A traditional Chinese medicine taste-masking composition and its application in Lanqin oral preparation

Abstract

The present invention provides a traditional Chinese medicine taste-masking composition, which solves the contradiction between the large volume of traditional Chinese medicine compound preparations and the low drug loading of cyclodextrin, improves the taste-masking effect while reducing the amount of excipients used, and achieves synergistic effect. The traditional Chinese medicine taste-masking composition includes sulfobutyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and the mass ratio is 1:1. The composition also contains methyl-β-cyclodextrin and α-cyclodextrin; or it also contains polymerized-β-cyclodextrin, cationic-β-cyclodextrin, and methyl-β-cyclodextrin. The above-mentioned cyclodextrin and its derivatives are used as pharmaceutical excipients with low production costs and are suitable for industrial promotion. In addition, the present invention also provides the use of the traditional Chinese medicine taste-masking composition in Lanqin oral preparations. Compared with the commercially available Lanqin granules, the bitterness value of the Lanqin granules prepared by the present invention is reduced by 27% to 48%, and the Lanqin granules provided by the present invention have good hygroscopicity and stable quality.

Description

Technical Field

[0001] The invention belongs to the field of drug taste masking, and particularly relates to a traditional Chinese medicine taste masking composition and application thereof. Background Art

[0002] Traditional Chinese medicine dosage forms have always been known to taste bitter. However, most granules and oral liquid preparations made using modern formulation technologies still have a pronounced bitter taste, with little noticeable improvement in taste. However, as living standards improve, patients have higher expectations for medication compliance. The unpleasant taste and odor of Chinese medicines can reduce patient compliance and even affect clinical efficacy.

[0003] In recent years, various taste-masking technologies have been successfully applied to the taste-masking of chemical drugs, with good results. Common taste-masking methods have different disadvantages when applied to compound Chinese medicine preparations: 1. Microencapsulation of drugs will prolong production time and increase production costs. Microencapsulation will also prolong the dissolution of drugs, affecting bioavailability. 2. The large-scale use of sweeteners can mask some of the bitterness of drugs but may affect the efficacy. The quality of medicinal materials affects the content of bitter components in compound preparations, making product quality control more difficult. 3. The use of ion exchange resins and the addition of bitterness eliminators are more suitable for chemical drugs with clear ingredients. However, the ingredients of Chinese medicine are complex and the dosage is relatively large. It is difficult to determine the specific substances that produce bitterness and develop targeted taste-masking methods. At this stage, most compound Chinese medicine preparations use universal methods such as adding sweeteners and flavors to mask the taste, but the effect is limited.

[0004] Cyclodextrin is a cyclic oligosaccharide with a cavity structure. Hydrophobic or non-dissociated drugs enter its hydrophobic cavity to form inclusion complexes, which can block the contact between drug molecules and bitter receptors, thereby achieving a taste masking effect. Different types of cyclodextrin are composed of different amounts of glucose, have different molecular cavities, and can include molecules of different sizes. β-cyclodextrin is composed of 7 glucose molecules, with an inner diameter of the molecular cavity of 0.7 to 0.8 nm and a cavity volume of 34.6 nm. 3 , usually combined with aromatic compounds and heterocycles; α-cyclodextrin is composed of 6 glucose molecules, with a cavity inner diameter of 0.45-0.6nm and a cavity volume of 17.6nm 3 , which can usually be combined with low molecular weight molecules or compounds with aliphatic side chains; γ-cyclodextrin is composed of 8 glucose molecules, with an inner diameter of the molecular cavity of 0.85-1.0nm and a cavity volume of 51.0nm 3, typically with macrocycles and steroids. Cyclodextrin inclusion is a stoichiometric molecular phenomenon, in which typically only one guest molecule interacts with the cyclodextrin cavity and is retained. In the case of some low-molecular-weight molecules, more than one guest molecule can fit into the cavity, and in the case of some high-molecular-weight molecules, more than one cyclodextrin molecule can bind to the guest. When cyclodextrin is used in combination with other excipients, these other excipients may also bind to the cyclodextrin, reducing the inclusion rate of bitter substances in the traditional Chinese medicine compound and failing to achieve a good taste-masking effect.

[0005] "Reflections on the Study of Taste-Masking Technology for Traditional Chinese Medicine Granules" (Zhonghua Journal of Traditional Chinese Medicine, 2016, 31(09), 3658-3661) points out that when traditional Chinese medicine granules are encapsulated with cyclodextrin, the drug loading capacity of the cyclodextrin inclusion complex is low and it is only suitable for low-dose drugs. The taste-masking effect of the cyclodextrin inclusion complex depends on the type and dosage of the cyclodextrin, the dosage and properties of the drug, the type and composition of the preparation, etc. By combining different bitterness suppression methods - such as different bitterness suppression principles and different bitterness inhibitors - with preparation methods - such as cyclodextrin inclusion and solid dispersion systems, the taste-masking effect of traditional Chinese medicine compound preparations can be improved.

[0006] "R&D Strategy and Practice of Traditional Chinese Medicine Decoction Companions Based on the "Shotgun Theory": Taking Huanglian Jiedu Decoction as an Example" (Chinese Herbal Medicine, 2021, 52(15): 4443-4454) organically integrates the characteristics of cyclodextrin inclusion, flavoring agents, and amphiphilic block polymers to achieve a "synergistic effect" of taste masking. The polymer breaks the system balance and reduces the distribution of bitter components in the solution; cyclodextrin plays an inclusion role, blocking the contact between bitter components and receptors; and the flavoring agent plays a competitive role, interfering with the formation or conduction of bitter signals. However, the requirements for preparation process and raw material costs have increased, and the industrial promotion of special bitter suppression methods and preparation processes is relatively difficult.

[0007] "Research on the Flavor Correction Technology of Pediatric Xiaoji Zhike Oral Liquid Based on Electronic Tongue Evaluation" (Modern Chinese Medicine, 19(06), 853-857) optimized the flavor correction process of sugar-free preparations and determined the ratio of β-cyclodextrin: xylitol: sucralose: menthol to be 3:10:0.05:0.05, thereby improving the taste of Pediatric Xiaoji Zhike Oral Liquid and increasing the compliance of children with the drug. However, in this technical solution, sweeteners were mainly used to mask the bitter taste of the traditional Chinese medicine compound, and β-cyclodextrin did not achieve a good taste masking effect.

[0008] CN114177079A "A Chinese medicine diagnosis, decoction, and taste improvement system" (application date 2021.12.27, publication date 2022.03.15) discloses a Chinese medicine companion whose main components are three cyclodextrins α, β, and γ, which avoids the low efficiency of single cyclodextrin inclusion and solves the problems of poor odor and taste when taking medicine. Different types of cyclodextrins correspond to different sizes of space, forming molecular capsules that encapsulate small molecules, medium molecules, and large molecules in the medicine, but the dosage of cyclodextrin is not reduced due to the combined use of different types of cyclodextrins.

[0009] CN112516326A “A flavoring agent for traditional Chinese medicine and its preparation method” (application date 2020.12.24, publication date 2021.03.19) uses citric acid-modified cyclodextrin and then cross-linked with chitosan. The cross-linked cyclodextrin-chitosan not only encapsulates and adsorbs bitter substances, but the synergistic effect of the two significantly improves the flavor correction effect and reduces the amount of cyclodextrin used. However, the yield of modified cyclodextrin is closely related to the product yield, and the modification process of cyclodextrin will prolong the production time and increase production costs. Therefore, there is an urgent need to develop a flavor-masking agent suitable for traditional Chinese medicine compound preparations that has good taste-masking effect, lower cost and can be promoted industrially.

[0010] Both Lanqin Granules and Lanqin Oral Liquid are composed of five medicinal herbs: Isatis Root, Scutellaria Baicalensis, Gardenia Fructus, Phellodendron Amurense, and Sterculia Sea. They clear heat and detoxify, relieve sore throat swelling, and are used to treat acute pharyngitis and sore throat, dry throat, and burning throat caused by lung and stomach heat syndrome. The two dosage forms utilize the same extract preparation process; the difference lies in the excipients added during the preparation of the extract.

[0011] In the Lanqin formula, the ingredients Scutellaria baicalensis and Gardenia jasminoides are quite bitter. The Lanqin granules produced by Zhejiang Kangenbei Pharmaceutical Co., Ltd. use the formula and preparation method of CN1616032A, "A Preparation Method and Quality Control Method for Granules for Treating Pharyngeal Diseases" (application date: September 23, 2004, publication date: May 18, 2005). The Lanqin granules use β-cyclodextrin for flavor correction to reduce their bitterness and improve the extract's adhesion to the wall during the spray drying process. However, the existing technology only uses oral tasting to evaluate the taste-masking effect, without using more objective electronic tongue testing methods for verification. Market research and oral tasting feedback indicate that the Lanqin granules produced using existing technology still have a certain bitterness.

