw materials of the composite colloid include the following components: by mass parts, 8-10 parts whey protein, 3-5 parts sodium alginate, 1-3 parts poly-L-lysine, and 50-80 parts distilled water; the raw materials of the aqueous phase include the following components: by mass parts, 1-2 parts probiotics, 65-75 parts composite colloid, and 10-15 parts distilled water; the raw materials of the probiotic microcapsules include the following components: by mass parts, 1 part aqueous phase, 5-6 parts oil phase, and 10-12 parts calcium chloride solution; the concentration of the calcium chloride solution is 0.1-0.2M; and the particle size of the probiotic microcapsules is 40-65µm.

[0015] In a more optimized form, the raw materials of the gastric coating solution include the following components: by mass parts, 15-20 parts modified hydroxypropyl methylcellulose, 3-6 parts PEG, 2-5 parts pregelatinized starch, and 100 parts deionized water.

[0016] A more optimized method for preparing the modified hydroxypropyl methylcellulose is as follows: hydroxypropyl methylcellulose is added to a mixed solvent, lauric acid is added and stirred at 60-75°C for 15-20 minutes, immobilized lipase is added, and stirring is continued for 22-24 hours. The mixture is then filtered, lyophilized to remove the solvent, washed with n-hexane, and purified to obtain the modified hydroxypropyl methylcellulose.

[0017] In a more optimized form, the raw materials for the modified hydroxypropyl methylcellulose include the following: by mass parts, 10-15 parts hydroxypropyl methylcellulose, 70-100 parts mixed solvent, 5-8 parts lauric acid, and 2-4 parts immobilized lipase; wherein the mass ratio of acetonitrile to tert-butanol in the mixed solvent is (7-8):2.

[0018] Compared with the prior art, the beneficial effects of the present invention are:

[0019] In this method, the tablet core is first prepared by mixing and granulating Tripterygium wilfordii glycosides, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, binder, magnesium stearate, and silica as raw materials. The tablet core is then coated with a pregelatinized starch aqueous solution through a bottom-spray fluidized bed to form a moist adhesive layer. Probiotic microcapsules are then sprayed onto the surface of the tablet core to obtain an embedded probiotic tablet core. Finally, a gastric coating solution is sprayed onto the tablet core to form a coating layer, thus obtaining Tripterygium wilfordii glycoside tablets.

[0020] In this tablet, low-substituted hydroxypropyl cellulose acts as a disintegrant, pregelatinized starch serves as both a filler and a binder, and magnesium stearate and silica act as a lubricant and a flow aid, respectively. The combination of these excipients ensures both the formability of the tablet core and rapid disintegration in the stomach, thus synergizing with the design of the subsequent coating layer.

[0021] In this formulation, to address the gastrointestinal side effects (such as diarrhea and nausea) of Tripterygium wilfordii glycosides, probiotic microcapsules are introduced. Probiotics regulate the intestinal flora balance, alleviating the gastrointestinal side effects of Tripterygium wilfordii glycosides. However, most probiotics are acid-sensitive, and contact with Tripterygium wilfordii glycosides may affect efficacy. To address this issue, the formulation encapsulates the probiotics using acid-resistant materials to obtain probiotic microcapsules. These microcapsules are then sprayed onto the surface of Tripterygium wilfordii glycoside tablets. However, research has shown that excessive spraying can affect the drug's disintegration time in gastric acid, while insufficient spraying can affect efficacy. Therefore, this formulation employs a bottom-spray fluidized bed coating method, spraying a pregelatinized starch aqueous solution onto the tablet core to form an adhesive. After the first layer, it is sprayed together with probiotic microcapsules (solid) to embed the probiotic microcapsules on the surface of the tablet core. The proportion of probiotic microcapsules on the surface of the Tripterygium wilfordii polyglycoside tablet is controlled to prevent excessive disintegration time in gastric acid. In this scheme, the sprayed gastric coating solution has a certain fixing effect on the probiotic microcapsules and at the same time encapsulates the embedded probiotic microcapsules to prevent the microcapsules from falling off during tablet compression or storage. Hydroxypropyl methylcellulose, PEG, and pregelatinized starch are used as raw materials for the gastric coating solution. However, the water absorption is too high. Therefore, in this scheme, hydroxypropyl methylcellulose is modified with lauric acid to not destroy its gastric solubility properties, while also reducing the water absorption of the material and improving the moisture resistance of the coating layer.

