A large radix swertiae honeyed pill with reduced bitterness and good taste, and a preparation method and application thereof

Abstract

The present application belongs to the technical field of traditional Chinese medicine decoction pill preparation, and relates to a jujuboside large honeyed pill with reduced bitterness and good taste and a preparation method thereof. The present application significantly reduces the bitterness of the pill by performing ultrafine pulverization treatment on the dried jujuboside and combining a specific auxiliary material mixing process, and further improves the appearance quality and taste of the pill, improves the drug compliance, and has a wide market application prospect. At the same time, the preparation method is simple, the process parameters are quantifiable and measurable, and does not involve the addition of additional flavoring agents, and has a significant industrial scale application prospect.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine decoction piece pill preparation technology, and relates to a large honey pill made from Swertia japonica with reduced bitterness and good taste, as well as its preparation method and application. Background Technology

[0002] Swertia japonica is the whole herb of plants in the genus Swertia of the family Gentianaceae. Its extremely strong bitterness comes from iridoid glycosides (such as swertiaside and gentiopicrin). These bitter components are the material basis for its core medicinal effects, such as liver protection, choleretic, stomachic, and anti-inflammatory properties. The bitterness and medicinal effects are highly consistent. Among them, Swertia japonica of western Sichuan is a plant in the family Gentianaceae. Swertia mussotii Franch's whole herb is bitter and cold in nature, and has the effects of clearing heat and detoxifying, soothing the liver and gallbladder, and promoting diuresis and relieving jaundice. It contains active ingredients such as gentiopicrin, swertiamarin, and mangiferin. Modern pharmacological studies have confirmed that it has liver-protecting, anti-inflammatory, and antibacterial effects, and is widely used in the adjuvant treatment of hepatobiliary diseases such as acute and chronic hepatitis and cholecystitis.

[0003] To reduce the bitter, cold, and drastic properties of Swertia japonica, such as Swertia japonica from western Sichuan, and to improve drug compliance, it is often made into large honey pills in clinical practice and pharmaceutical preparations. The traditional preparation process of large honey pills includes steps such as pulverizing the medicinal material into fine powder (meaning that all of it can pass through the No. 5 sieve of the Pharmacopoeia, and at least 95% of the powder can pass through the No. 6 sieve of the Pharmacopoeia), refining honey, mixing, making pills into strips or granules, and packaging. Among these steps, the pulverized medicinal powder is sieved, and the medicinal powder and refined honey are mixed in a ratio of 1:1 to 1:1.5. After the medicine is awakened and the pills are made by the molding method, they are sealed in a wax shell.

[0004] However, Swertia japonica, such as Swertia japonica from western Sichuan, is generally hard in texture. When it is crushed into fine powder according to conventional methods, it is still difficult to mix evenly when preparing pills. Moreover, the finished honey pills have a rough cross-section, obvious fibers, and poor taste.

[0005] Meanwhile, Swertia contains a variety of bitter components, such as swertiamarin and gentiopicrin, which have a strong bitter taste. Existing honey pills rely solely on honey and sucrose dissolved in them to mask the bitterness, which has limited effect. The bitterness is obvious when taken, which leads to poor medication compliance, especially for children and people with sensitive spleen and stomach, and even refusal to take the medicine.

[0006] Furthermore, when balancing and optimizing the bitterness of *Swertia zedoaria* honey pills with its preparation, it is generally believed that the finer the powder of the medicinal material in the large honey pills is pulverized, the more pronounced the bitterness will be when chewing. According to the existing Chinese patent CN 113749202A, a method for preparing a solid beverage, ultrafine pulverization technology increases the contact area, significantly increases the specific surface area, increases porosity, enhances adsorption and solubility, and increases the chemical reaction rate. This allows for the full release of nutrients, bitter substances, or aromatic components from within the cells. Therefore, the finer the pulverization, the more likely it is to intensify the bitterness. However, not pulverizing further leads to difficulties in pill making, affecting chewing and absorption. Moreover, current methods for addressing the bitterness of traditional Chinese medicine have significant limitations. For example, while physical separation methods can fundamentally remove bitterness, they have high technical barriers, expensive equipment, and may inadvertently remove active ingredients, posing a potential risk to efficacy and making industrialization difficult. Chemical bonding methods are highly targeted at alkaloids, but have a narrow range of applications, are limited by the chemical properties of the drug, and the process of selecting suitable resins is complex and costly. Physical barrier methods (such as cyclodextrin inclusion and coating technology) have reliable taste-masking effects, but the equipment and processes are complex, have high requirements for production conditions, and there is a risk of incomplete coating or unstable inclusion compounds leading to taste-masking failure. Excessive addition of flavoring agents may affect the medication safety of special populations such as diabetics, and some flavoring agents may even interfere with the absorption process of the drug in the body. This results in the current lack of a good method for preparing Swertia honey pills that balances bitterness with preparation and efficacy.