[0012] Therefore, developing a Lanqin granule with better taste-masking effect will improve patient compliance and increase the competitive advantage among similar products. Summary of the Invention

[0013] To address the issues of poor taste-masking and high cyclodextrin usage in existing traditional Chinese medicine compound preparations, the present invention provides a traditional Chinese medicine taste-masking composition suitable for traditional Chinese medicine compound preparations, exhibiting excellent taste-masking efficacy, lowering costs, and enabling industrialized deployment. The present invention also provides the use of this taste-masking composition in Lanqin oral preparations, particularly Lanqin granules, thereby producing Lanqin granules with enhanced taste-masking efficacy and improving patient medication compliance.

[0014] The specific contents of the present invention are as follows:

[0015] A traditional Chinese medicine taste-masking composition, characterized in that the composition comprises sulfobutyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and the mass ratio is 1:1.

[0016] Furthermore, the composition further comprises methyl-β-cyclodextrin and α-cyclodextrin, and the mass ratio of sulfobutyl-β-cyclodextrin: methyl-β-cyclodextrin: hydroxypropyl-β-cyclodextrin: α-cyclodextrin is 3: (1-2): 3: (1-3), preferably 3: 1: 3: 1. Alternatively, the composition further comprises polymerized-β-cyclodextrin, cationic-β-cyclodextrin, and methyl-β-cyclodextrin, and the mass ratio of sulfobutyl-β-cyclodextrin: polymerized-β-cyclodextrin: methyl-β-cyclodextrin: cationic-β-cyclodextrin: hydroxypropyl-β-cyclodextrin is 1: 1: 1: 1: 1.

[0017] The present invention also provides a blue scutellaria baicalensis oral preparation comprising a traditional Chinese medicine taste-masking composition. The blue scutellaria baicalensis oral preparation comprises a blue scutellaria baicalensis extract and the traditional Chinese medicine taste-masking composition. The mass ratio of the blue scutellaria baicalensis extract to the traditional Chinese medicine taste-masking composition is (34-54): (46-66). The dosage forms of the blue scutellaria baicalensis oral preparation include granules and oral liquid.

[0018] Furthermore, the traditional Chinese medicine taste-masking composition component of the Lanqin oral preparation contains sulfobutyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and the mass ratio of the Lanqin extract to the traditional Chinese medicine taste-masking composition is 1:1. Preferably, the traditional Chinese medicine taste-masking composition component of the Lanqin oral preparation can also be selected from sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and α-cyclodextrin, and the mass ratio of the Lanqin extract to the traditional Chinese medicine taste-masking composition is (34-42): (58-66). Preferably, the mass ratio of the Lanqin extract to the traditional Chinese medicine taste-masking composition is 42:58

[0019] Alternatively, the ingredients of the traditional Chinese medicine taste-masking composition of the Lanqin oral preparation can also be selected from sulfobutyl-β-cyclodextrin, polymerized-β-cyclodextrin, methyl-β-cyclodextrin, cationic-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin. The mass ratio of the Lanqin extract to the traditional Chinese medicine taste-masking composition is 54:46.

[0020] The invention provides Lanqin granules comprising a traditional Chinese medicine taste-masking composition.

[0021] Preferably, the Lanqin granules further contain citric acid and its salts, the ratio of the sulfobutyl-β-cyclodextrin to the citrate is 1:1, and the pH of the Lanqin granule aqueous solution is not greater than 6.0.

[0022] The present invention also provides a method for preparing an oral preparation of Lanqin, comprising the following steps:

[0023] (1) Preparation of Blue Scutellaria baicalensis extract: 150 parts of Radix Isatidis, 120 parts of Radix Scutellariae, 150 parts of Fructus Gardeniae, 60 parts of Cortex Phellodendri, and 50 parts of Sterculia lychnophora were taken and decocted three times with water, the first time for 2 hours, the second and third times for 1 hour each, the decoctions were combined, filtered, and concentrated under reduced pressure to a relative density of 1.10 to 1.16 measured at 50°C. Ethanol was added to make the alcohol content reach 60%, and the mixture was allowed to stand for 12 hours. The mixture was filtered, and the ethanol was recovered under reduced pressure and concentrated to obtain a Blue Scutellaria baicalensis extract paste with a relative density of 1.10 to 1.18 measured at 50°C, which was then dried to obtain the Blue Scutellaria baicalensis extract;

[0024] (2) Adding the traditional Chinese medicine taste-masking composition: adding the traditional Chinese medicine taste-masking composition to the blue scutellaria extract, adding an appropriate amount of purified water to dissolve, stirring evenly, and spray drying to obtain the blue scutellaria extract taste-masking spray-dried powder;

[0025] (3) Preparation into different dosage forms: Add the taste-masking spray-dried powder of the blue scutellaria extract to the preparation excipients to prepare blue scutellaria baicalensis granules or blue scutellaria baicalensis oral solution.

[0026] The present invention also provides a method for preparing Lanqin granules, comprising the following steps:

[0027] (1) Preparation of a paste of blue scutellaria extract: 150 parts of Radix Isatidis, 120 parts of Radix Scutellariae, 150 parts of Fructus Gardeniae, 60 parts of Cortex Phellodendri, and 50 parts of Sterculia lychnophora were taken and decocted three times with water, the first time for 2 hours, the second and third times for 1 hour each, the decoctions were combined, filtered, and concentrated under reduced pressure to a relative density of 1.10 to 1.16 at 50°C. Ethanol was added to make the alcohol content reach 60%, and the mixture was allowed to stand for 12 hours. The mixture was filtered, the ethanol was recovered under reduced pressure and concentrated to obtain a blue scutellaria extract paste having a relative density of 1.10 to 1.18 at 50°C.

[0028] (2) Addition of a Chinese herbal taste-masking composition: Add the Chinese herbal taste-masking composition to the clear paste, add an appropriate amount of purified water to dissolve, stir evenly, and spray-dry to obtain a spray-dried powder of the blue scutellaria extract; preferably, citric acid and its sodium salt may also be added to the clear paste, add an appropriate amount of purified water to dissolve, stir evenly, and spray-dry to obtain a spray-dried powder of the blue scutellaria extract. Preferably, the mass ratio of sulfobutyl-β-cyclodextrin to isatis root in the Chinese herbal taste-masking composition is 1:4.

[0029] (3) Mix the taste-masking spray-dried powder of the blue qin extract with a lubricant, a filler, and a sweetener, and dry granulate to obtain blue qin granules. Preferably, the lubricant can be selected from one or more of magnesium stearate, talc, polyethylene glycol, and hydrogenated vegetable oil; and the filler can be selected from one or more of dextrin, microcrystalline cellulose, starch, lactose, and mannitol.

[0030] The advantages of the present invention are:

[0031] (1) The present invention provides a traditional Chinese medicine taste-masking composition and a Lanqin oral preparation prepared therefrom, which solves the contradiction between the large volume of traditional Chinese medicine compound preparations and the low drug loading of cyclodextrin, improves the taste-masking effect while reducing the amount of excipients used, and achieves synergistic enhancement.

[0032] The present invention provides a traditional Chinese medicine flavor-masking composition composed of sulfobutyl-β-cyclodextrin, polymerized-β-cyclodextrin, methyl-β-cyclodextrin, cationic-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin in a mass ratio of 1:1:1:1:1. Testing of the flavor-masking effectiveness of cyclodextrins and their derivatives revealed that the order of flavor-masking effectiveness was: sulfobutyl-β-cyclodextrin > α-cyclodextrin > γ-cyclodextrin > cationic-β-cyclodextrin > polymerized-β-cyclodextrin > methyl-β-cyclodextrin > hydroxypropyl-β-cyclodextrin. F8, composed of sulfobutyl-β-cyclodextrin, cationic-β-cyclodextrin, polymerized-β-cyclodextrin, methyl-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin in a mass ratio of 1:1:1:1:1, exhibited a bitterness value of 4.7, lower than the 5.3 corresponding to sulfobutyl-β-cyclodextrin (F1) with the same total amount of cyclodextrin. Ranking by taste-masking ability reveals that the remaining β-cyclodextrin derivatives have lower taste-masking abilities than sulfobutyl-β-cyclodextrin. However, the combination of the five cyclodextrin derivatives in specific ratios demonstrates a surprising taste-masking effect superior to that of sulfobutyl-β-cyclodextrin alone. Furthermore, the present invention demonstrates that the inclusion complexation effect of sulfobutyl-β-cyclodextrin does not reach saturation at a dosage of 4g, demonstrating that the five cyclodextrin derivatives achieve enhanced taste-masking effectiveness through synergistic synergy while reducing the cyclodextrin dosage.