[0022] In order to improve the survival rate of probiotics in gastric acid, a composite colloid is prepared by mixing denatured whey protein, sodium alginate, and poly-L-lysine. This colloid is then mixed with probiotics as the aqueous phase and with the oil phase. Calcium chloride solution is injected from the bottom to form microbeads, thus avoiding uneven gel layers caused by excessively high local concentrations, and producing probiotic microcapsules.

[0023] Among them, denatured whey protein forms a hydrophobic core to encapsulate probiotics and reduce water contact; sodium alginate and calcium chloride slowly gel to form a gel layer, enhancing mechanical stability; poly-L-lysine (cation) and sodium alginate (anion) form a polyelectrolyte complex, improving the microcapsule's tolerance to gastric acid. Detailed Implementation

[0024] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all 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.

[0025] In the following specific embodiments, "parts" refers to parts by weight. In this embodiment, it should be noted that there are no special restrictions on the manufacturers of all raw materials involved in this invention. Exemplary examples include: hydroxypropyl methylcellulose with product number 1-9, food grade; lauric acid with CAS number 143-07-7; PEG (polyethylene glycol) with a molecular weight of 6000; whey protein with CAS number 68458-87-7; poly-L-lysine with an average molecular weight of 4700; sodium alginate with CAS number 9005-38-3; pregelatinized starch with CAS number 47261-18-7; and low-substituted hydroxypropyl cellulose with product number HBWS-D179, a pharmaceutical raw material.

[0026] The modified hydroxypropyl methylcellulose was prepared as follows: 13 parts of hydroxypropyl methylcellulose were added to 80 parts of mixed solvent, 6 parts of lauric acid were added and stirred at 70°C for 20 minutes, 3.5 parts of immobilized lipase (1050 PLU) were added, and stirring was continued for 22 hours. The mixture was filtered, lyophilized to remove the solvent, washed with hexane, purified by reverse-phase column chromatography, and lyophilized to obtain modified hydroxypropyl methylcellulose. The mass ratio of acetonitrile to tert-butanol in the mixed solvent was 7:2.

[0027] The raw materials for the gastric coating solution include the following components: by mass, 20 parts modified hydroxypropyl methylcellulose, 6 parts PEG6000, 5 parts pregelatinized starch, and 100 parts deionized water.

[0028] Example 1: A method for preparing Tripterygium wilfordii polyglycoside tablets, comprising the following steps:

[0029] Pre-preparation: The preparation method of probiotic microcapsules is as follows: (1) 10 parts whey protein are added to 50 parts distilled water, denatured at 80°C, cooled and allowed to stand, sodium alginate aqueous solution (5 parts sodium alginate are added to 20 parts distilled water and mixed) and stirred evenly, 2 parts poly-L-lysine are added and stirred to obtain a composite colloid; (2) 2 parts probiotics (Bifidobacterium animalis) are washed with physiological saline, resuspended in 15 parts distilled water, and 70 parts composite colloid are added and mixed to obtain an aqueous phase; corn oil containing 0.5wt% Tween 80 is used as the oil phase, 1 part of the aqueous phase is mixed with 5 parts of the oil phase, 10 parts of 0.1M calcium chloride solution are injected from the bottom to form microbeads, collected by centrifugation, and freeze-dried to obtain probiotic microcapsules; the particle size of the probiotic microcapsules is 46µm;

[0030] Step 1: Mix 1 part Tripterygium wilfordii polyglycoside, 3 parts corn starch, 1 part pregelatinized starch, and 1 part low-substituted hydroxypropyl cellulose evenly. Add 1 part binder and mix to form granules. Mix with 0.1 parts magnesium stearate and 0.3 parts silica, and compress to obtain tablet cores.

