Prescription,Design,and,Preparation,Process,of,Paeonol,Bead,Popping,Gum,with,Hypoglycemic,Effect

Fuhao HU, Yicheng WANG, Hui YANG, Yaokun XIONG, Ming YANG, Xinli LIANG, Fei HAN*

1. School of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China; 2. Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

Abstract [Objectives] To develop a paeonol bead popping gum with hypoglycemic effect. [Methods] The paeonol bead popping gum was prepared by the "two-step method", that is, the pill core was prepared by the guttate pill method, and then the coating was cured by sodium alginate solution and CaCl2 solution. The single factor method was used to determine the effects of PEG-4000: paeonol dosage ratio, dropper diameter, condensation time, dropping distance, melting temperature on the comprehensive score of paeonol guttate pill, and the effects of sodium alginate solution concentration, CaCl2 solution concentration, number of coating layers, drying time on the comprehensive score of popping gum. Finally, the optimal process was determined and verified by orthogonal experiment method. [Results] When the dosage ratio of PEG-4000: paeonol was 4∶1, the dropper diameter was 4 mm, the condensation time was 5 min, the dropping distance was 6 cm, and the melting temperature was 90 ℃, the quality of the prepared guttate pill was the optimal. When the concentration of sodium alginate solution was 0.02 g/mL, the concentration of CaCl2 solution was 0.25 g/mL, the number of coating layers was 3, and the drying time was 25 min, the appearance and comprehensive score of the obtained popping beads were the optimal. [Conclusions] This study is expected to provide some reference and basis for the development and utilization of hypoglycemic products of traditional Chinese medicine.

Key words Paeonol, Guttate pill, Bead popping gum, High performance liquid chromatography (HPLC)

Diabetes, as a chronic heterogeneous disease, has become the "third deadly disease" that seriously threatens human life and health. While suffering from diabetes and its complications, people with diabetes also have to suffer the pain of "quitting sugar" every day, and they dare not eat sweet foods at all. This may cause anxiety, depression and other mental illnesses for many patients who love sweets. In recent years, there have been numerous reports about the treatment or improvement of diabetes with traditional Chinese medicine and its active components. Compared with traditional chemical drugs, traditional Chinese medicines have the advantages of low toxicity and side effects, and available for long-term use. Among them, paeonol, as the main active component of traditional Chinese medicines Xuchangqing (Cynanchi Paniculati Radix Et Rhizoma) and Mudanpi (Moutan Cortex), has been confirmed by many domestic and foreign research reports to have a good hypoglycemic effect[1-3]. Studies have shown that paeonol can reduce insulin resistance in surrounding tissue cells by regulating various signaling pathways such as PI3K-AKT and AMPK, improve insulin sensitivity, and effectively reduce blood glucose concentration and improve oral glucose tolerance[4-5]. In addition, paeonol has a good therapeutic effect on diabetic nephropathy[6], vascular disease[7], myocardial injury[8], retinopathy[9]and other complications caused by diabetes.

In this study, we intended to develop a paeonol bead popping gum with hypoglycemic effect, and to explore its optimal formulation design and preparation process through single factor and orthogonal experiments. Compared with traditional hypoglycemic drugs, paeonol bead popping gum has the advantages of convenient taking, good compliance, fresh breath, and leaving fragrance in mouth and lips and teeth. While meeting the needs of diabetic patients for sweet taste, it also has a certain hypoglycemic effect and can refresh the breath, so it can be said to have multiple purposes. Furthermore, paeonol is a pure traditional Chinese medicine component with stable properties and will not conflict with commercially available hypoglycemic drugs. It can even be taken together with hypoglycemic drugs to reduce the dosage and improve the compliance of hypoglycemic drugs. It will have a certain market demand and development potential, thus it is worthy of in-depth study.