[0033] Table 1 Prescriptions F1-F5, F8 and their bitterness values

[0034]

[0035] Note: This test uses Scutellaria baicalensis extract as a control. It is divided into 5 levels, with a bitterness value ranging from 0 to 10. The lower the bitterness value, the less bitter it is.

[0036] The present invention also provides a traditional Chinese medicine taste-masking composition composed of sulfobutyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin in a 1:1 mass ratio. Formula F11 of the present invention reduces the cyclodextrin dosage by 40% compared to the control group F10, without adding any additional cyclodextrin types, yet achieves a bitterness value similar to that of F10, significantly reducing production costs. Furthermore, compared to the control group F9, F11 achieves a bitterness value similar to that of F9 by replacing three times the amount of high-taste-masking polymeric-β-cyclodextrin, methyl-β-cyclodextrin, and cationic-β-cyclodextrin with two times the amount of low-taste-masking hydroxypropyl-β-cyclodextrin, yielding an unexpected result. The 1:1 ratio of sulfobutyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin achieves a synergistic taste-masking effect, reducing the cyclodextrin dosage, lowering production costs, and effectively lowering the bitterness of the Lanqin oral preparation.

[0037] Table 2 Prescriptions F9-F11 and their bitterness values

[0038]

[0039] Note: This test uses Scutellaria baicalensis extract as a control. It is divided into 5 levels, with a bitterness value ranging from 0 to 10. The lower the bitterness value, the less bitter it is.

[0040] The present invention has been further optimized to provide a traditional Chinese medicine flavor-masking extract with a lower cyclodextrin dosage, lower production cost and better taste-masking effect. When using only polymerized-β-cyclodextrin or α-cyclodextrin to mask the taste of the Scutellaria baicalensis extract, 60g and 64g, respectively, need to be added to achieve a bitterness value of 2.5-2.6; the total amount of cyclodextrin in F12-F14 can reach the same bitterness value when it is 32-44g, which is about 30% less than the amount of cyclodextrin used alone. In addition, combined with the test results of Example 5, it can be seen that the cyclodextrin dosage of F10 is 40g, and the corresponding bitterness value is 3.1. Compared with the cyclodextrin composition F10, the total amount of cyclodextrin in F12-F14 is reduced by up to 20%, and the bitterness value is reduced by up to 23%. It can be seen that the taste-masking composition obtained by the cyclodextrin composition corresponding to F12-F14, that is, sulfobutyl-β-cyclodextrin, α-cyclodextrin, methyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin in a ratio of 3:(1-2):3:(1-3), uses less cyclodextrin and has a better taste-masking effect.

[0041] Further analysis revealed that F13, which uses sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and α-cyclodextrin in a ratio of 3:1:3:1, has a total cyclodextrin content of 32g and a corresponding bitterness value of 2.4. Compared to F12 and F14, F13 reduces the amount of α-cyclodextrin and methyl-β-cyclodextrin, yet maintains the same or similar bitterness values. This suggests that a 3:1:3:1 ratio of sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and α-cyclodextrin can achieve synergistic taste masking.

[0042] Table 3 Prescriptions F12-F16 and their bitterness values

[0043]

[0044]

[0045] Note: This test uses Scutellaria baicalensis extract as a control. It is divided into 5 levels, with a bitterness value ranging from 0 to 10. The lower the bitterness value, the less bitter it is.

[0046] (2) The present invention provides a Lanqin granule prepared from a traditional Chinese medicine taste-masking composition, which has a better taste-masking effect than the prior art.

[0047] In order to optimize the bitterness evaluation system, the present invention uses berberine hydrochloride as a control for oral tasting and uses an electronic tongue for evaluation.

[0048] Table 4: Formulas F17-F20 and prior art formulas

[0049]

[0050] Note: This test uses berberine hydrochloride as the control. The bitterness value ranges from 0 to 5.5. The lower the bitterness value, the less bitter it is.

[0051] The taste-masked Lanqin granules F17-F20 provided by the present invention, which contain a traditional Chinese medicine taste-masking composition, have significantly improved bitterness values ​​compared with commercially available Lanqin granules and F21 (commercially available Lanqin granules without sweetener).

[0052] F17 and F19 both use a traditional Chinese medicine flavor-masking composition with a 1:1:1 mass ratio of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sodium citrate. F18 and F20 both use a 3:1:3:1:3 mass ratio of sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, α-cyclodextrin, and sodium citrate. Compared to F17 and F18, F19-F20 also incorporates the sweetener aspartame. The bitterness value evaluation results showed that Lanqin Granules F18 (bitterness value 1.49) fell into the range of almost no bitterness (0.5-1.5); F17, F19-F20 all fell into the range of slightly bitterness (1.5-2.5), which was significantly lower than the acceptable bitterness range (2.5-3.5) described by the bitterness values ​​of commercially available Lanqin Granules and F21, and the bitterness value was reduced by 27% to 48%.

[0053] The present invention also verifies the taste masking result by electronic tongue, and the test results are as follows Figure 2 As shown. The electronic tongue three-dimensional PCA plot shows that the flavors of commercially available Lanqin granules, F19, and F20 all significantly changed compared to the Lanqin extract. The flavor of commercially available Lanqin granules differed significantly from that of the blank excipient, suggesting that the change in flavor of commercially available Lanqin granules is not due to the inclusion of bitter substances in β-cyclodextrin, resulting in a taste similar to that of the blank excipient, but rather to flavor modification that alters the flavor of the Lanqin granules. The relative distance between Lanqin granules F19 and F20 is small, indicating similar flavors; they also have a similar flavor to the corresponding blank excipient, indicating that the inclusion of cyclodextrin in the Lanqin extract achieves taste masking, resulting in a nearly non-bitter taste.

[0054] It can be obtained that the Lanqin granules containing a traditional Chinese medicine taste-masking composition of sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and sodium citrate in a mass ratio of 1:1:1, and the Lanqin granules containing a traditional Chinese medicine taste-masking composition of sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, α-cyclodextrin and sodium citrate in a mass ratio of 3:1:3:1:3, can both achieve the taste masking of the Lanqin extract by synergistically improving the cyclodextrin inclusion rate. The Lanqin granules obtained in this way taste closer to the blank excipient and have better bitterness inhibition effect than the commercially available Lanqin granules.

[0055] (3) The Lanqin granules prepared by the scheme of the present invention have good hygroscopicity and stable quality.

[0056] Compared to a physical mixture of a blue qin extract, excipients, and the extract, the blue qin granules prepared by the present invention can effectively reduce the hygroscopicity of the granules, making the product more stable. Electron microscopy results show that the cyclodextrin inclusion of blue qin granules F19 and F20 improves the hygroscopicity of the extract powder. High temperature, high humidity, and light exposure tests show that the fingerprint similarity between commercially available blue qin granules and blue qin granules F19 and F20 is greater than 0.995. The active ingredients of the blue qin granules after taste masking are almost identical to those of commercially available blue qin granules, and the product is stable under high temperature, high humidity, and light conditions.

[0057] (4) Cyclodextrin raw materials are easily available and the preparation process is simple. It meets the taste masking requirements of Lanqin granules and oral solution and is suitable for industrial promotion.

[0058] The present invention utilizes specific cyclodextrin and its derivative types and contents to produce a traditional Chinese medicine flavor-masked extract that uses less cyclodextrin, has lower production costs, and exhibits improved flavor-masking effects. The cyclodextrin and its derivatives described in the present invention have good dosage form and molecular applicability as pharmaceutical excipients, low production costs, and are suitable for industrialization and promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] The accompanying drawings, which constitute part of this application, are intended to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are intended to explain the present invention and do not constitute an undue limitation of the present invention. In the accompanying drawings:

[0060] Figure 1 is a bitter component analysis diagram, where Figure 1 a is the liquid phase spectrum and taste evaluation results of sample 1 in Example 3, Figure 1 b is the liquid phase spectrum and taste evaluation results of sample 2 in Example 3, Figure 1 c is the liquid phase spectrum and taste evaluation results of sample 3 in Example 3, Figure 1 d is the liquid phase spectrum and taste evaluation results of sample 4 in Example 3. Figure 1 The taste of a and 1b was evaluated as bitter. Figure 1 The taste of c was evaluated as slightly bitter. Figure 1 The taste of d was evaluated as not bitter, and ① was alkaloids. The bitterness was reduced after the cation exchange resin adsorbed the alkaloids, indicating that alkaloids were the main source of bitterness.