[0031] Step 2: (1) A pregelatinized starch aqueous solution (8wt% pregelatinized starch and 0.3wt% glycerol) is first sprayed onto the surface of the tablet core through a bottom spray fluidized bed to form a 12μm thick wet adhesive layer. Then, probiotic microcapsules are sprayed together to form a probiotic microcapsule embedding layer, thus obtaining an embedded probiotic tablet core; (2) A gastric coating solution is sprayed to form an 18μm thick coating layer, thus obtaining Tripterygium wilfordii polyglycoside tablets; the probiotic embedding layer accounts for 50% of the total surface area of ​​Tripterygium wilfordii polyglycoside tablets.

[0032] Example 2, a method for preparing Tripterygium wilfordii polyglycoside tablets, comprising the following steps:

[0033] Pre-preparation: The preparation method of probiotic microcapsules is as follows: (1) 10 parts whey protein are added to 50 parts distilled water, denatured at 80°C, cooled and allowed to stand, sodium alginate aqueous solution (5 parts sodium alginate are added to 20 parts distilled water and mixed) and stirred evenly, 2 parts poly-L-lysine are added and stirred to obtain a composite colloid; (2) 2 parts probiotics (Bifidobacterium animalis) are washed with physiological saline, resuspended in 15 parts distilled water, and 70 parts composite colloid are added and mixed to obtain an aqueous phase; corn oil containing 0.5wt% Tween 80 is used as an oil phase, 1 part of the aqueous phase is mixed with 5 parts of the oil phase, 10 parts of 0.1M calcium chloride solution are injected from the bottom to form microbeads, collected by centrifugation, and freeze-dried to obtain probiotic microcapsules; the particle size of the probiotic microcapsules is 46µm;

[0034] Step 1: Mix 1 part Tripterygium wilfordii polyglycoside, 3 parts corn starch, 1 part pregelatinized starch, and 1 part low-substituted hydroxypropyl cellulose evenly. Add 1 part binder and mix to form granules. Mix with 0.1 parts magnesium stearate and 0.3 parts silica, and compress to obtain tablet cores.

[0035] Step 2: (1) A pregelatinized starch aqueous solution (8wt% pregelatinized starch and 0.3wt% glycerol) is first sprayed onto the surface of the tablet core through a bottom spray fluidized bed to form a 12μm thick wet adhesive layer. Then, probiotic microcapsules are sprayed together to form a probiotic microcapsule embedding layer, thus obtaining an embedded probiotic tablet core; (2) A gastric coating solution is sprayed to form an 18μm thick coating layer, thus obtaining Tripterygium wilfordii polyglycoside tablets; the probiotic embedding layer accounts for 30% of the total surface area of ​​Tripterygium wilfordii polyglycoside tablets.

[0036] Example 3, a method for preparing Tripterygium wilfordii polyglycoside tablets, comprising the following steps:

[0037] Pre-preparation: The preparation method of probiotic microcapsules is as follows: (1) 10 parts whey protein are added to 50 parts distilled water, denatured at 80°C, cooled and allowed to stand, sodium alginate aqueous solution (5 parts sodium alginate are added to 20 parts distilled water and mixed) and stirred evenly, 2 parts poly-L-lysine are added and stirred to obtain a composite colloid; (2) 2 parts probiotics (Bifidobacterium animalis) are washed with physiological saline, resuspended in 15 parts distilled water, and 70 parts composite colloid are added and mixed to obtain an aqueous phase; corn oil containing 0.5wt% Tween 80 is used as an oil phase, 1 part of the aqueous phase is mixed with 5 parts of the oil phase, 10 parts of 0.1M calcium chloride solution are injected from the bottom to form microbeads, collected by centrifugation, and freeze-dried to obtain probiotic microcapsules; the particle size of the probiotic microcapsules is 46µm;

[0038] Step 1: Mix 1 part Tripterygium wilfordii polyglycoside, 3 parts corn starch, 1 part pregelatinized starch, and 1 part low-substituted hydroxypropyl cellulose evenly. Add 1 part binder and mix to form granules. Mix with 0.1 parts magnesium stearate and 0.3 parts silica, and compress to obtain tablet cores.