2.1 Materials and reagentsPEG-4000 (Fuchen (Tianjin) Chemical Reagent Co., Ltd, batch No.20210607); paeonol (Shanghai yuanye Bio-Technology Co., Ltd, batch No.B20266-20); paeonol standard (Beijing Solarbio Science & Technology Co., Ltd., batch No.409F023); dimethicone (Shanghai Macklin Biochemical Co., Ltd., batch No.C10110588); sodium alginate (Sinopharm Chemical Reagent Co., Ltd., batch No.20211110); anhydrous calcium chloride (Xilong Chemical Co., Ltd., batch No.1601073); acesulfame (food grade, Shanghai Juechen Biotechnology Co., Ltd.); xylitol (food grade, Nanjing Ganzhiyuan Sugar Co., Ltd.); peppermint essence (food grade, Shenzhen Chenxin Flavors & Fragrances Co., Ltd., batch No.CXR-51801E); methanol (chromatographic grade, Xilong Scientific Co., Ltd., batch No.B2104061); phosphoric acid (chromatographic grade, Xilong Scientific Co., Ltd., batch No.2112131); carmine (food grade, Shanghai Dyestuffs Research Institute Co., Ltd., batch No.10121022); tartrazine (food grade, Sinopharm Chemical Reagent Co., Ltd., batch No.20211112).

2.2 InstrumentsWater bath (Changzhou Langyue Instrument Manufacturing Co., Ltd., model: HH-2); electric heating blast drying oven (Shanghai Bosun Industrial Co., Ltd., model: GZX-9023MBE); Agilent liquid chromatograph 1260 (Agilent Technologies Co., Ltd., model: 1260); Kromasil C18column (AkzoNobel Company, Sweden, 250 mm×4.6 mm, 5.0 μm); analytical balance (Beijing Sartorius Scientific Instrument Co., Ltd., model: SQP).

3.1 Technical routeThe paeonol bead popping gum prepared in this experiment is purely handmade, with simple operation and low equipment requirements, and is suitable for the preparation of laboratory and factory conditions. The preparation method of paeonol bead popping gum includes two steps. The first step: place the precisely weighed PEG-4000 in a beaker, add paeonol and flavoring agents (such as acesulfame, xylitol,etc.) after heating and melting in a water bath to obtain a mixed eutectic, then use a dropper with a certain diameter to drop the uniformly stirred eutectic into dimethicone and cool it into pellets. The second step: after wiping the silicone oil on the surface of the guttate pill, add it to the CaCl2solution for a little soaking, then add it to the sodium alginate solution, move to the CaCl2solution again to solidify into a coat and dry, that is, the one-coat bead. Repeat this operation to obtain multi-coated bead popping gum (Fig.1).

Fig.1 Preparation process of paeonol bead popping gum

3.2 Single factor experiment

3.2.1Test on formulation design of paeonol bead popping gum. (i) Effects of PEG-4000: paeonol dosage ratio on indicators. Separately took 7, 6, 5, 4, 3, and 2 g of PEG-4000 and 1 g of paeonol and placed them in a 50 mL beaker. Melted in the water bath together and fully mixed to obtain the eutectic with the dosage ratio of PEG4000: paeonol being 8∶1, 7∶1, 6∶1, 5∶1, 4∶1, 3∶1 respectively. Absorbed a small amount of eutectic with a plastic tip dropper and dropped it into dimethicone, condensed it into guttate pill. After wiping to dry and weighing, randomly selected 10 guttate pills to measure theirRSDvalues, entrapment efficiency and drug loading, and calculated the comprehensive score.

(ii) Effects of concentration of sodium alginate solution on indicators. Took 8 g of PEG-4000 in a 50 mL beaker, heated and melted it in a water bath at 90 ℃, added 2 g of paeonol, continued to heat and melt, and stirred well. Took a small amount of eutectic with a dropper with a diameter of 4 mm and dropped it into dimethicone at a distance of 4 cm from the liquid surface, condensed for 5 min to form a guttate pill, wiped to dry and weighed. Soaked the prepared guttate pill slightly in 0.25 g/mL CaCl2solution, and after drying, soaked the guttate pill separately in 0.005, 0.01, 0.015, 0.02, 0.025, 0.03 g/mL sodium alginate solution. Soaked in calcium chloride solution again, dried in 40 ℃ oven for 30 min, repeated this operation 2 times to get 3-layer coated popping beads. Randomly selected 10 popping beads and measured theirRSDvalues (%), entrapment efficiency and drug loading, and then calculated the comprehensive score.