[0061] Figure 2 This is the PCA analysis diagram of electronic tongue data, where ● is Lanqin Granule F19, ○ is the blank excipient of Lanqin Granule F19, ▼ is Lanqin Granule F20, and ▽ is the blank excipient of Lanqin Granule F20. = Lanqin extract, ◆ = commercially available Lanqin granules, and ◇ = commercially available blank excipient. In the PCA analysis, the greater the relative distance, the greater the difference in flavor. Lanqin granules F19 and F20 have a small relative distance, and the relative distance to the corresponding blank excipient is also small, indicating similar flavors. The relative distance between the commercially available Lanqin granules and their blank excipient is large, indicating a significant difference in flavor.

[0062] Figure 3 is the liquid phase spectrum of samples with different pH values, Figure 3 a is the extract of Scutellaria baicalensis, Figure 3 b is Lanqin Granule F17, Figure 3 c is Lanqin Granule F18, Figure 3 d is the pH value of the blue scutellaria extract adjusted to 1.2, Figure 3 e is the pH value of the blue scutellaria extract adjusted to 6.0, Figure 3 f is the pH value of the blue scutellaria extract adjusted to 9.0, Figure 3 Figure g shows the Scutellaria baicalensis extract adjusted to pH 11.0. In the liquid chromatography, Peak 1 is geniposide, Peak 2 is magnolamine, Peak 3 is baicalin, and Peak 4 is berberine. As shown in the figure, Peak 3 is completely degraded at pH values ​​above 9.

[0063] Figure 4 These are the hygroscopic results of Lanqin Granules F19, including the hygroscopic curves of Lanqin extract spray-dried powder, Lanqin Granules F19, and Lanqin Granules F19 formula physical mixed powder.

[0064] Figure 5 These are the hygroscopic results of Lanqin Granules F20, including the hygroscopic curves of Lanqin extract spray-dried powder, Lanqin Granules F20, and physical mixed powder of Lanqin Granules F20 formula.

[0065] Figure 6 Scanning electron microscope images of different samples, Figure 6 a, 6d are extracts of Scutellaria baicalensis, Figure 6 b is the physical mixed powder of Lanqin Granule F19 formula, Figure 6 c is Lanqin Granule F19, Figure 6 e is the physical mixed powder of Lanqin granules 20, Figure 6 F is Lanqin Granule F20. The spray-dried powder of the extract contains irregular spherical and amorphous states; the physically mixed powder shows a coexistence of spherical and granular states; Lanqin Granules F19 and F20 form spherical particles of varying sizes due to the inclusion of cyclodextrin in the ingredients. DETAILED DESCRIPTION

[0066] In order to better understand the content of the present invention, further description will be given in conjunction with embodiments. It should be understood that the embodiments of the present invention should not be limited to the exemplary embodiments described below.

[0067] Example 1: Establishment of a bitter taste evaluation method

[0068] Two different scoring methods were used for the taste evaluation during the formulation screening process and the taste verification evaluation after the formulation was optimized. Finally, an electronic tongue was used to confirm the bitterness value of the formulation before and after optimization, thereby proving the accuracy of the taste masking result scoring.

[0069] The formulation screening process uses the bitterness value of the extract itself as the optimization basis. Bitterness values ​​corresponding to different extract concentrations are set and evaluated using a taste grading and scoring method. The resulting data is statistically analyzed to determine the bitterness differences between products.

[0070] The preferred formulations were subjected to a second taste verification evaluation. This evaluation used a ranking and scoring method, with strict control over the tasting process by the evaluators. Scoring was performed using berberine hydrochloride solution as a reference, and the resulting data was statistically analyzed to determine differences in bitterness between products.

[0071] 1.1 Establishment of bitterness evaluation method during the formulation screening process

[0072] First, the bitterness level was divided into 5 levels based on the facial expressions and subjective feelings of the tasters, as shown in Table 5.

[0073] Table 5 Bitterness Grading Score Table

[0074]

[0075] Five concentrations of Chinese herbal extract solutions were prepared using purified water and graded for bitterness as shown in Table 5. A random sample of healthy adult volunteers (>10) was selected for oral evaluation and signed an informed consent form. Before the experiment began, the evaluators rinsed their mouths with purified water to eliminate other oral flavor interference. The sample solution was poured into a 30 mL tasting cup and then poured into the mouth all at once. Do not swallow, but stir with the tongue. The bitterness of each sample was promptly scored. After scoring, the drug solution was spit out and the mouth was rinsed with purified water until the bitterness was almost gone. After waiting for 10 minutes, the taste evaluation of the next sample began. Each sample could be tasted repeatedly during scoring.

[0076] Taste evaluation experiments conducted at different times should include at least one batch of samples from the previous evaluation, with the same score after tasting. This batch of samples should be used as a reference for bitterness scoring of other batches to reduce errors caused by factors such as the physical condition of the reviewers at different times. Each sample should be evaluated for bitterness by three reviewers, and the average value should be taken as the bitterness value of the sample.

[0077] 1.2 Establishment of bitterness evaluation method for the preferred formula

[0078] Referring to “Establishment of a method for rapid elimination of outliers based on Grubbs rule and MATLAB language and its application in drug bitterness evaluation” (China Pharmacy, 2019, 30(2):176-182), berberine hydrochloride solutions of different concentrations were first prepared as bitterness standard solutions, and the bitterness was divided and assigned scores, as shown in Table 6.

[0079] Table 6 Bitterness Grading Table

[0080]

[0081] A random sample of healthy adult volunteers (>10) was selected for oral evaluation and signed informed consent. First, the volunteers were asked to taste standard solutions of varying bitterness and were informed of the corresponding scores. This was followed by bitterness training. Volunteers who were unable to significantly distinguish bitterness during the training were removed.

[0082] The volunteers who passed the test first rinsed their mouths with purified water until the bitterness in their mouths was almost gone, and then began to taste the samples. The drug solution was poured into the tasting cup and poured into the mouth at once. Do not swallow it, but stir it with the tongue. The bitterness of each sample should be scored in time. After scoring, the drug solution should be spit out and the mouth should be rinsed with purified water until the bitterness is almost gone. After waiting for 10 minutes, the taste evaluation of the next sample will begin. The tasting order is random.

[0083] The obtained bitterness value data were firstly subjected to cyclic elimination of outliers using the Grubbs test method with a test level of 0.05. Then, the remaining data were analyzed by independent sample T test using IBM SPSS Statistics software. The mean bitterness values ​​and P values ​​of different samples were compared to determine whether there were significant differences in bitterness between the samples.

[0084] 1.3 Electronic tongue taste evaluation method

[0085] The electronic tongue, also known as a bionic taste sensor, is an artificial taste system designed to mimic the human sense of taste. It features an array of inert metal sensors with different properties, similar to human taste cells. These sensors capture the flavor information of a sample and transmit it to a computer, where it is analyzed using a specific intelligent self-learning and self-identification pattern recognition algorithm. Currently, the electronic tongue is widely used for food flavor evaluation, tea quality grading, beverage and condiment quality assessment, origin identification of Traditional Chinese Medicine, and bitterness evaluation.

[0086] The experiment used ISENSO's Super Tongue electronic tongue to test different types of medicinal powder samples and evaluate the taste differences between them. Principal component analysis (PCA) was used to perform a linear transformation on the raw data vectors, reducing the dimensionality of the data and converting them into a small number of comprehensive indicators. This algorithm maintains no sample information and distinguishes samples by simply changing the coordinate axes, providing a more intuitive way to analyze and differentiate data.

[0087] Example 2: Preparation of Scutellaria baicalensis Extract

[0088] Various raw materials are measured according to the weight ratio of 1500g of Isatis root, 1200g of Scutellaria baicalensis, 1500g of Gardenia jasminoides, 600g of Phellodendron chinense, and 500g of Sterculia lychnophora. The above five ingredients are decocted three times with water, the first time for 2 hours, the second and third times for 1 hour each, the decoctions are combined, filtered, and concentrated under reduced pressure to a relative density of 1.10-1.16 (50°C), ethanol is added to make the alcohol content reach 60%, the mixture is allowed to stand for 12 hours, filtered, the ethanol is recovered under reduced pressure, concentrated and dried, and crushed to obtain the Scutellaria baicalensis extract.

[0089] Example 3: Analysis of bitter components in Scutellaria baicalensis extract

[0090] 1. Test method

[0091] 1.1 Sample preparation

[0092] Take 1 g of Scutellaria baicalensis extract, add 150 mL of purified water, stir to dissolve, filter, transfer 2 mL of the filtrate to a 5 mL volumetric flask, dilute with methanol, and bring to volume. Shake well to obtain Test Sample 1. Taste the remaining filtrate and evaluate its bitterness according to three levels: bitter, slightly bitter, and not bitter.