[0039] Step 2: (1) A pregelatinized starch aqueous solution (8wt% pregelatinized starch and 0.3wt% glycerol) is first sprayed onto the surface of the tablet core through a bottom spray fluidized bed to form a 12μm thick wet adhesive layer. Then, probiotic microcapsules are sprayed together to form a probiotic microcapsule embedding layer, thus obtaining an embedded probiotic tablet core; (2) A gastric coating solution is sprayed to form an 18μm thick coating layer, thus obtaining Tripterygium wilfordii polyglycoside tablets; the probiotic embedding layer accounts for 40% of the total surface area of ​​Tripterygium wilfordii polyglycoside tablets.

[0040] Example 4: A method for preparing Tripterygium wilfordii polyglycoside tablets, comprising the following steps:

[0041] Pre-preparation: Step 1: Mix 1 part Tripterygium wilfordii polyglycoside, 3 parts corn starch, 1 part pregelatinized starch, and 1 part low-substituted hydroxypropyl cellulose evenly, add 1 part binder to mix and granulate, granulate, mix with 0.1 part magnesium stearate and 0.3 parts silica, compress into tablets to obtain tablet cores;

[0042] Step 2: Spray the gastric coating solution to form a coating layer with a thickness of 18μm to obtain Tripterygium wilfordii polyglycoside tablets;

[0043] The raw materials for the gastric coating solution include the following components: by mass, 20 parts hydroxypropyl methylcellulose, 6 parts PEG6000, 5 parts pregelatinized starch, and 100 parts deionized water.

[0044] Comparative Example 1 is based on Example 3, but the proportion of probiotic microcapsules on the surface of Tripterygium wilfordii polyglycoside tablets is increased to 70%; the remaining operation steps remain unchanged.

[0045] Pre-preparation: The preparation method of probiotic microcapsules is as follows: (1) 10 parts whey protein are added to 50 parts distilled water, denatured at 80°C, cooled and allowed to stand, sodium alginate aqueous solution (5 parts sodium alginate are added to 20 parts distilled water and mixed) and stirred evenly, 2 parts poly-L-lysine are added and stirred to obtain a composite colloid; (2) 2 parts probiotics (Bifidobacterium animalis) are washed with physiological saline, resuspended in 15 parts distilled water, and 70 parts composite colloid are added and mixed to obtain an aqueous phase; corn oil containing 0.5wt% Tween 80 is used as an oil phase, 1 part of the aqueous phase is mixed with 5 parts of the oil phase, 10 parts of 0.1M calcium chloride solution are injected from the bottom to form microbeads, collected by centrifugation, and freeze-dried to obtain probiotic microcapsules; the particle size of the probiotic microcapsules is 46µm;

[0046] Step 1: Mix 1 part Tripterygium wilfordii polyglycoside, 3 parts corn starch, 1 part pregelatinized starch, and 1 part low-substituted hydroxypropyl cellulose evenly. Add 1 part binder and mix to form granules. Mix with 0.1 parts magnesium stearate and 0.3 parts silica, and compress to obtain tablet cores.

[0047] Step 2: (1) A pregelatinized starch aqueous solution is first sprayed onto the surface of the tablet core through a bottom spray fluidized bed to form a 12μm thick wet adhesive layer. Then, probiotic microcapsules are sprayed together to form a probiotic microcapsule embedding layer, thus obtaining an embedded probiotic tablet core; (2) A gastric coating solution is sprayed to form an 18μm thick coating layer, thus obtaining Tripterygium wilfordii polyglycoside tablets; the probiotic embedding layer accounts for 70% of the total surface area of ​​Tripterygium wilfordii polyglycoside tablets.

[0048] Comparative Example 2 is based on Example 3, except that poly-L-lysine was not added to the probiotic microcapsules; the other operating steps remained the same.