(iii) Effects of CaCl2concentration on indicators. Took 8 g of PEG-4000 in a 50 mL beaker, heated and melted it in a water bath at 90 ℃, added 2 g of paeonol, continued to heat and melt, and stirred well. Took a small amount of eutectic with a dropper with a diameter of 4 mm and dropped it into dimethicone at a distance of 4 cm from the liquid surface, condensed for 5 min to form a guttate pill, wiped to dry and weighed. Slightly soaked the prepared guttate pills separately in 0.05, 0.1, 0.15, 0.2, 0.25, 0.3 g/mL CaCl2solution. After drying, soaked guttate pill in 0.02 g/mL sodium alginate solution, soaked in calcium chloride solution again, dried in 40 ℃ oven for 30 min, repeated this operation 2 times to get 3-layer coated popping beads. Randomly selected 10 popping beads and measured theirRSDvalues (%), entrapment efficiency and drug loading, and then calculated the comprehensive score.

3.2.2Test of paeonol bead popping gum preparation process. (i) Effects of dropper diameter on indicators of popping beads. Took 8 g of PEG-4000 in a 50 mL beaker, heated and melted it, then added 2 g of paeonol, continued to heat and melt, and stirred well. Took a small amount of eutectic with a dropper separately with a diameter of 2, 2.5, 3, 3.5, 4, and 4.5 mm and dropped it into dimethicone, condensed for 5 min to form a guttate pill, wiped to dry and weighed. Randomly selected 10 popping beads and measured theirRSDvalues (%), entrapment efficiency and drug loading, and then calculated the comprehensive score.

(ii) Effects of condensation time on comprehensive score of popping beads. Took 8 g of PEG-4000 in a 50 mL beaker, heated and melted it, then added 2 g of paeonol, continued to heat and melt, and stirred well. Took a small amount of eutectic with a dropper with a diameter of 4 mm and dropped it into dimethicone at a distance of 4 cm from the liquid surface, separately condensed for 0.5, 1, 3, 5, 7 and 9 min to form a guttate pill, wiped to dry and weighed. Randomly selected 10 popping beads and measured theirRSDvalues (%), entrapment efficiency and drug loading, and then calculated the comprehensive score.

(iii) Effects of dropping distance on indicators of popping beads. Took 8 g of PEG-4000 in a 50 mL beaker, heated and melted it, then added 2 g of paeonol, continued to heat and melt, and stirred well. Took a small amount of eutectic with a dropper with a diameter of 4 mm and dropped it into dimethicone at a distance of 0, 2, 4, 6, 8 and 10 cm from the liquid surface, condensed for 5 min to form a guttate pill, wiped to dry and weighed. Randomly selected 10 popping beads and measured theirRSDvalues (%), entrapment efficiency and drug loading, and then calculated the comprehensive score.

(iv) Effects of melting temperature on comprehensive score of popping beads. Took 8 g of PEG-4000 in a 50 mL beaker, heated and melted it in a water bath separately at 50, 60, 70, 80, 90 and 100 ℃, added 2 g of paeonol, continued to heat and melt, and stirred well. Took a small amount of eutectic with a dropper with a diameter of 4 mm and dropped it into dimethicone at a distance of 4 cm from the liquid surface, condensed for 5 min to form a guttate pill, wiped to dry and weighed. Randomly selected 10 popping beads and measured theirRSDvalues (%), entrapment efficiency and drug loading, and then calculated the comprehensive score.

(v) Effects of drying time on indicators of popping beads. Took 8 g of PEG-4000 in a 50 mL beaker, heated and melted it in a water bath at 90 ℃, added 2 g of paeonol, continued to heat and melt, and stirred well. Took a small amount of eutectic with a dropper with a diameter of 4 mm and dropped it into dimethicone at a distance of 4 cm from the liquid surface, condensed for 5 min to form a guttate pill, wiped to dry and weighed. Slightly soaked the prepared guttate pills in 0.25 g/mL CaCl2solution. After drying, soaked guttate pill in 0.02 g/mL sodium alginate solution, soaked in calcium chloride solution again, dried in 40 ℃ oven separately for 5, 10, 15, 20, 25 and 30 min, repeated this operation 2 times to get 3-layer coated popping beads. Randomly selected 10 popping beads and measured theirRSDvalues (%), entrapment efficiency and drug loading, and then calculated the comprehensive score.