[0007] Therefore, there is an urgent need for a pill preparation method that can effectively mask the bitterness of Swertia japonica, especially Swertia japonica from western Sichuan, is easy to prepare, does not affect efficacy, and is applicable to a wide range of people. This invention is based on this need and aims to solve the problems of insufficient bitterness masking, affected efficacy, and complex preparation process in the existing preparation of large honey pills, improve the drug compliance and clinical applicability of the formulation, and optimize the corresponding preparation process. Summary of the Invention

[0008] The purpose of this invention is to solve the above-mentioned technical problems and provide a large honey pill made from Swertia japonica with reduced bitterness and good taste, as well as a method for its preparation. Through creative and synergistic adjustments to the preparation process of the large honey pill made from Swertia japonica, this invention can significantly improve the bitterness and taste of pills made from Swertia japonica, such as Swertia japonica from western Sichuan, by adding only appropriate amounts of excipients.

[0009] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing Swertia honey pills with reduced bitterness and good taste. The method includes: drying the plant, pulverizing it into micro powder, mixing it with excipients, and preparing it into honey pills using a molding method; wherein the plant is a Swertia species, and the excipients include sucrose and honey.

[0010] Preferably, the *Swertia* species include the genus *Swertia* (…). SwertiaThe whole plant, above-ground parts, roots, rhizomes, or any combination thereof.

[0011] Preferably, the *Swertia* species is a plant belonging to the *Swertia* genus of the Gentianaceae family, specifically *Swertia medica*, more preferably a medicinal *Swertia* species rich in bitter active ingredients such as swertinoside and gentioside, and even more preferably including but not limited to *Swertia spp.* (Sichuan) Swertia mussotii ), Indian Swertia Swertia chirayita ), Swertia japonica ( Swertia bimaculata ), Yunnan swert ( Swertia yunnanensis ), Eastern Sichuan Swertia ( Swertia davidii ), Northern Swertia Swertia diluta ), Japanese Swertia ( Swertia japonica Common bitter medicinal swerts such as Swertia japonica and any combination thereof, preferably Swertia japonica from western Sichuan.

[0012] Preferably, the method specifically includes the following steps: (1) Drying: Place Swertia plants under appropriate conditions for drying treatment; Preferably, the drying method is selected from at least one of natural sun drying, natural shade drying, constant temperature drying, and vacuum drying; preferably, natural shade drying or vacuum drying; the drying endpoint is that the medicinal material feels dry to the touch. Preferably, the drying method is a 45°C vacuum drying method, in which the medicinal materials to be dried are evenly spread on a special tray of a vacuum dryer, the drying temperature is set to 45°C and the vacuum degree is 0.15 kPa, and the drying is carried out under these conditions until the medicinal materials are completely dry and have a brittle and hard texture; preferably, the drying time is 1-2 days, more preferably 1.5 days; (2) Pulverization: The dried medicinal materials are pulverized by ultra-fine grinding to obtain Swertia micro powder (medicinal material micro powder); Preferably, Swertia micro powder of the corresponding particle size is obtained by ultra-fine grinding using a grinding and mixing machine. Preferably, the dried medicinal materials are first subjected to preliminary pulverization to ensure smooth and continuous entry into the grinding cylinder, and then subjected to ultrafine pulverization to further ensure the smooth progress of ultrafine pulverization; the preliminary pulverization includes, but is not limited to, cutting treatment, mechanical pulverization treatment, etc. Preferably, the average particle size of the micro powder (ultra-micro pulverizer) obtained by grinding and mixing is 10-50 μm, more preferably 15-25 μm; and / or, the micro powder is a powder that can pass through a sieve of 200 mesh to 2500 mesh, more preferably a powder that can pass through at least one sieve selected from 500 mesh, 700 mesh and 900 mesh. Preferably, the grinding and mixing mill's parameters include: using zirconium oxide or wear-resistant and non-polluting material as the grinding medium, with a material-to-medium volume ratio of 1:2 to 1:3; running at the highest frequency of 80% to 100% for 15 minutes, and turning on forced cooling to control the discharge temperature to ≤60℃; (3) Mixing of excipients: Mix sucrose powder, honey and swamp agar powder to obtain a plastic mass; Preferably, sucrose is used, and high-quality honey is used as a binder; the honey meets pharmaceutical standards and is free of odor and impurities. Preferably, the sucrose is pulverized into sucrose powder that can pass through an 80-mesh sieve. Preferably, the honey is heated to 100°C, and the mixture is stirred during the heating process to remove foam and impurities; Preferably, the mixture is weighed in a mass ratio of swertia micro-powder to sucrose powder of 1:0.1-0.5, more preferably 1:0.2-0.5; and in a mass ratio of mixed powder to honey of 1:1.4-1.6, more preferably 1:1.5. Preferably, the sucrose powder and the herbal powder are mixed in advance to form a mixed powder before adding honey; more preferably, for making pills: the mixed powder of Swertia micro powder and sucrose powder is placed in a clean container, and heated honey is slowly added to the mixed powder and stirred until a uniform plastic block with suitable softness and no dry powder particles is formed. (4) Pelletizing process: rolling strips and making pellets: evenly apply a small amount of sesame oil to the surface of the wooden pellet rolling board, take the lump and roll it into a uniform strip, divide it and roll it into a round shape to make large honey pills with a weight of ≥0.5g each.

[0013] The present invention also provides a Swertia honey pill with reduced bitterness and good taste prepared by any of the above preparation methods.

[0014] The present invention also provides the application of Swertia japonica honey pills prepared by any of the above preparation methods, which have reduced bitterness and good taste, in the preparation of drugs for treating and / or preventing hepatobiliary diseases.