[0049] Pre-preparation: The preparation method of probiotic microcapsules is as follows: (1) 10 parts whey protein are added to 50 parts distilled water, denatured at 80°C, cooled and allowed to stand, and sodium alginate aqueous solution (5 parts sodium alginate are added to 20 parts distilled water) are added and stirred evenly to obtain a composite colloid; (2) 2 parts probiotics (Bifidobacterium animalis) are washed with physiological saline, resuspended in 15 parts distilled water, and 70 parts composite colloid are added and mixed to obtain an aqueous phase; corn oil containing 0.5wt% Tween 80 is used as the oil phase, 1 part of the aqueous phase is mixed with 5 parts of the oil phase, 10 parts of 0.1M calcium chloride solution are injected from the bottom to form microbeads, collected by centrifugation, and freeze-dried to obtain probiotic microcapsules; the particle size of the probiotic microcapsules is 46µm;

[0050] Step 1: Mix 1 part Tripterygium wilfordii polyglycoside, 3 parts corn starch, 1 part pregelatinized starch, and 1 part low-substituted hydroxypropyl cellulose evenly. Add 1 part binder and mix to form granules. Mix with 0.1 parts magnesium stearate and 0.3 parts silica, and compress to obtain tablet cores.

[0051] Step 2: (1) A pregelatinized starch aqueous solution is first sprayed onto the surface of the tablet core through a bottom spray fluidized bed to form a 12μm thick wet adhesive layer. Then, probiotic microcapsules are sprayed together to form a probiotic microcapsule embedding layer, thus obtaining an embedded probiotic tablet core; (2) A gastric coating solution is sprayed to form a 18μm thick coating layer, thus obtaining Tripterygium wilfordii polyglycoside tablets; the probiotic embedding layer accounts for 40% of the total surface area of ​​Tripterygium wilfordii polyglycoside tablets.

[0052] Comparative Example 3 is based on Example 3, in which hydroxypropyl methylcellulose is directly introduced into the gastric coating solution; the remaining operation steps remain unchanged;

[0053] Pre-preparation: The preparation method of probiotic microcapsules is as follows: (1) 10 parts whey protein are added to 50 parts distilled water, denatured at 80°C, cooled and allowed to stand, sodium alginate aqueous solution (5 parts sodium alginate are added to 20 parts distilled water and mixed) and stirred evenly, 2 parts poly-L-lysine are added and stirred to obtain a composite colloid; (2) 2 parts probiotics (Bifidobacterium animalis) are washed with physiological saline, resuspended in 15 parts distilled water, and 70 parts composite colloid are added and mixed to obtain an aqueous phase; corn oil containing 0.5wt% Tween 80 is used as an oil phase, 1 part of the aqueous phase is mixed with 5 parts of the oil phase, 10 parts of 0.1M calcium chloride solution are injected from the bottom to form microbeads, collected by centrifugation, and freeze-dried to obtain probiotic microcapsules; the particle size of the probiotic microcapsules is 46µm;

[0054] The raw materials for the gastric coating solution include the following components: by mass, 20 parts hydroxypropyl methylcellulose, 6 parts PEG6000, 5 parts pregelatinized starch, and 100 parts deionized water;

[0055] Step 1: Mix 1 part Tripterygium wilfordii polyglycoside, 3 parts corn starch, 1 part pregelatinized starch, and 1 part low-substituted hydroxypropyl cellulose evenly. Add 1 part binder and mix to form granules. Mix with 0.1 parts magnesium stearate and 0.3 parts silica, and compress to obtain tablet cores.

[0056] Step 2: (1) A pregelatinized starch aqueous solution is first sprayed onto the surface of the tablet core through a bottom spray fluidized bed to form a 12μm thick wet adhesive layer. Then, probiotic microcapsules are sprayed together to form a probiotic microcapsule embedding layer, thus obtaining an embedded probiotic tablet core; (2) A gastric coating solution is sprayed to form a 18μm thick coating layer, thus obtaining Tripterygium wilfordii polyglycoside tablets; the probiotic embedding layer accounts for 40% of the total surface area of ​​Tripterygium wilfordii polyglycoside tablets.

[0057] Test 1: Preparation of artificial gastric fluid: Add 10g of pepsin to 16.5mL of hydrochloric acid (0.1mol / L), stir well, dilute to 1L volumetric flask, adjust pH to 1.2, filter with a 0.2μm sterile microporous membrane, and set aside for later use;

[0058] Preparation of artificial intestinal fluid: Add 6.5g of potassium dihydrogen phosphate to deionized water and mix, adjust the pH to 7.4, add 10g of trypsin and mix, bring the volume to 1L, filter with a 0.2μm sterile microporous membrane, and set aside for later use;