[0093] Take 1 g of Scutellaria baicalensis extract, add 150 mL of purified water, stir to dissolve, add about 3 g of anion exchange resin (chloride type 717 anion exchange resin), stir for about 10 minutes, filter, transfer 2 mL of the filtrate, place it in a 5 mL volumetric flask, dilute with methanol and make up to the mark, shake well, and obtain test sample 2. The remaining filtrate was tasted and evaluated for bitterness.

[0094] Take 1 g of Scutellaria baicalensis extract, add 150 mL of purified water, stir to dissolve, add about 3 g of cation exchange resin (sodium polystyrene sulfonate), stir for about 10 minutes, filter, and prepare test sample 3 according to the above method, and evaluate its bitterness.

[0095] Take 1 g of Scutellaria baicalensis extract, add 150 mL of purified water, stir to dissolve, add about 3 g of anion exchange resin, stir for about 10 minutes, filter, add about 3 g of cation exchange resin to the filtrate, stir for about 10 minutes, filter, prepare test sample 4 according to the above method, and evaluate its bitterness.

[0096] 1.2 Sample testing

[0097] Take the above-mentioned sample 1, sample 2, sample 3 and sample 4 and test them on a high performance liquid chromatograph as follows: the chromatographic column is MS C18 (4.6*250mm, 5μm), column temperature was 30℃, injection volume was 10μL, wavelength was 230nm, mobile phase was 0.2% phosphoric acid aqueous solution (A) and acetonitrile (B), running time was 70min, gradient elution (0~12min, 95%→89%A; 12~24min, 89%A; 24~38min, 89%→77%A; 38~50min, 77%→72%A; 50~55min, 72%→69%A; 55~70min, 69%→0%A).

[0098] 2. Test results

[0099] Compare the HPLC chromatograms and oral taste results of Sample 1, Sample 2, Sample 3, and Sample 4. Figure 1 The results showed that the bitterness of Scutellaria baicalensis extract mainly comes from the alkaline components adsorbed by cation exchange resin, such as berberine, phellodendronine, and magnolamine. The acidic and neutral components have almost no bitterness. This conclusion provides a reference for the subsequent selection of cyclodextrin types.

[0100] Example 4: Screening of different types of cyclodextrins

[0101] The inclusion effect of cyclodextrins is primarily influenced by the magnitude of intermolecular forces. Therefore, cyclodextrins of different structures exhibit varying inclusion effects on different substrates, necessitating screening of cyclodextrins of varying structures. There are numerous varieties of cyclodextrins and their derivatives, primarily α-cyclodextrin, γ-cyclodextrin, β-cyclodextrin, and β-cyclodextrin derivatives, such as sulfobutyl-β-cyclodextrin, polymerized-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and cationic-β-cyclodextrin.

[0102] 1. Test method

[0103] Based on the crude drug amount of Lanqin oral preparation, 23.2g of Lanqin extract was selected as the optimization basis, and bitterness was evaluated after adding different types of cyclodextrin and its derivatives. The evaluation was carried out according to the method described in Example 1, Section 1.1.

[0104] Weigh 8 portions of Scutellaria baicalensis extract (23.2 g each) and add cyclodextrin and its derivatives according to the formulation in Table 7. Dissolve in purified water, stir for 40 minutes, and spray dry to produce Scutellaria baicalensis extract taste-masking spray-dried powder. Add 300 mL of purified water to each sample, stir to dissolve, continue stirring at room temperature for 2 hours, and then dilute with 900 mL of purified water to obtain test samples F1-F8. The resulting solutions were evaluated for bitterness according to the method described in Section 1.1 of Example 1.

[0105] Table 7 Composition and dosage of Scutellaria baicalensis extract and F1-F8 cyclodextrin

[0106]

[0107] Table 8 Percentage of composition of Scutellaria baicalensis extract and F1-F8 cyclodextrin

[0108]

[0109] 2. Test results

[0110] The results of different formulations and bitterness evaluation are shown in Table 9.

[0111] Table 9 Bitterness evaluation results of Scutellaria baicalensis extract and F1-F8

[0112]

[0113] The results showed that inclusion of α-cyclodextrin, γ-cyclodextrin, and β-cyclodextrin derivatives in the extract of Scutellaria baicalensis reduced its bitterness to varying degrees. Based on the observation that greater taste-masking effectiveness correlates with lower bitterness, the order of taste-masking ability among cyclodextrins and their derivatives was as follows: F1 > F6 > F7 > F4 > F2 > F3 > F5, i.e., sulfobutyl-β-cyclodextrin > α-cyclodextrin > γ-cyclodextrin > cationic-β-cyclodextrin > polymeric-β-cyclodextrin > methyl-β-cyclodextrin > hydroxypropyl-β-cyclodextrin. The similar taste-masking effects of F2, F4, and F7 indicate that polymeric-β-cyclodextrin, cationic-β-cyclodextrin, and γ-cyclodextrin are similar in their taste-masking effectiveness. Similarly, the similar taste-masking effects of F1 and F6 indicate that sulfobutyl-β-cyclodextrin and α-cyclodextrin are similar in their taste-masking effectiveness.

[0114] Different cyclodextrins and their derivatives have different chemical properties of cavity sizes. When the molecular weight and chemical properties of the remaining compounds during the inclusion process do not match those of cyclodextrin, even if the cyclodextrin ratio is increased, the remaining compounds cannot be included. That is, the inclusion effect of cyclodextrin reaches saturation and cannot be further masked.

[0115] F8, composed of sulfobutyl-β-cyclodextrin, cationic-β-cyclodextrin, polymeric-β-cyclodextrin, methyl-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin in a ratio of 1:1:1:1:1, has a bitterness value of 4.7, lower than sulfobutyl-β-cyclodextrin (F1) at the same total cyclodextrin content. The ranking of taste-masking ability reveals that the remaining β-cyclodextrin derivatives have lower taste-masking abilities than sulfobutyl-β-cyclodextrin. However, the combination of the five cyclodextrin derivatives in a specific ratio exhibits superior taste-masking effects compared to sulfobutyl-β-cyclodextrin alone, yielding an unexpected benefit. As mentioned above, sulfobutyl-β-cyclodextrin exhibits excellent taste-masking properties. If the inclusion of bitter substances by this cyclodextrin derivative reaches saturation at a 4.0g addition, 4.0g of sulfobutyl-β-cyclodextrin would have the same taste-masking effect as 20.0g, thus failing to demonstrate synergistic effects when the dosage is reduced. At a dosage of 4.0g, the inclusion rate of sulfobutyl-β-cyclodextrin had not yet reached saturation. The five cyclodextrins described above achieved enhanced taste-masking effectiveness while reducing the cyclodextrin dosage, a result achieved through synergistic synergy. Therefore, further verification of sulfobutyl-β-cyclodextrin inclusion efficiency was conducted, with the goal of exploring more optimized traditional Chinese medicine taste-masking compositions.

[0116] Example 5: Optimization of the Taste-Masking Formula of Lanqin Oral Liquid 1

[0117] Compared to other cyclodextrins, sulfobutyl-β-cyclodextrin has a better bitterness-reducing effect on this product, and its combination with sulfobutyl-β-cyclodextrin demonstrates even greater bitterness-reducing efficacy than either cyclodextrin alone. Therefore, the present invention optimized a taste-masking combination formulation using sulfobutyl-β-cyclodextrin as the primary ingredient. Evaluation was conducted using the method described in Example 1, Section 1.1.

[0118] 1. Test method

[0119] According to the preparation method of Example 4, cyclodextrin and its derivatives were added according to the formulations in Table 10 to prepare test samples F9-F11, and then bitterness was evaluated.

[0120] Table 10F9-F11 cyclodextrin formula and dosage

[0121]

[0122] Table 11F9-F11 cyclodextrin formula and dosage percentage

[0123]

[0124] 2. Test results

[0125] The bitterness evaluation results are shown in Table 12.

[0126] Table 12 Bitterness evaluation results of F9-F11

[0127]

[0128] To confirm whether the inclusion effect of sulfobutyl-β-cyclodextrin reaches saturation at a dosage of 4g, this example increases the amount of sulfobutyl-β-cyclodextrin on the basis of F8, and oral bitterness evaluation is performed. The bitterness value results show that the average bitterness value of F9 is 3.5, which is lower than the bitterness value of 4.7 corresponding to F8. This shows that the inclusion effect of sulfobutyl-β-cyclodextrin does not reach saturation at a dosage of 4g. Therefore, the traditional Chinese medicine taste-masking composition obtained by combining sulfobutyl-β-cyclodextrin, cationic-β-cyclodextrin, polymerized-β-cyclodextrin, methyl-β-cyclodextrin, and hydroxypropyl-β-cyclodextrin in F8 in a ratio of 1:1:1:1:1 has a synergistic effect and can better achieve the taste masking of the blue scutellaria extract.