[0015] Compared with the prior art, the beneficial effects of the present invention are: (1) Improved pill texture and increased medication compliance: This invention uses a grinding and mixing machine to perform ultrafine grinding of *Swertia* species, such as *Swertia spp.*, resulting in powder with an average particle size of 25-15 μm, significantly smaller than powder obtained by conventional mechanical grinding (passing through a 65-100 mesh sieve) (particle size approximately 212-150 μm). Ultrafine grinding fully breaks down the fiber structure of the medicinal material, significantly increasing the specific surface area. After mixing the powder with the honey-sucrose system, a uniform and dense pill structure is formed. The resulting large honey pills have a fine and uniform cross-section, without obvious fibrous or granular feel. When chewed, they have a delicate and smooth texture, effectively improving the rough and astringent taste defect caused by the coarse and long fibers of traditional *Swertia spp.* pills, significantly improving medication compliance, especially for children and the elderly.

[0016] (2) Enhanced masking effect and reduced bitterness perception: In this invention, the ultrafine grinding process easily adheres excessively to honey, forming a dense structure that hinders drug release. This is often a disadvantage in conventional drug preparation. However, this invention utilizes this characteristic to delay the release of bitter substances. Furthermore, the synergistic effect of ultrafine grinding technology and sucrose premixing process is used to mask the bitterness of Swertia species. On the one hand, ultrafine grinding makes the powder particles small and uniform, forming a tight inclusion structure with honey, effectively delaying the instantaneous release of bitter components such as gentiopicrin and sucrose in the oral cavity. On the other hand, the premixing of powder and sucrose allows sucrose molecules to be uniformly adsorbed on the surface of the powder particles, producing a synergistic masking effect on bitterness. Sensory evaluation results show that the bitterness score of the large honey pills prepared by this invention is 3.95~5.25, which is significantly better than the III~IV grades (acceptable to relatively bitter) of pills prepared by conventional processes, achieving an excellent medication experience while ensuring the dissolution of effective ingredients.

[0017] (3) Simplified and controllable process flow: This invention achieves significant optimization in the process flow, making operation simpler and more efficient. First, the honey refining process is simplified, using refining conditions of heating to 100℃ and maintaining it for 5 minutes. Compared with the traditional high-temperature refining of 112-118℃, this condition is easier to control and has higher operational safety. It can effectively kill miscellaneous bacteria, reduce damage to active ingredients, and appropriately increase the viscosity of honey, thereby better ensuring the stability of the preparation. Second, the overall operation process is simple and efficient; the feeding method of adding honey directly after premixing the powder and sucrose eliminates the cumbersome steps of pre-dissolving sucrose or adding purified water in the traditional process, reducing material loss and processing time. All key process parameters are quantifiable and measurable, solving the drawback of the traditional process relying on the operator's experience and ensuring the uniformity and stability of product quality.

[0018] This invention significantly reduces the bitterness of pills by ultra-fine pulverization of dried Swertia species and combining it with a specific excipient mixing process. This further improves the appearance and taste of the pills, enhancing medication adherence and demonstrating broad market application prospects. Furthermore, the preparation method of this invention is simple, with all process parameters quantifiable and measurable, and it does not involve the addition of additional flavoring agents, indicating significant potential for large-scale industrial application. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the core process flow of the present invention; Figure 2 These are images of the appearance of *Swertia stenoptera* from western Sichuan after different drying methods, as described in Example 5 of this invention. Figure 2 Part A contains the whole fresh herb of *Swertia spicata* from western Sichuan. Figure 2 Part B consists of the whole herb of *Swertia stenoptera* from western Sichuan, which has been naturally air-dried indoors. Figure 2 Part C is the whole herb of *Swertia stenoptera* from western Sichuan, processed by vacuum drying at 45℃. Figure 3 These are cross-sectional views of embodiments 1-4 of the present invention; Figure 4 These are schematic diagrams of the appearance of embodiments 1-4 of the present invention; Figure 5 These are the dissolution curves of gentiopicrin in Example 3, Comparative Example 2, and Comparative Example 3 of the present invention; Figure 6 These are the mangiferin dissolution curves of Example 3, Comparative Example 2, and Comparative Example 3 of the present invention; Figure 7 These are schematic diagrams of the appearance of Embodiment 3, Comparative Example 2, and Comparative Example 3 of the present invention; Figure 8 These are schematic diagrams and cross-sectional views of Embodiment 4 and Comparative Example 4 of the present invention; Figure 9 These are the principal component analysis (PCA) score graphs of the electronic tongue detection in Comparative Examples 1-5 of this invention. Detailed Implementation

[0020] To better clarify and understand the objectives, process solutions, and advantages of this invention, the technical solutions and implementation methods of this invention will be further described clearly, completely, and in detail below through specific embodiments and in conjunction with the accompanying drawings. It should be understood that the embodiments described in this invention are implemented under the premise of the technical solutions of this invention, providing detailed implementation methods and specific operating procedures, but they are only some embodiments of this invention, not all embodiments. The specific implementation methods described are limited to illustrating and explaining this invention and do not limit this invention. Based on the embodiments of this invention, all other implementation methods obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0021] Unless otherwise specified, the experimental methods and conditions used in the embodiments of this invention are conventional methods and conditions. The materials, reagents, instruments, and equipment used in the embodiments, unless otherwise specified, are all conventional substances or equipment known to those skilled in the art and can be obtained commercially or prepared by conventional methods. The reaction conditions described in the invention's content can all achieve the stated reactions and obtain the desired products. Due to space limitations, some embodiments are listed below to further illustrate the advantages of the technical solution of this invention.