[0059] (1) The complete disintegration time of Tripterygium wilfordii polyglycosides in artificial gastric fluid was tested in Examples 1-4 and Comparative Examples 1-3, as shown in Table 1;

[0060] (2) The probiotic microcapsules prepared in Example 3, Comparative Example 2, and Comparative Example 3 were disintegrated with 0.06 mol / L sodium citrate solution; 0.1 g of probiotic microcapsules and unencapsulated probiotics (blank control) were added to 10 mL (denoted as V) of 0.06 mol / L sodium citrate solution and mixed, and placed in a constant temperature shaker at 37±1℃ and shaken at 180 r / min for 1.3 hours; 0.1 mL of the disintegration solution and 0.1 mL of the blank control were diluted 10 mL each. 4 The number of viable probiotics (denoted as D) was determined by plate counting (denoted as N), and the average value was calculated from three parallel experiments.

[0061] Total viable bacteria count in probiotic microcapsules = N × D × V ÷ 0.1; The calculation method for viable bacteria count in the blank control group is the same; Calculate the encapsulation rate; The formula for calculating the encapsulation rate is: Encapsulation rate = (Number of viable bacteria in probiotic microcapsules / Number of added viable bacteria) × 100%; See Table 2;

[0062] Example 2, Comparative Example 2, and Comparative Example 3 were placed at 42% humidity for 24 hours. Then, after being treated with gastric acid for 25 minutes, Example 2, Comparative Example 2, and Comparative Example 3 were centrifuged, freeze-dried, and 0.1g of each was placed in 10mL of artificial intestinal fluid and shaken at 180r / min for 40 minutes. The viable number of probiotics was determined by plate counting method to detect the viable number of probiotics in the enteric environment, and the survival rate was calculated. See Table 2.

[0063] Table 1

[0064]

[0065] Table 2

[0066]

[0067] Conclusions: The disintegration time of the examples was less than 30 minutes; Comparative Example 1, based on Example 3, increased the proportion of probiotic microcapsules on the surface of Tripterygium wilfordii glycoside tablets to 70%; Comparative Example 2, based on Example 3, did not add poly-L-lysine to the probiotic microcapsules; Comparative Example 3, based on Example 3, directly introduced hydroxypropyl methylcellulose; Table 1 shows that the proportion of probiotic microcapsules has a certain impact on the release of Tripterygium wilfordii glycoside tablets; a high proportion of 70% may cause probiotic microcapsules to accumulate on the tablet core surface, preventing the subsequent coating layer from forming a continuous and dense film, resulting in the need to destroy a large number of microcapsules before disintegration, significantly prolonging the time; controlling the proportion of probiotic microcapsules to 30-50% can prevent the disintegration time of Tripterygium wilfordii glycoside tablets in gastric acid from being too long; Table 2 shows that poly-L-lysine can improve the tolerance of probiotics in gastric acid; the modified hydroxypropyl methylcellulose can alleviate hygroscopicity and improve stability, and poly-L-lysine has certain antibacterial properties, which can improve the survival rate of probiotics.

[0068] Experiment 2: Six-week-old male Wistar rats were randomly divided into 5 groups of 10 rats each: model group, normal group, Example 3, and Example 4. After feeding, the rats were administered the drug at a dose of 10 mg / kg once daily for 28 consecutive days. The body weight of the Wistar rats was measured on days 0, 14, and 28, and the average value was recorded. The length diameter (mm) of the right hind paw of the rats was also measured and the average value was recorded. In the normal group, male Wistar rats were injected with 0.1 mL of physiological saline into the plantar base of their right hind paw. In the other groups, male Wistar rats were injected with 0.1 mL of Firth's complete adjuvant into the plantar base of their right hind paw to establish an adjuvant-induced arthritis (AA) rat model. The daily feeding amount was fixed, and feeding behavior was observed.

[0069] Table 3

[0070]

[0071] Conclusion: It can be seen that probiotic microcapsules can alleviate the side effects of Tripterygium wilfordii polyglycosides.