[0129] This embodiment also fixes the content of sulfobutyl-β-cyclodextrin, further adjusts the other cyclodextrin components and proportions, and obtains F10 and F11. Among them, F10 increases the content of hydroxypropyl-β-cyclodextrin to 20g, and removes cationic-β-cyclodextrin at the same time, and the resulting bitterness value is 3.1. Combined with the taste masking results of Example 4, it can be concluded that increasing the content of a large amount of cyclodextrin with low taste masking ability can replace a small amount of cyclodextrin with high taste masking ability. In actual production, companies can reduce production costs by increasing a large amount of low-priced cyclodextrin with poor taste masking ability to replace high-priced cyclodextrin with good taste masking ability.

[0130] F11, based on F10, removes polymerized β-cyclodextrin and methyl β-cyclodextrin, while reducing the amount of hydroxypropyl β-cyclodextrin to 3 / 5 of the original, achieving an average bitterness value of 3.7. The bitterness value achieved by F11 is similar to that of F10, but the cyclodextrin content is reduced by 40%, significantly reducing production costs.

[0131] Compared with F9, F11 removed 3 times the amount of polymerized-β-cyclodextrin, methyl-β-cyclodextrin, and cationic-β-cyclodextrin, while increasing 2 times the amount of hydroxypropyl-β-cyclodextrin. On the one hand, in conjunction with the taste-masking results of Example 4, it can be concluded that the taste-masking effect of hydroxypropyl-β-cyclodextrin is lower than that of polymerized-β-cyclodextrin, methyl-β-cyclodextrin, and cationic-β-cyclodextrin. The increased amount of hydroxypropyl-β-cyclodextrin should not replace the type and content of the cyclodextrin removed to achieve the same taste-masking effect. On the other hand, the formula and bitterness value results of F10 show that hydroxypropyl-β-cyclodextrin can still further mask the taste even after increasing it by 4 times. It can be seen that hydroxypropyl-β-cyclodextrin does not reach the saturated state of inclusion complexation under the dosage of F11. According to the above theory, the bitterness value corresponding to the cyclodextrin type and content of F11 should be significantly higher than that of F9. However, the test results show that the taste-masking effects of F9 and F11 are similar, producing unexpected results. Sulfobutyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin in a ratio of 1:1 can achieve a synergistic taste-masking effect, reduce the amount of cyclodextrin used, reduce production costs, and effectively reduce the bitterness value of Lanqin oral liquid.

[0132] Example 6: Optimization of the Taste-Masking Formula of Lanqin Oral Liquid 2

[0133] To further enhance the taste-masking effect, a composition based on sulfobutyl-β-cyclodextrin and α-cyclodextrin, both of which have strong taste-masking abilities, was supplemented with other less expensive cyclodextrins. This resulted in a composition with a lower dosage, lower production costs, and improved taste-masking effectiveness. Evaluation was conducted using the method described in 1.1 of Example 1.

[0134] 1. Test method

[0135] According to the preparation method of Example 4, cyclodextrin and its derivatives were added according to the formulations in Table 13 to prepare test samples F12-F16, and then bitterness was evaluated.

[0136] Table 13F12-F16 cyclodextrin formula and dosage

[0137]

[0138] Table 14F12-F16 cyclodextrin formula and dosage percentage

[0139]

[0140] 2. Test results

[0141] The bitterness evaluation results are shown in Table 15.

[0142] Table 15 Bitterness evaluation results of F12-F16

[0143]

[0144] When using either polymerized β-cyclodextrin or hydroxypropyl β-cyclodextrin alone to mask the taste of Scutellaria baicalensis extract, formulations F15 and F16 required 60g and 64g, respectively, to achieve a bitterness value of 2.5-2.6. However, formulations F12-F14 achieved the same bitterness value with a total cyclodextrin content of 32-44g, a reduction of approximately 30% compared to using cyclodextrin alone. Furthermore, based on the experimental results of Example 5, a cyclodextrin content of 40g in F10 resulted in a bitterness value of 3.1. Compared to the cyclodextrin composition F10, formulations F12-F14 reduced the total cyclodextrin content by up to 20% and the bitterness value by up to 23%. This suggests that a taste-masking composition composed of sulfobutyl β-cyclodextrin, α-cyclodextrin, methyl β-cyclodextrin, and hydroxypropyl β-cyclodextrin in a specific ratio of 3:(1-2):3:(1-3) can achieve better taste masking while reducing the total cyclodextrin content.

[0145] Further analysis revealed that F13, using sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and α-cyclodextrin in a ratio of 3:1:3:1, with a total cyclodextrin content of 32g, achieved a bitterness value of 2.4. Compared to F12 and F14, which reduced the amount of α-cyclodextrin and methyl-β-cyclodextrin, the bitterness values ​​remained the same or similar. The taste-masking results for F12 and F14 also showed that increasing the amount of methyl-β-cyclodextrin and α-cyclodextrin further reduced the bitterness values, indicating that saturation of these cyclodextrins was not yet achieved. This suggests that a 3:1:3:1 ratio of sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and α-cyclodextrin can achieve synergistic taste masking.

[0146] Example 7: Preparation of Taste-Masked Lanqin Granules

[0147] Measure various raw materials according to the weight ratio of 1500g of Isatis Root, 1200g of Scutellaria, 1500g of Gardenia, 600g of Phellodendron, and 500g of Sterculia. Add water and boil three times for the first time for 2 hours, and for the second and third times for 1 hour each. Combine the decoctions, filter, and concentrate under reduced pressure to a relative density of 1.10-1.16 (50°C). Add ethanol to make the alcohol content reach 60%, let it stand for 12 hours, filter, recover the ethanol under reduced pressure and concentrate to a relative density. To the clear paste with a temperature of 1.10-1.18 (50°C), add cyclodextrin, citric acid and sodium citrate according to the amounts in Table 16, add appropriate amount of purified water to dissolve, stir for 40 minutes, and spray dry to obtain the taste-masking spray-dried powder of Lanqin extract. Add auxiliary materials magnesium stearate and aspartame according to the amounts in Table 16 to the spray-dried powder and supplement with dextrin to the total weight. Mix well and perform dry granulation. After granulation and sieving, Lanqin granules F17-F21 are obtained.

[0148] Table 16 Composition of excipients for taste-masking Lanqin granules F17-F21

[0149]

[0150] Baicalin, the active ingredient in Lanqin extract, degrades under alkaline conditions, necessitating adjustment of the solution's pH. Furthermore, sodium citrate improves mouthfeel and suppresses bitterness. Therefore, the above formulations, based on the preferred formulations F11 and F13, were supplemented with a certain amount of citric acid and sodium citrate. To evaluate the impact of sweeteners on the product, formulations F17, F18, and F21 were all free of sweeteners and served as controls for subsequent oral evaluation experiments. F21 served as a control group for commercially available Lanqin granules without sweeteners.

[0151] Example 8: Evaluation of the Preferred Formula of Taste-Masked Lanqin Granules

[0152] Using the bitterness evaluation method for the optimized formula in Example 1, we evaluated the taste of Lanqin Granules F17-F21 and commercially available Lanqin Granules (manufactured by Zhejiang Kangenbei Co., Ltd., batch number 211104). We also increased the number of evaluators to assess whether there was a significant difference in bitterness between the optimized formula and the commercially available Lanqin Granules.

[0153] 1. Test method

[0154] Lanqin granules with the same crude drug dosage were used as the evaluation subjects. According to Table 17, Lanqin granules of different formulations were weighed and added to 600 mL of warm water at 50°C. Stirring was performed until the granules dissolved. Samples were then evaluated for taste using the ranking and scoring method described in Example 1, with berberine hydrochloride as the control sample. Bitterness values ​​ranged from 0 to 5.5. The pH value was also measured.

[0155] Table 17 Taste evaluation sample preparation

[0156]

[0157] 2. Test results

[0158] The test results are shown in Table 18.

[0159] Table 18 Evaluation results of bitterness of Lanqin granules

[0160]

[0161] Note: F test P>0.05 indicates that the variance is homogeneous and T test can be performed; T test P<0.05 indicates that there is a statistically significant difference between the two groups of data.

[0162] The bitterness value of F21 (commercially available Lanqin granules without sweetener) was 2.84, and the bitterness value of commercially available Lanqin granules was 2.50, both of which were within the acceptable bitterness range (2.5-3.5). The bitterness value of Lanqin granules (F17), prepared using a taste-masking composition of sulfobutyl-β-cyclodextrin: hydroxypropyl-β-cyclodextrin: sodium citrate in a ratio of 1:1:1, was 2.05, which was within the slightly bitter range (1.5-2.5). The bitterness value of F17 was reduced by 18% compared to commercially available Lanqin granules and by 28% compared to F21 (T test P < 0.05), and the taste-masking effect was significantly improved.