[0022] The raw material sources and apparatus information for each example in this invention are as follows. Similar products with the information below can be applied to this invention and obtain the aforementioned beneficial effects; therefore, the invention is not limited to the sources described below: The embodiments of this invention are exemplified using *Swertia spicata* as the raw material. Other bitter plants in the same genus *Swertia* can be expected to have a similar effect in reducing bitterness and improving taste. *Swertia spicata* is a plant belonging to the Gentianaceae family. Swertia mussotii The whole herb of *Swertia fragrans* is produced in Qinghai, Tibet, Sichuan, and other regions. The place of origin has a significant impact on the efficacy of the medicinal material in this invention. *Swertia fragrans* from the specific production area of ​​western Sichuan, due to its unique ecological environment of high altitude, strong ultraviolet radiation, and large diurnal temperature range, accumulates its active ingredients (such as swertia glycosides, swertia glycosides, ketone compounds, etc.) more fully, resulting in a clear authentic medicinal material with excellent efficacy, but also an extremely strong bitter taste. This invention uses the whole herb of *Swertia fragrans* from Ganzi Tibetan Autonomous Prefecture, Sichuan Province as raw material, clearly demonstrating the excellent effect of this invention in reducing bitterness. The honey used is pharmaceutical-grade honey that meets the industry standard GH / T 1494-2025 "Medicinal Honey". This invention uses multifloral honey produced by Shanghai Senfengyuan Bee Industry Co., Ltd. The sucrose used is pharmaceutical-grade sucrose that meets the requirements of the latest edition (current version) of the Chinese Pharmacopoeia. This invention uses refined white granulated sugar produced by Guangzhou Huatang Food Co., Ltd. The vacuum dryer conforms to the requirements of the People's Republic of China Machinery Industry Standard JB / T 20047-2013 "Pharmaceutical Vacuum Dryer". This invention uses a DZF model vacuum dryer from Shanghai Mousse Experimental Equipment Co., Ltd. The grinding and mixing mill is a multi-functional grinding and mixing device suitable for laboratory or pilot production. This invention uses a WZJ6 (BFM6) grinding and mixing mill from Jinan Beili Powder Technology Engineering Co., Ltd. The specifications of the sieves are shown in Table 1; all sieves shall conform to the GB / T 6003.1-2012 standard "Technical Requirements and Inspection of Test Sieves" and shall be made of stainless steel woven mesh. The sieves used in this invention are manufactured by Zhejiang Shangyu Huafeng Hardware Instrument Co., Ltd. Table 1. Screen specifications involved in this invention

[0023] Example 1 Drying: Spread the clean whole herb of Sichuan swert evenly on a special tray of a vacuum dryer. Set the drying temperature to 45℃ and the vacuum degree to 0.15 kPa. Dry under these conditions for 1.5 days until the herb is completely dry and has a brittle and hard texture. Pulverization: The dried medicinal materials are subjected to temperature-controlled ultrafine pulverization using a WZJ6 (BFM6) type grinding and mixing mill. After being chopped, the *Swertia stenoptera* from western Sichuan is fed into the mill cylinder through the feeding port, maintaining a material-to-medium volume ratio of 1:2 to 1:3. Under temperature-controlled cooling water circulation (inlet temperature 15-25℃), forced cooling is activated to control the outlet temperature to ≤60℃. The mill is run at the highest frequency of 80%-100% for 15 minutes, and then passed through a 500-mesh sieve to obtain medicinal powder. Preparation of excipients: Heat the honey at room temperature to 100℃ and maintain for 5 minutes, stirring constantly to remove impurities during the heating process; crush the sucrose and pass it through an 80-mesh sieve to obtain sucrose powder, and set aside; weigh the ingredients according to the mass ratio of medicine powder: sucrose powder = 1:0.2 and mixed powder: honey = 1:1.5. Pill making: First, mix the medicinal powder and sucrose powder evenly to form a mixed powder. Then, add the processed honey and mix and stir to form a plastic dough. Coat a wooden rolling board with a small amount of sesame oil, roll the dough into strips, divide it into balls, and make large honey pills with each pill weighing ≥0.5g. After air-drying until the surface hardens, seal the pills in a medicinal wax shell and store them in a cool, dry place.

[0024] Example 2 Based on Example 1, the mass ratio was changed to powdered medicine: sucrose powder = 1:0.5; other steps were the same as in Example 1.

[0025] Example 3 Based on Example 2, the dried medicinal materials were processed by a grinding and mixing machine and then passed through a 700-mesh sieve; the other steps were the same as in Example 1.

[0026] Example 4 Based on Example 2, the dried medicinal materials were processed by a grinding and mixing machine and then passed through a 900-mesh sieve; other steps were the same as in Example 1.