[0072] Test 3: Test Basis: Examples 3 and 4 were tested according to the National Drug Standard WS3-B-3350-98-2011;

[0073] Table 4

[0074]

[0075] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

Claims

1. A preparation method of Tripterygium glycosides tablets, characterized in that: The method comprises the following steps: ​ Step 1: uniformly mix tripterygium glycosides, corn starch, pre-gelatinized starch and low-substituted hydroxypropyl cellulose, add a binder to mix and granulate, integrate, mix with magnesium stearate and silicon dioxide, press tablets to obtain a tablet core; Step 2: (1) spray a pre-gelatinized starch aqueous solution on the surface of the tablet core through a bottom-spraying fluidized bed to form a wet adhesion layer, and then spray probiotic microcapsules to form a probiotic microcapsule inlay layer to obtain a probiotic tablet core; (2) spray a gastric-soluble coating liquid to form a coating layer to obtain tripterygium glycoside tablets; The thickness of the wet adhesion layer is 10-15 μm; the thickness of the coating layer is 15-20 μm; the probiotic inlay layer accounts for 30%-50% of the total surface area of the tripterygium glycoside tablets; The preparation method of the probiotic microcapsules is as follows: (1) add whey protein to distilled water to denature at 75-85°C, cool and stand, add a sodium alginate aqueous solution to stir uniformly, and then add poly-L-lysine to continue stirring to obtain a composite colloid; (2) wash probiotics with normal saline, resuspend in distilled water, add the composite colloid to mix to obtain an aqueous phase; corn oil containing Tween 80 is used as an oil phase, the aqueous phase and the oil phase are mixed, calcium chloride solution is injected from the bottom, microbeads are formed, centrifugation is performed to collect the microbeads, and freeze-drying is performed to obtain probiotic microcapsules; The raw materials of the gastric-soluble coating liquid comprise the following components: 15-20 parts of modified hydroxypropyl methylcellulose, 3-6 parts of PEG, 2-5 parts of pre-gelatinized starch, and 100 parts of deionized water according to mass fraction; The preparation method of the modified hydroxypropyl methylcellulose is as follows: hydroxypropyl methylcellulose is added to a mixed solvent, lauric acid is added to stir at 60-75°C for 15-20 minutes, immobilized lipase is added, and stirring is continued for 22-24 hours; filtration is performed, and freeze-drying is performed to remove the solvent; n-hexane is used for washing and purification to obtain modified hydroxypropyl methylcellulose.

2. The preparation method of the Tripterygium glycosides tablets according to claim 1, characterized in that: The raw materials of the tablet core comprise the following components: 1-2 parts of tripterygium glycosides, 3-5 parts of corn starch, 1-3 parts of pre-gelatinized starch, 1-3 parts of low-substituted hydroxypropyl cellulose, 1-2 parts of a binder, 0.1-0.4 parts of magnesium stearate, and 0.3-0.5 parts of silicon dioxide according to mass fraction.

3. The preparation method of the Tripterygium glycosides tablets according to claim 1, characterized in that: The raw materials of the composite colloid comprise the following components: 8-10 parts of whey protein, 3-5 parts of sodium alginate, 1-3 parts of poly-L-lysine, and 50-80 parts of distilled water according to mass fraction; the raw materials of the aqueous phase comprise the following components: 1-2 parts of probiotics, 65-75 parts of the composite colloid, and 10-15 parts of distilled water according to mass fraction; The raw materials of the probiotic microcapsules comprise the following components: 1 part of the aqueous phase, 5-6 parts of the oil phase, and 10-12 parts of calcium chloride solution according to mass fraction; the concentration of the calcium chloride solution is 0.1-0.2 M; the particle size of the probiotic microcapsules is 40-65 µm; and the probiotics comprise one or two of the following: Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium animalis, Bifidobacterium longum, and Bifidobacterium infantis.

4. The preparation method of the Tripterygium glycosides tablets according to claim 1, characterized in that: The raw material of the modified hydroxypropyl methyl cellulose comprises the following components: 10-15 parts of hydroxypropyl methyl cellulose, 70-100 parts of mixed solvent, 5-8 parts of lauric acid and 2-4 parts of immobilized lipase by mass fraction; in the mixed solvent, the mass ratio of acetonitrile to t-butyl alcohol is (7-8):

2.

5. The tripterygium glycosides tablet prepared by the preparation method according to any one of claims 1-4.

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