(vi) Effects of number of coating layers on indicators of popping beads. Took 8 g of PEG-4000 in a 50 mL beaker, heated and melted it in a water bath at 90 ℃, added 2 g of paeonol, continued to heat and melt, and stirred well. Took a small amount of eutectic with a dropper with a diameter of 4 mm and dropped it into dimethicone at a distance of 4 cm from the liquid surface, condensed for 5 min to form a guttate pill, wiped to dry and weighed. Slightly soaked the prepared guttate pills in 0.25 g/mL CaCl2solution. After drying, soaked guttate pill in 0.02 g/mL sodium alginate solution, soaked in calcium chloride solution again, dried in 40 ℃ oven for 25 min, repeated this operation separately for 1, 2, 3, 4, 5, 6 times, to get 2-layer, 3-layer, 4-layer, 5-layer, 6-layer, and 7-layer coated popping beads. Randomly selected 10 popping beads and measured theirRSDvalues (%), entrapment efficiency and drug loading, and then calculated the comprehensive score.

3.3 Evaluation indicators

3.3.1Relative standard deviation (RSD) of pill weight. Randomly selected 10 bead popping gums, precisely weighed the total weight and individual weight. Then, calculated theRSD(%) of the 10 popping beads using the Formula (1).

(1)

3.3.2Entrapment efficiency and drug loading. Randomly selected 6 popping beads, broke them with tweezers, dissolved the contents in anhydrous ethanol, and fixed the volume to a 100 mL volumetric flask. Used a syringe to pipette 1 mL to pass through a 22 μm microporous membrane, injected the sample, and detected its peak area in a high performance liquid chromatograph, and calculated the entrapment efficiency in accordance with the Formula (2) and the drug loading in accordance with the Formula (3).

Entrapment efficiency (%)=W1/W2

(2)

whereW1denotes the measured paeonol content in all guttate pills, andW2denotes the added weight of paeonol.

Drug loading (%)=W3/W4

(3)

whereW3stands for the content of paeonol in a popping bead andW4refers to the weight of a popping bead.

3.3.3Comprehensive score. The comprehensive score of each group was calculated using the Formula (4), and the preparation conditions of each group were evaluated by the comprehensive score.

Comprehensive score=Entrapment efficiency (%)+Drug loading (%)-RSD(%)

(4)

3.4 Weight difference test for guttate pillIn accordance with to the quality requirements of General Rules 0108 Pills ofChinesePharmacopoeia(2020 Edition)[10], guttate pills need to be tested for the weight difference and dissolution time limit. However, because paeonol guttate pill is only an intermediate of popping beads, after preparation of popping beads, the pill core exists in liquid form, so there is no need to test the dissolution time limit, only the weight difference is tested.

Took 20 guttate pills prepared under the optimal process conditions, precisely weighed the total weight, and calculated the average pill weight, and then precisely weighed each pill separately. We compared the weight of each pill with the average pill weight: when the indicated pill weight or the average pill weight is 0.03 g and below 0.03 g, the weight difference limit is ±15%; when the indicated pill weight or the average pill weight is 0.03-0.10 g, the weight difference limit is ±12%; when the indicated pill weight or the average pill weight is 0.1-0.3 g, the weight difference limit is ±10%; when the indicated pill weight or the average pill weight is greater than 0.3 g, the weight difference limit is ±7.5%; the number of pills that exceed the weight difference limit should not be larger than two, and the number of pills that exceed one time of the limit should not be larger than one.

3.5 Orthogonal experimentOn the basis of single factor experiments, we selected factors including number of coating layers, sodium alginate concentration, PEG4000: paeonol dosage ratio and other factors to conduct orthogonal experiments with three factors and three levels. The levels of the orthogonal experimental factors are shown in Table 1.

Table 1 Levels of orthogonal experimental factors for preparation of paeonol bead popping gum preparation

Table 2 Effects of PEG-4000 paeonol dosage ratio on indicators of guttate pills

4.1 Results of single factor experiments

4.1.1Investigation results of prescription design. (i) Effects of PEG-4000: paeonol dosage ratio on indicators of popping beads. Through comparing theRSD(%), drug loading, entrapment efficiency and comprehensive score of guttate pill prepared with different PEG-4000: paeonol dosage ratios, it can be clearly seen that when the matrix: API dosage ratio was 4∶1, entrapment efficiency and drug loading were both the highest, but theRSD(%) of guttate pill was the smallest, and when the dosage ratio was greater than 4∶1, the guttate pill could not be formed, so we tentatively determined that the dosage ratio of 4∶1 is the optimal dosage ratio condition.