[0027] Example 5: Different Drying Methods The Sichuan swert was naturally air-dried and then vacuum-dried at 45℃. The natural air-drying method involves placing the medicinal material (whole herb of Swertia japonica from western Sichuan) in a cool, well-ventilated indoor place with a temperature of 20℃-28℃ and a relative humidity of 45%-65%, spreading it out flat, and letting it dry naturally for 5 days. The 45℃ vacuum drying method is the same as the drying method in Example 1. Specifically, the medicinal materials to be dried are evenly spread in a special tray of the vacuum dryer, the drying temperature is set to 45℃ and the vacuum degree is 0.15 kPa, and the materials are dried for 1.5 days until they are completely dry and have a brittle and hard texture.

[0028] Figure 2 These are images showing the appearance of the *Swertia stenoptera* from western Sichuan after different drying methods. Figure 2 Part A contains the whole fresh herb of *Swertia spicata* from western Sichuan. Figure 2 Part B consists of the whole herb of *Swertia stenoptera* from western Sichuan, which has been naturally air-dried indoors. Figure 2 Part C is the whole herb of *Swertia stenoptera* from western Sichuan, processed by vacuum drying at 45℃. Depend on Figure 2 As can be seen, the fresh whole herb of *Swertia stenoptera* (A) is bright green overall, with distinct layers of stems, leaves, and flowers, interspersed with small dark purplish-red flowers that contrast sharply with the bright green stems and leaves, and has a crisp and tender texture. *Swertia stenoptera* (B), after being naturally air-dried indoors, retained its inherent dark green color and intact shape, with clear stem and leaf structure, and no wrinkling or fading. This indicates that gentle air convection drying is beneficial for maintaining the integrity of the medicinal material's appearance and the stability of its internal components, but it requires a longer time. The medicinal material (C), after being vacuum-dried, also exhibits good appearance quality, with a natural color and full shape, and the drying efficiency is higher than that of natural air drying. Low-temperature dehydration under vacuum conditions can effectively avoid the damage of heat-sensitive active ingredients such as gentianin to high temperatures. At the same time, the drying process is controllable and unaffected by environmental factors, which better meets the requirements of industrial production.

[0029] Test Example 1 To verify the advantages of the technical solution of the present invention, the preparation of the Sichuan swert ball in each embodiment was systematically evaluated in terms of preparation difficulty, appearance, cross-sectional fineness, taste fineness and bitterness intensity.

[0030] Figure 3 These are cross-sectional views of embodiments 1-4 of the present invention. Figure 4 These are schematic diagrams of the appearance of embodiments 1-4 of the present invention, and the sensory evaluation results of bitterness are shown in Table 4.

[0031] Example 1: The powder was ultra-finely pulverized using a grinding and mixing machine and passed through a 500-mesh sieve. The powder was premixed with sucrose and then mixed with honey (at 100°C) at a ratio of powder:sugar powder:=1:0.2 and mixed powder:honey:=1:1.5 to form pills. The resulting pills were round and smooth in appearance with uniform color; the cross-sectional structure was dense and uniform with no obvious granular texture; the taste was delicate when chewed, and the bitterness score was 5.65, belonging to Grade III (acceptable bitterness).

[0032] Example 2 increased the sucrose ratio to 0.5 based on Example 1. The pills were round and smooth in appearance, with a finer and denser cross-section, and the taste was further improved. The bitterness score was reduced to 5.35, indicating that increasing sucrose can enhance the bitterness masking effect.

[0033] Example 3 improves upon Example 2 by increasing the fineness of the powder to 700 mesh, resulting in better powder dispersibility, a more round and smooth appearance of the pills, a fine and uniform cross-section, almost no grainy feeling when chewing, and a bitterness score of 4.95, which is further reduced compared to Example 2.

[0034] Example 4 improves the fineness of the powder to 900 mesh based on Example 2. The powder and excipients have excellent adhesion. The pills are round and smooth with uniform color. The cross-section is extremely fine and dense with no visible particles. The taste is delicate and smooth. The bitterness score is 4.30, which is the lowest among all examples and close to the upper limit of Grade II (slightly bitter).

[0035] In summary, with the increase in powder fineness (500 mesh to 900 mesh) and the optimization of the sucrose ratio (0.2 to 0.5), the ease of pill preparation remained good, and the appearance, cross-sectional fineness, and mouthfeel gradually improved. The bitterness score decreased from 5.65 to 4.30, showing a clear dose-effect relationship. It can be seen that compared with Examples 2 and 3, the smaller the particle size, the lower the bitterness sensory score and the less pronounced the bitterness. This is clearly the opposite of the conventional rule in the art that "the finer the powder, the more pronounced the bitterness." Therefore, the large honey pill preparation process pioneered by this invention has significant and unexpected superior effects, breaking through the conventional thinking barriers and technical constraints of existing technologies.

[0036] In summary, this invention, through ultra-fine pulverization technology, sucrose premixing process, and optimized pharmaceutical excipient ratio, can significantly improve the bitterness and taste of Sichuan swert pills without adding other flavoring agents, while ensuring good formability and appearance quality. Among these, Example 4 shows the best overall effect.