[0163] Lanqin Granules F18 uses a taste-masking composition of sulfobutyl-β-cyclodextrin: methyl-β-cyclodextrin: hydroxypropyl-β-cyclodextrin: α-cyclodextrin: sodium citrate in a ratio of 3:1:3:1:3, with a small amount of citric acid added. Its bitterness value is 1.49, which falls within the almost no bitterness range (0.5-1.5). F18's bitterness value is 27% lower than F17 and 48% lower than F21, respectively, demonstrating a significant improvement in taste-masking effectiveness (T-test P ≤ 0.05).

[0164] This indicates that the taste-masking compositions corresponding to Lanqin Granules 17 and 18 more effectively encapsulate bitter components such as berberine, phellodendrine, and magnololamine in Lanqin extracts compared to the prior art method using only β-cyclodextrin. The addition of methyl-β-cyclodextrin and α-cyclodextrin to Lanqin Granule F18 further enhances the inclusion of bitter components, resulting in a lower bitterness value for F18 than for Lanqin Granule F17. The bitterness evaluation results using berberine hydrochloride as a control are consistent with the bitterness evaluation results using the Lanqin extract itself as a control in Examples 5-6.

[0165] Lanqin Granules F19 and F20 were prepared by adding sweetener to Lanqin Granules F17 and F18, respectively, with corresponding bitterness values ​​of 1.82 and 1.57. Compared with commercially available Lanqin Granules, the bitterness values ​​were reduced by 27% and 37%, respectively, and the taste masking effect was significantly improved (T-test P < 0.05). Furthermore, the addition of sweeteners can improve the taste to a certain extent, improving palatability.

[0166] Example 9: Electronic tongue evaluation

[0167] 1. Test method

[0168] The experiment used ISENSO's Super Tongue electronic tongue to measure the samples. Before the sample test, the sensor was preheated, cleaned and the parameters were set (maximum voltage 1V, minimum voltage -1V, pulse interval 100MV, sensitivity 10 -4), with each sample measured in parallel four times. Commercially available Lanqin Granules, Lanqin Granule F19, Lanqin Granule F20, a commercially available Lanqin Granule blank excipient, a Lanqin Granule F19 blank excipient, and a Lanqin Granule F20 blank excipient were prepared according to the method described in Example 8. A sample solution containing the same concentration of Lanqin extract, untreated or taste-corrected, was also prepared as a bitterness control. Principal Component Analysis (PCA) was used on the data obtained to illustrate the differences in bitterness between the different samples.

[0169] 2. Test results

[0170] The PCA analysis results of the electronic tongue data of the above sample particles and the corresponding blank excipient samples are shown in Figure 2 .

[0171] In the three-dimensional PCA plot, principal component 1 + principal component 2 + principal component 3 = 97% > 75%, indicating that this result accurately reflects the actual characteristics of the samples. Principal component 1's relative contribution is 80.8%, indicating that distance along the X-axis (principal component 1) is the most important factor in distinguishing samples and can represent the flavor characteristics of the samples. Therefore, the X-axis distances between different samples were calculated, and the results are shown in Table 19. The greater the relative distance between samples, the greater the difference in flavor.

[0172] The three-dimensional PCA plot and Table 19 show that the flavors of commercially available Lanqin Granules, Lanqin Granule F19, and Lanqin Granule F20 all exhibited significant changes compared to the Lanqin extract. The significant difference in flavor between the commercially available Lanqin Granules and the blank excipient suggests that the change in flavor of the commercially available Lanqin Granules is not due to the inclusion of bitter substances in β-cyclodextrin, resulting in a flavor similar to that of the blank excipient, but rather to flavor modification that alters the flavor of the Lanqin Granules. The relative distance between Lanqin Granules F19 and F20 is small, indicating similar flavors; they also exhibit a similar flavor to the corresponding blank excipient, indicating that the inclusion of cyclodextrin in the Lanqin extract results in taste masking.

[0173] In addition, the taste of Lanqin Granules F19 and F20 is similar, and is close to the taste of the corresponding excipients, that is, it has a non-bitter taste, indicating that Lanqin Granules F19 and F20 have better bitterness inhibition effect than commercially available Lanqin Granules.

[0174] Table 19 Distances between different samples in PCA analysis

[0175]

[0176] Example 11: Solution pH Optimization

[0177] Based on the bitterness evaluation results of Examples 8 and 9, Lanqin Granules F17-F18 have a good taste masking effect. The active ingredients in Lanqin oral preparations are complex, and the effect of pH on the components of Lanqin extract was explored to optimize the dosage of pH regulator in the formulation.

[0178] 1. Test content

[0179] Dissolve 0.3g of Lanqin extract and Lanqin granules F17-F18 in 70% methanol-water solution, transfer to a 50mL volumetric flask, dilute to the mark with 70% methanol-water solution, and shake well to obtain the test solution. Simultaneously adjust the pH to 1.2, 6.0, 9.0, and 11.0 to determine changes in the active ingredient. Perform liquid phase analysis according to the sample detection method described in Example 3.

[0180] 2. Test results

[0181] Table 20 pH value test results corresponding to the samples

[0182]

[0183] The test results are as follows Figure 3 As shown. There were no significant differences in the active ingredients of Lanqin extract, Lanqin Granule F17, and Lanqin Granule F18 at pH 1.2 and 6.0; however, significant changes occurred when the pH was adjusted to 9.0 and 11.0. Specifically, the main component of Lanqin extract, baicalin, degraded under alkaline conditions, while the extract was relatively stable under acidic conditions. The aqueous solutions of Lanqin Granules F17 and F18 had a pH of 4.6. Citric acid and its salts were used in combination to form a buffer with a pH below 6.0 to enhance product stability.

[0184] Example 12: Hygroscopicity Study

[0185] The extract of Scutellaria baicalensis is extracted by water extraction and alcohol precipitation, which has strong hygroscopicity. Therefore, the hygroscopicity of different samples was investigated.

[0186] 1. Test method

[0187] Weigh appropriate amounts of the extract spray-dried powder, Lanqin Granule F19, Lanqin Granule F19 formula physical mixed powder, Lanqin Granule F20, and Lanqin Granule F20 formula physical mixed powder as the test samples. Weigh empty petri dishes (Mp). Spread the test samples evenly onto the petri dishes, maintaining a similar thickness between samples. Place the samples in a 60°C vacuum drying oven and dry to constant weight. Record the sample weight (M0). Place the samples at 25°C and 60% relative humidity and weigh them at 3, 6, 15, and 25 hours. Record the weight (Mt). Calculate the moisture absorption rate at different times using the formula (Mt-M0) / (M0-Mp)×100%, and plot a dilution curve.

[0188] Scanning electron microscopy (SEM) was used to study the changes in the surface morphology of the extract after complexation with blank excipients.

[0189] 2. Test results

[0190] The test results are as follows Figure 4 and Figure 5 shown.

[0191] The hygroscopicity of the physically mixed powder of Lanqin Granules F19 was comparable to that of the spray-dried powder of Lanqin extract, indicating that the physical mixing of the excipients and the extract had almost no effect on the hygroscopicity of the extract; whereas the hygroscopicity of Lanqin Granules F19 was significantly reduced, indicating that the inclusion complexation of Lanqin Granules F19 could effectively reduce the hygroscopicity of the granules and make the product more stable.

[0192] The hygroscopic capacity of the physically mixed powder of Lanqin Granule F20 was higher than that of the Lanqin extract. This may be because the physical mixing of excipients not only did not improve the hygroscopicity of the extract, but instead increased the contact surface and accelerated the hygroscopic rate. The hygroscopic rate of Lanqin Granule F20 was significantly reduced.

[0193] Scanning electron microscopy (SEM) was used to study the changes in the surface morphology of the extract after complexation with the blank excipient. Figure 6 shown.

[0194] The extract of this product is a spray-dried powder, and therefore was observed to have irregular spherical and amorphous shapes. The extract alone, in addition to its spherical structure, also contained a considerable number of clinging round particles. As a traditional Chinese medicine extract, this product has significant hygroscopic properties, so it is speculated that this is likely due to the melting and clinging of some of the spray-dried spheres. In contrast, a physical mixture of the blank excipient and the extract showed a coexistence of spherical and granular shapes. Lanqin Granules F19 and F20, due to the inclusion of their components in cyclodextrin, formed spherical particles of varying sizes. Combined with the results of the hygroscopic tests, the formation of the inclusion complex altered the hygroscopic properties of the original extract.