(ii) Effects of sodium alginate solution concentration on indicators of popping beads. When the concentration of sodium alginate solution was 0.005 g/mL, the concentration of sodium alginate solution was too low and the viscosity was too small to form a complete and stable film on the surface of guttate pill. When the concentration of sodium alginate solution was 0.01 g/mL, the formed coating film had poor toughness and was easily broken. When the concentration of sodium alginate solution was greater than 0.015 g/mL, the formed coating film had good toughness. However, when the concentration was greater than 0.025 g/mL, the viscosity was too large, the coating film formed was too thick, the weight gain was too large, and the drug loading was greatly reduced (Table 3). Therefore, we tentatively determined that the sodium alginate solution concentration of 0.02 g/mL was the optimal sodium alginate concentration condition.

Table 3 Effects of sodium alginate solution on indicators of popping beads

(iii) Effects of CaCl2solution concentration on comprehensive score of popping beads. When the concentration of CaCl2solution was lower than 0.1 g/mL, the formed coating film had too low toughness, insufficient strength, easy to break, and too low bead formation rate. When the concentration was greater than 0.15 g/mL, the coating film had strong toughness, and when the concentration of CaCl2solution was 0.25 g/mL, the entrapment efficiency and drug loading are the largest, theRSD(%) was the smallest, and the appearance was beautiful, round and clear (Table 4). Thus, we tentatively determined that the CaCl2solution concentration of 0.25 g/mL is the optimal concentration.

Table 4 Effects of CaCl2 solution concentration on indicators of popping beads

4.2 Experimental results of the preparation process

4.2.1Effects of dropper diameter on indicators of popping beads. Different dropper diameters had little effect on entrapment efficiency of guttate pills, but drug loading was significantly higher than other groups when the diameter was 4 mm. And theRSD(%) of the guttate pill obtained was the smallest, and the comprehensive score was also the highest, indicating that the quality of the guttate pill was the best when the dropper diameter was 4 mm (Table 5). Therefore, we tentatively determined that 4 mm is the optimal condition of dropper diameter.

4.2.2Effects of condensation time on indicators of popping beads. When the condensation time was less than 1 min, the guttate pill was soft and has certain viscosity, and difficult to separate. When the condensation time was less than 5 min, both the entrapment efficiency and drug loading showed an upward trend. When the condensation time was greater than 5 min, the entrapment efficiency and drug loading had a certain decline (Table 6). Therefore, we tentatively determined that 5 min is the optimal condensation time.

Table 5 Effects of dropper diameter on indicators of popping beads

Table 6 Effects of condensation time on indicators of popping beads

4.2.3Effects of dropping distance on indicators of popping beads. When the dropper mouth was 4 cm away from the liquid surface of dimethicone, the guttate pill had the highest entrapment efficiency, drug loading and comprehensive score, while theRSD(%) was the smallest, indicating that the guttate pill had the best quality when the dropping distance was 4 cm (Table 7). Therefore, we tentatively determined that 4 cm is the optimal dropping distance.

Table 7 Effects of dropping distance on indicators of popping beads

4.2.4Effects of melting temperature on indicators of popping beads. When the melting temperature was 50 ℃, the melting speed was low and could not be completely melted. When the temperature was higher than 60 ℃, both PEG-4000 and paeonol could be dissolved better. When the melting temperature was 90 ℃, both entrapment efficiency and drug loading were significantly higher than those of the other groups, and theRSD(%) was also the smallest, possibly because the melting was not complete enough when the temperature was lower than 90 ℃, and the paeonol and PEG-4000 could not be completely and uniformly mixed. However, when the melting temperature was higher than 90 ℃, paeonol would volatilize to a certain extent, resulting in a decrease in entrapment efficiency and drug loading (Table 8). Therefore, we tentatively determined that 90 ℃ is the optimal melting temperature.

Table 8 Effects of melting temperature on indicators of guttate pill

4.2.5Effects of drying time on indicators of popping beads. The drying time has little effect on the entrapment efficiency, drug loading andRSD(%) of popping beads. When the drying time was 25 min, the indicators were the best (Table 9). Therefore, we tentatively determined that 25 min is the optimal drying time.