[0037] Comparative Example 1 This example uses ultrafinely pulverized medicinal powder, combined with conventional honey refining temperature and procedures, as follows: Drying: Spread the clean whole herb of Sichuan swert evenly on a special tray of a vacuum dryer. Set the drying temperature to 45℃ and the vacuum degree to 0.15 kPa. Dry under these conditions for 1.5 days until the herb is completely dry and has a brittle and hard texture. Pulverization: The dried medicinal materials are subjected to temperature-controlled ultrafine pulverization using a WZJ6 (BFM6) type grinding and mixing mill. After being chopped, the Sichuan swert is fed into the mill cylinder through the feeding port, ensuring a material-to-medium volume ratio of 1:2 to 1:3. Under temperature-controlled cooling water circulation (inlet temperature 15-25℃), forced cooling is activated to control the outlet temperature to ≤60℃. The mill is run at the highest frequency of 80%-100% for 15 minutes, and then passed through a 900-mesh sieve to obtain medicinal powder. Preparation of excipients: Honey is refined to 112℃ (young honey), and impurities are removed by constant stirring during the heating process. Sucrose and purified water are heated and dissolved, and then added to the refined honey to prepare a composite binder, which is mixed at the ratio of medicinal powder:honey:sucrose:purified water = 1:1.5:0.1:0.05. Making pills: Add a compound binder to the medicinal powder and stir it into a plastic lump. Coat a wooden rolling board with a small amount of sesame oil, roll the dough into strips, divide it into rounds, and make large honey pills with each pill weighing ≥0.5g.

[0038] Comparative Example 2 Based on Example 1, the pulverization process involves mechanically pulverizing the dried medicinal materials using a pulverizer and then passing them through a 100-mesh sieve without ultrafine pulverization. Other steps are the same as in Example 1.

[0039] Comparative Example 3 Based on Example 1, the pulverization process involves mechanically pulverizing the dried medicinal materials using a pulverizer and then passing them through a 65-mesh sieve without ultrafine pulverization. Other steps are the same as in Example 1.

[0040] Test Example 2 Dissolution testing method: The dissolution experiment was conducted using the slurry method. After confirming that the intelligent dissolution tester was connected normally, the stirring speed was set to 100 r / min and the temperature to 37 ℃. The dissolution medium was transferred into the dissolution vessel for preheating. Nine large honey pills were taken, along with three pills each of the three powder particle sizes from Example 4, Comparative Example 2, and Comparative Example 3. The mass of each pill was weighed, and the powder was cut into small pieces using a cross-cutting shear. The pieces were then placed into the center of the bottom of nine dissolution vessels, and the timing was started immediately. Samples were taken at 5, 15, 30, 45, 75, 105, 135, and 180 min. Two mL of the dissolution solution was taken and filtered through a 0.45 μm microporous membrane. The filtrate was used as the test solution. An equal amount of preheated dissolution medium was added promptly after sampling to maintain the stability of the system. The contents of gentiopicroside and mangiferin were determined by HPLC. The peak area, retention time, and other data were recorded. The cumulative dissolution rate was calculated according to the formula, and a dissolution curve was plotted with time as the x-axis and cumulative dissolution rate as the y-axis.

[0041] Table 2 shows the particle size data of *Swertia stenoptera* powder from Examples 3 and Comparative Examples 2-3 of this invention. The table reveals significant differences in average particle size obtained from different grinding methods: Comparative Example 2 (mechanically ground through a 100-mesh sieve) has a particle size of 148.2 μm, Comparative Example 3 (mechanically ground through a 65-mesh sieve) has a particle size of 200.5 μm, and Example 3 (ultra-finely ground through a 700-mesh sieve) has a particle size of 20.3 μm, all significantly smaller than the former two. A clear decreasing trend in particle size is observed with optimization of the grinding method. This result indicates that a grinding and mixing machine can effectively reduce the particle size of medicinal powder, allowing for more complete release of medicinal components. This facilitates uniform mixing and tight adhesion with excipients such as honey and sucrose, improving the formability and internal structural uniformity of the formulation. Powder obtained through conventional mechanical grinding has a larger particle size and relatively weaker binding with excipients, easily leading to uneven mixing of the powder and excipients, thus affecting the appearance, cross-sectional fineness, and taste quality of the pills.

[0042] Table 2. Particle size data of *Swertia stenoptera* powder under different treatment methods in western Sichuan

[0043] Figure 5 These are the dissolution curves of gentiopicrin in Example 3, Comparative Example 2, and Comparative Example 3 of the present invention. Figure 6 This is a dissolution curve of mangiferin in Example 3, Comparative Example 2, and Comparative Example 3 of the present invention. (From...) Figures 5-6 It can be seen that Comparative Example 2 showed higher dissolution rates of active ingredients and higher final cumulative dissolution amounts than the other two groups, with a steeper slope in the early stage of the dissolution curve and more rapid initial dissolution kinetics. Comparative Example 3 was second best. The dissolution curve of Example 3 was relatively flat overall, with a slower release rate of active ingredients and a relatively lower cumulative dissolution amount. The experimental results indicate that ultrafine pulverization can reduce the particle size of medicinal powder, increase the specific surface area, and improve dispersibility, making the powder adhere more tightly to excipients such as honey and sucrose, forming a more compact pill structure. This structure can significantly delay the initial dissolution rate of bitter substances such as gentiopicroside and mangiferin, reduce the instantaneous release concentration of bitter active ingredients in the oral cavity, thereby effectively weakening the bitterness of the preparation and improving medication compliance. By regulating the dissolution behavior of active ingredients, the ultrafine pulverization process achieves a balance between mitigating bitterness and ensuring the formability of the preparation, realizing the synergistic unity of bitterness control and efficacy assurance.