[0195] The above results demonstrate that Lanqin Granules F19 and Lanqin Granules F20 not only have a significant bitterness-inhibiting effect, but also can improve the hygroscopicity of the extract powder.

[0196] Example 13: Stability Test

[0197] The same amount of crude drug Lanqin granules was used as the evaluation object. 0.3g of commercially available Lanqin granules, 0.5g of Lanqin granules F19 and 0.6g of Lanqin granules F20 were weighed and placed in high temperature (60℃) and high humidity (25℃, 75%RH) light (visible light 5000Lux, near ultraviolet 100μw / cm 2) conditions, and allowed to stand for 5 and 10 days, then dissolved and transferred to a 50 mL volumetric flask, diluted to the mark with a 70% methanol solution, and shaken to obtain the test solution. The fingerprint was determined according to the sample detection method described in Example 3, and the fingerprints of each sample at 0 days, 5 days, and 10 days were evaluated for similarity using the Traditional Chinese Medicine Chromatographic Fingerprint Similarity Evaluation System to evaluate the stability of the sample.

[0198] Table 21 Comparison of stability of Lanqin granules

[0199]

[0200] From the results, it can be seen that the stability of the prescription after taste masking is almost the same as that of the commercially available Lanqin granules, and it is very stable under high temperature, high humidity and light conditions.

Claims

1. An oral preparation of Radix Scutellariae containing a traditional Chinese medicine taste-masking composition, characterized in that: The oral preparation of Lanqin contains a Lanqin extract and a traditional Chinese medicine taste-masking composition, wherein the traditional Chinese medicine taste-masking composition contains sulfobutyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and the mass ratio of the sulfobutyl-β-cyclodextrin to the hydroxypropyl-β-cyclodextrin is 1:1; the mass ratio of the Lanqin extract to the traditional Chinese medicine taste-masking composition is (34-54): (46-66), and the dosage form of the oral preparation of Lanqin includes granules or oral liquid.

2. The oral preparation of Lanqin according to claim 1, characterized in that The components of the traditional Chinese medicine taste-masking composition are sulfobutyl-β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and the mass ratio of the blue scutellaria extract to the traditional Chinese medicine taste-masking composition is 1:

1.

3. An oral preparation of Radix Scutellariae containing a traditional Chinese medicine taste-masking composition, characterized in that: The oral preparation of Lanqin contains a Lanqin extract and a traditional Chinese medicine taste-masking composition, wherein the traditional Chinese medicine taste-masking composition contains sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin and α-cyclodextrin, and the mass ratio of the sulfobutyl-β-cyclodextrin:methyl-β-cyclodextrin:hydroxypropyl-β-cyclodextrin:α-cyclodextrin is 3:(1-2):3:(1-3); the mass ratio of the Lanqin extract:the traditional Chinese medicine taste-masking composition is (34-54):(46-66), and the dosage form of the oral preparation of Lanqin includes granules or oral liquid.

4. The Lanqin oral preparation according to claim 3, characterized in that The mass ratio of the sulfobutyl-β-cyclodextrin:methyl-β-cyclodextrin:hydroxypropyl-β-cyclodextrin:α-cyclodextrin is 3:1:3:

1.

5. The Lanqin oral preparation according to claim 3 or 4, characterized in that The components of the traditional Chinese medicine taste-masking composition are sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and α-cyclodextrin, and the mass ratio of the blue scutellaria extract to the traditional Chinese medicine taste-masking composition is (34-42): (58-66).

6. The Lanqin oral preparation according to claim 5, characterized in that The mass ratio of the blue scutellaria extract to the traditional Chinese medicine taste-masking composition is 42:

58.

7. An oral preparation of Radix Scutellariae containing a traditional Chinese medicine taste-masking composition, characterized in that: The oral preparation of Lanqin comprises a Lanqin extract and a traditional Chinese medicine taste-masking composition, wherein the traditional Chinese medicine taste-masking composition comprises sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, polymeric-β-cyclodextrin, cationic-β-cyclodextrin and methyl-β-cyclodextrin, wherein the mass ratio of sulfobutyl-β-cyclodextrin:polymeric-β-cyclodextrin:methyl-β-cyclodextrin:cationic-β-cyclodextrin:hydroxypropyl-β-cyclodextrin is 1:1:1:1:1; the mass ratio of the Lanqin extract:the traditional Chinese medicine taste-masking composition is (34-54):(46-66), and the dosage form of the oral preparation of Lanqin comprises granules or oral liquid.

8. The Lanqin oral preparation according to claim 7, characterized in that The components of the traditional Chinese medicine taste-masking composition are sulfobutyl-β-cyclodextrin, polymerized-β-cyclodextrin, methyl-β-cyclodextrin, cationic-β-cyclodextrin and hydroxypropyl-β-cyclodextrin, and the mass ratio of the blue scutellaria extract to the traditional Chinese medicine taste-masking composition is 54:

46.

9. The Lanqin oral preparation according to any one of claims 1, 3 to 4, and 7, characterized in that The Lanqin oral preparation is Lanqin granules.

10. The Lanqin oral preparation according to claim 9, characterized in that The Lanqin granules further contain citric acid and its salt, and the mass ratio of the sulfobutyl-β-cyclodextrin to the citrate is 1:

1.

11. A method for preparing the Lanqin oral preparation according to any one of claims 1, 3 to 4, and 7, characterized in that: The preparation method comprises the following steps: (1) Preparation of Blue Scutellaria baicalensis extract: 150 parts of Radix Isatidis, 120 parts of Radix Scutellariae, 150 parts of Gardeniae, 60 parts of Cortex Phellodendri, and 50 parts of Sterculia lychnophora were taken and decocted three times with water, the first time for 2 hours, the second and third times for 1 hour each, the decoctions were combined, filtered, and concentrated under reduced pressure to a relative density of 1.10-1.16 at 50°C. Ethanol was added to make the alcohol content reach 60%, and the mixture was allowed to stand for 12 hours. The mixture was filtered, and the ethanol was recovered under reduced pressure and concentrated to obtain a Blue Scutellaria baicalensis extract paste with a relative density of 1.10-1.18 at 50°C. The Blue Scutellaria baicalensis extract was dried; (2) Addition of the Chinese herbal taste-masking composition: Add the Chinese herbal taste-masking composition to the blue scutellaria extract, add an appropriate amount of purified water to dissolve, stir evenly, and spray-dry to obtain the blue scutellaria extract taste-masking spray-dried powder; (3) Prepare into different dosage forms: Add the taste-masking spray-dried powder of the blue scutellaria extract to the preparation excipients to prepare blue scutellaria baicalensis granules or blue scutellaria baicalensis oral solution.

12. A method for preparing the Lanqin oral preparation according to claim 9, characterized in that: The preparation method comprises the following steps: (1) Preparation of a paste of blue scutellaria extract: 150 parts of Radix Isatidis, 120 parts of Radix Scutellariae, 150 parts of Fructus Gardeniae, 60 parts of Cortex Phellodendri, and 50 parts of Sterculia lychnophora were taken and decocted three times with water, the first time for 2 hours, the second and third times for 1 hour each, the decoctions were combined, filtered, and concentrated under reduced pressure to a relative density of 1.10-1.16 at 50°C. Ethanol was added to make the alcohol content reach 60%, and the mixture was allowed to stand for 12 hours. The mixture was filtered, the ethanol was recovered under reduced pressure and concentrated to obtain a blue scutellaria extract paste with a relative density of 1.10-1.18 at 50°C. (2) Addition of the Chinese herbal taste-masking composition: Add the Chinese herbal taste-masking composition to the clear paste, add an appropriate amount of purified water to dissolve, stir evenly, adjust the pH to no more than 6.0, and spray dry to obtain the blue scutellaria extract taste-masking spray-dried powder; (3) Take the flavor-masking spray-dried powder of the blue qin extract and mix it with a lubricant, a filler and a sweetener, and dry granulate it to obtain the blue qin granules.

13. The preparation method according to claim 12, characterized in that The Chinese medicine taste-masking composition, citric acid and its salt are added to the clear paste of step (2), and an appropriate amount of purified water is added to dissolve, stirred evenly, and spray-dried to obtain the taste-masking spray-dried powder of the blue scutellaria extract.

14. The preparation method according to any one of claims 12 to 13, characterized in that The mass ratio of sulfobutyl-β-cyclodextrin to Radix Isatidis in the traditional Chinese medicine taste-masking composition of step (2) is 1:

4.

15. The preparation method according to any one of claims 12 to 13, characterized in that The lubricant is selected from one or more of magnesium stearate, talc, polyethylene glycol, and hydrogenated vegetable oil; the filler is selected from one or more of dextrin, microcrystalline cellulose, starch, lactose, and mannitol.

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