Table 9 Effects of drying time on indicators of popping beads

4.2.6Effects of number of coating layers on indicators of popping beads. When the coating was 2 layers, the film was too thin and easy to break. When the coating was more than three layers, the coating film was relatively tough, and with the increase of the number of coating layers, the weight increased, the entrapment efficiency and drug loading decreased, and the comprehensive score also showed a downward trend. When the coating layers were more than 5, the coating film was too thick and too hard, difficult to bite and has poor taste (Table 10). Therefore, we tentatively determined that 3 layers are as the optimal number of coating layers.

Table 10 Effects of number of coating layers on indicators of popping beads

4.3 Orthogonal experimental results and optimal process verification

4.3.1Orthogonal experiment. The experimental results and analysis of variance were separately shown in Table 11 and Table 12.

From the data in Table 11, it can be seen that the effects of each factor on the comprehensive score of paeonol bead popping gum were A>B>D, that is, the concentration of sodium alginate solution > number of coating layers > PEG-4000: paeonol dosage ratio; the average value of the comprehensive score of each factor level was: A2>A1>A3, B1>B3>B2, D3>D2>D1, the optimal preparation process was A2B1D3, that is, sodium alginate solution concentration 0.02 g/mL, 3 coating layers, and PEG-4000: paeonol dosage ratio of 4∶1. The results of variance analysis in Table 12 show that the effects of factors A, B and D on the comprehensive score of paeonol bead popping gum were all significant (P<0.01).

Table 11 Orthogonal experiment for preparation process of paeonol bead popping gum

Table 12 Orthogonal experimental analysis of variance for the preparation method of paeonol bead popping gum

According to the results of single factor experiments and orthogonal experiment, the optimal prescription design of paeonol bead popping gum is as follows: PEG-4000: paeonol dosage ratio is 4∶1, sodium alginate solution concentration is 0.02 g/mL, and CaCl2solution concentration is 0.25 g/mL; the optimal preparation conditions are: dropper diameter is 4 mm, condensation time is 5 min, dropping distance is 4 cm, melting temperature 90 ℃,drying time 25 min, number of coating layers 3 layers.

4.3.2Optimal process verification. According to the orthogonal experiment results, we prepared 3 batches of bead popping gums according to the optimal preparation conditions, carried out the mensuration of entrapment efficiency, drug loading, pill weightRSD(%) and comprehensive score, the results were shown in Table 13.

Table 13 Optimal process verification results

According to the optimal process verification data, the comprehensive scores of the three optimal process verification experiments were 59.24, 58.98 and 59.17, respectively; the average values of entrapment efficiency, drug loading and pill weightRSD(%) of the three groups of experiments were: 52.76%, 7.85% and 1.48%, respectively; theRSD(%)of each indicator was less than 3%, indicating that the quality of paeonol bead popping gum prepared by this optimal process was stable and had certain reproducibility.

As a chronic heterogeneous disease, diabetes often plagues the majority of patients, and its complications make patients suffer untold misery. Once getting this disease, it is basically necessary to take medicines for the whole life. Most of the traditional hypoglycemic drugs have certain side effects, and the side effects are even greater after long-term use. Our research aims to develop a product, paeonol bead popping gum, which can replace or reduce the dosage of traditional hypoglycemic drugs. This product uses pure traditional Chinese medicine ingredient paeonol as the raw material. Paeonol has a good hypoglycemic effect and has a certain therapeutic effect on its complications. Besides, as a pure traditional Chinese medicine component, paeonol has the characteristics of high safety and long-term use, and has unique advantages as a substitute for hypoglycemic drugs. Thus, paeonol bead popping gum has a large development space.

Acesulfame, xylitol and peppermint essence were added to the prescription of this experiment, and only bead popping gums with mint flavor were prepared. Due to the limited laboratory conditions, a purely manual method is used, which is inefficient and not suitable for mass production in factories. If this achievement is valued and appreciated by enterprises, mechanized mass production can be adopted to greatly improve production efficiency and put it into the market. Moreover, paeonol bead popping gum is po-sitioned as a substitute for traditional hypoglycemic drugs, and has the effect of refreshing breath, refreshing and removing halitosis (bad breath). It is not only suitable for diabetic patients, but also a good choice for ordinary people. In general, the bead popping gums have a tremendous market demand. In this experiment, we only performed a preliminary study on paeonol bead popping gum, hoping to provide some reference and basis for hypoglycemic products of traditional Chinese medicine.