[0044] Figure 7 shows the appearance of Example 3, Comparative Example 2, and Comparative Example 3 of the present invention. As shown in Figure 7, Example 3 has a smooth and round appearance with uniform color, no cracks, adhesion, or obvious impurities, exhibiting the best formability and appearance quality. Comparative Example 2 has a relatively regular appearance, but its surface smoothness is slightly inferior to that of Example 3, and its particle texture is less pronounced. Comparative Example 3 exhibits more obvious appearance defects, with a rougher surface and some fine particle protrusions. This is attributed to the larger particle size of the coarse powder and insufficient uniformity of mixing with the excipients, which hinders the formability during the pill-making process. This result fully demonstrates the core regulatory role of the particle size of the pulverized medicinal materials in the pill-making process, where the fineness of the pulverized particle size is a key factor determining the appearance quality. The present invention, through ultrafine pulverization, can significantly improve the appearance quality and medication compliance of the final pills compared to conventional mechanical pulverization.

[0045] Comparative Example 4 Based on Example 4, sucrose was pulverized into sugar powder that could pass through a 65-mesh sieve, and the other steps were the same as in Example 4.

[0046] Figure 8 The figures show the appearance and cross-sectional views of Example 4 and Comparative Example 4. As can be seen from the figures, the sucrose in Example 4 has a finer particle size, mixes more evenly with the medicinal powder, exhibits good plasticity when kneaded with honey, is easier to handle during pill making, and has better shapeability. The resulting pills have a smooth, round surface, uniform color, dense and fine cross-section, without obvious particles or gaps, and a delicate, smooth mouthfeel without any grainy texture. In Comparative Example 4, the sucrose used has a coarser particle size, resulting in slightly poorer mixing uniformity, slightly inferior shapeability, lower pill smoothness and cross-sectional fineness, a slightly grainy mouthfeel, and slightly weaker overall quality. In summary, using finer sucrose powder can significantly improve the mixing uniformity and kneading plasticity of the medicinal powder and excipients, effectively improving the pill-forming effect, resulting in a round, smooth appearance and a dense, fine cross-section, while also improving the smoothness of the mouthfeel. Conversely, excessively coarse sucrose particles will reduce mixing uniformity, leading to a decrease in the smoothness and fineness of the pill appearance and a deterioration in the overall quality of the preparation.

[0047] Comparative Example 5 Based on Example 4, sucrose was not added during the pelleting process, while the other steps were the same as in Example 4.

[0048] Test Example 3 Electronic tongue detection: Place the pretreated sample test solution on the sample stage, adjust the sensor position to ensure the electrode is completely immersed, and avoid air bubbles interfering with the detection signal. Set the detection parameters: response time 4 min, data acquisition interval 10 s. After the detection is completed, the instrument automatically records the taste data. To eliminate sample cross-contamination, after each sample test, the sensor is ultrasonically cleaned with purified water for 3 min, then immersed in blank purified water for equilibration for 2 min until the baseline stabilizes (response value fluctuation ≤ ±0.02). A purified water blank control is inserted after every 3 consecutive sample tests to correct instrument drift. Each group of parallel test solutions is tested 3 times, and the average value is taken as the final data. Results are attached. Figure 9 .

[0049] Sensory evaluation of bitterness: The bitterness intensity of the Sichuan Spirodela polyrhiza pills prepared in the above-mentioned embodiments and comparative proportions was evaluated using a tasting method. Evaluators were selected based on the following criteria: no history of taste impairment or smoking, and no pre-existing conditions affecting taste such as colds or medications. They were tested with standard bitter substances (quinine hydrochloride dilutions) and were able to accurately identify the five basic tastes (sour, sweet, bitter, salty, and umami), with their bitterness detection threshold within the normal range. An evaluation team of 10 qualified evaluators was formed. All drug samples were of the same weight. Each sample was tasted for 3-6 seconds. After each tasting, the mouth was rinsed with drinking water to remove residual bitterness and restore taste perception. The interval between tasting different samples was 10 minutes. After tasting all samples, the same evaluator scored them according to bitterness intensity, compared the bitterness levels, and ranked the samples.

[0050] Figure 9 This is a principal component analysis (PCA) score chart of the electronic tongue detection in Comparative Examples 1-5 of this invention. Figure 9 It can be seen that PC1 contributes 77.2%, constituting the core dimension for distinguishing comprehensive characteristics. From the score distribution, Comparative Example 3 exhibits the most significant clustering characteristics, with a dense spatial distribution and the smallest coverage area, indicating that this group has the best uniformity in comprehensive quality aspects such as bitterness perception and component distribution. Comparative Example 2 shows the most significant difference, not only with a large distribution span on the PC1 axis but also being far from the cluster centers of other groups, making it the sample with the highest dispersion of quality characteristics among all groups. This reflects that at this particle size, the bitterness-related characteristics and component dissolution behavior of the sample fluctuate significantly. Comparative Example 5 has a smaller distribution span and a gentler slope than Comparative Example 2, indicating that while the absence of sucrose did not change the correlation of quality characteristics, it weakened the magnitude of change, confirming the important role of sucrose in the synergistic system of pharmaceuticals and excipients. This PCA score chart confirms that the pills prepared using different pulverization processes and excipient ratios in this invention exhibit significant inter-group differences in comprehensive quality, providing intuitive statistical evidence for the regulatory effect of process optimization on formulation quality.

[0051] Table 3 is a qualitative description of the bitterness level, and Table 4 is a bitterness evaluation table for Examples 1-4 and Comparative Examples 1-5. As can be seen from Tables 3-4, Examples 1-4 reached Level II-III (slightly bitter to acceptable bitterness), with Examples 3 and 4 being the least bitter among all groups, demonstrating the superior dispersibility of the ultrafine grinding method and the synergistic bitterness masking effect of appropriate amounts of sucrose and honey. Comparative Example 1 was Level III (acceptable bitterness). Although the traditional pelleting method and the method used in this invention are at the same level, the bitterness score is higher than that of the Examples 1-4, highlighting the significant advantage of the sucrose and powder premixing process in improving bitterness. Comparative Examples 2 and 3 were Level III (…). The bitterness scores of Comparative Example 4 and Comparative Example 5 were Grade III (acceptable bitterness), with a slightly grainy texture and a slightly stronger bitterness compared to Example 4. Comparative Example 5 was Grade III (acceptable bitterness), highlighting the lack of sucrose synergy and poor bitterness masking effect. This further confirms that ultrafine grinding technology, sucrose and drug powder premixing process, and reasonable drug-excipient ratio (especially sucrose dosage) are the key to reducing the bitterness of Sichuan West Swertia Pills, and cannot be expected in the conventional way.

[0052] Table 3 Qualitative Description of Bitterness Grades

[0053] Table 4. Sensory evaluation of bitterness in Examples 1-4 and Comparative Examples 1-5

[0054] As can be seen from the above, the method of the present invention significantly reduces the bitterness of the final product pills, while further improving the appearance quality of the pills. It breaks through the current field constraints that make it difficult to balance bitterness with appearance and ease of preparation, thereby achieving significant improvement in all aspects, significantly improving medication compliance, and has broad market application prospects.

[0055] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications may be made without departing from the technical solutions described in the claims.

Claims

1. A method for preparing Swertia japonica honey pills with reduced bitterness and improved taste, characterized in that, The method includes: drying Swertia plants, pulverizing them into medicinal powder, then mixing the medicinal powder with sucrose powder to form a mixed powder, then adding honey, mixing and stirring to form a plastic mass, and using a molding method to make large honey pills; The medicinal powder mentioned above is a powder that can pass through a 900-mesh sieve; The sucrose powder mentioned is a powder that can pass through an 80-mesh sieve; The mass ratio of the medicinal herb powder to the sucrose powder is 1:0.5; The mass ratio of the mixed powder to honey is 1:1.

5.

2. The preparation method according to claim 1, characterized in that, The drying process is selected from at least one of the following: natural sun drying, natural shade drying, constant temperature drying, and vacuum drying.

3. The preparation method according to claim 2, characterized in that, The drying process described is a vacuum drying method at 45°C.

4. The preparation method according to claim 1, characterized in that, The honey mentioned is honey that has been heated to 100°C.

5. The preparation method according to claim 1, characterized in that, The *Swertia* species mentioned are plants belonging to the *Swertia* genus of the Gentianaceae family.

6. The preparation method according to claim 5, characterized in that, The *Swertia* species mentioned are selected from at least one of the following: *Swertia spp.*, *Swertia indicum*, *Swertia yunnanensis*, *Swertia spp.*, *Swertia davidii*, and *Swertia japonica*.

7. The preparation method according to claim 6, characterized in that, The *Swertia* species mentioned were selected from *Swertia spp.* in western Sichuan.

8. A method for preparing Swertia japonica honey pellets with reduced bitterness and improved taste, characterized in that, The aforementioned Swertia honey pellets are prepared through the following steps: (1) Drying: The Sichuan swert was vacuum dried for 1.5 days to obtain the medicinal material. The drying temperature was set at 45℃ and the vacuum degree was 0.15 kPa. (2) Pulverization: The dried medicinal materials are pulverized by high temperature using a grinding and mixing machine and passed through a 500-900 mesh sieve to obtain medicinal material powder; (3) Preparation of excipients: Heat the honey to 100℃ and stir during the heating process to remove foam and impurities; crush the sucrose and pass it through an 80-mesh sieve to obtain sucrose powder; weigh the powder according to the mass ratio of medicine powder: sucrose powder = 1:0.5 and mixed powder: honey = 1:1.

5. (4) Making pills: Mix the medicinal powder and sucrose powder evenly to form a mixed powder, then add the processed honey and mix and stir to form a plastic lump. Coat the wooden pill rolling board with a small amount of sesame oil, roll the dough into strips, divide it into sections and roll it into rounds to obtain large honey pills.

9. A type of Swertia honey pill prepared by the method according to any one of claims 1-8, characterized by reduced bitterness and good taste.

10. The use of Swertia japonica honey pills prepared by any one of claims 1-8, which have reduced bitterness and good taste, in the preparation of medicaments for treating and / or preventing hepatobiliary diseases.

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