Preparation process of Xiangtaoqingyou granules

Abstract

The present application belongs to the technical field of traditional Chinese medicine preparation, and particularly relates to a preparation process of Xiangtao Qingyou granules. Five-finger fig and clove are uniformly mixed, heated, reflux extracted, concentrated to form extract liquid, and then granulated together with any two of lactose, corn starch and beta-cyclodextrin. When the auxiliary materials are lactose-cyclodextrin (2:1) combination, the extract-mixed auxiliary materials are granulated in (1:4.8) or (1:4) combination, brown yellow uniform granules can be obtained, which can be completely dissolved in hot water within 5 min, the rest angle is 21.34° and 21.76° respectively, the forming rate is 98.13% and 98.33% respectively, and the moisture absorption rate within 24 h is 0.749% and 0.754% respectively. It is shown that the preparation process of the present application can obtain Xiangtao Qingyou granules with appearance and solubility meeting the requirements of pharmacopoeia, good fluidity, high forming rate and not easy to absorb moisture by using the above two combinations, and the preparation method is stable and feasible.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine preparation production technology, specifically relating to a preparation process of Xiangtao Qingyou granules. Background Technology

[0002] As a microaerophilic Gram-negative bacterium, Helicobacter pylori lives in various regions of the stomach or duodenum and is closely related to a variety of intragastric and extragastric diseases, such as peptic ulcers, gastritis, gastric mucosal lesions, and gastric cancer. Previous treatment for Helicobacter pylori primarily involved triple therapy, namely "two antibiotics + PPI". The antibiotics were mainly selected from clarithromycin, azithromycin, metronidazole, amoxicillin, and levofloxacin. Omeprazole was the first-line PPI, with lansoprazole, pantoprazole, esomeprazole, and rabeprazole as alternatives. Adding gastric mucosal protectants such as magnesium aluminum carbonate and bismuth potassium citrate could develop into quadruple therapy. However, excessive use of antibiotics can easily lead to increased bacterial resistance, thus preventing the eradication rate from reaching the expected level. At the same time, quadruple therapy still has many shortcomings, such as complex medication, high administration costs, and low compliance. Therefore, modified dual therapy has begun to receive renewed attention, with the combination of high-dose amoxicillin and the novel acid suppressant P-CAB showing high efficacy and safety.

[0003] Traditional Chinese medicine (TCM) treatment for Helicobacter pylori (H. pylori) has advantages such as low drug resistance, minimal toxicity and side effects, and low likelihood of inducing bacterial mutations. To date, various Chinese herbal medicines have been proven to inhibit or kill H. pylori. From the perspective of TCM theory, H. pylori infection falls under the category of "pathogenic factors." This can lead to pathological changes in the body such as qi stagnation, heat accumulation, and blood stasis, manifesting as various syndromes such as spleen deficiency with damp-heat, spleen and stomach deficiency with cold, and mixed cold and heat. Therefore, TCM treatment should be based on the principle of "strengthening the body's resistance and eliminating pathogenic factors," employing strategies of invigorating the spleen and stomach, replenishing qi and blood, and clearing heat and drying dampness at different stages after H. pylori infection (initial infection, recurrent infection, and eradication stage). There are cases where TCM decoctions and powders used in treatment have been shown to have synergistic effects with triple and quadruple therapies, significantly reducing the recurrence rate of H. pylori and improving the eradication rate. Meanwhile, compared to traditional decoction pieces, granules of traditional Chinese medicine offer advantages such as convenience in carrying and taking, controllable quality, and accurate dosage. They also eliminate the cumbersome steps involved in decoction, which require numerous precautions, making them more suitable for modern lifestyles. Therefore, exploring the preparation process of traditional Chinese medicine preparations with anti-Hyperisk potential is of great significance. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, this invention proposes a preparation process for Xiangtao Qingyou granules. The resulting granules meet the pharmacopoeia requirements in terms of appearance and solubility, have good flowability, high forming rate, and are not easily hygroscopic. The preparation method is stable and feasible.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] This invention provides a preparation process for fragrant peach granules, specifically: after mixing five-finger peach and clove, add 10-20 times the amount of water, heat and reflux at 90-110℃ for 1-3 hours to extract, and then concentrate to prepare an extract, which is then made into granules together with excipients. The excipients are selected from any two of lactose, corn starch, and β-cyclodextrin.

[0007] Traditional Chinese medicine (TCM) formulas based on the principle of "medicine and food sharing the same origin" have become an important strategy for treating Helicobacter pylori. Compared with traditional Chinese medicine decoction pieces, TCM granules eliminate the cumbersome steps of decocting and boiling, and do not suffer from the problem of decreased efficacy due to quality degradation during production, storage, and transportation. This makes medication more convenient and faster for patients, and to some extent, it can replace the use of decoction pieces. Therefore, this study investigated the experimental conditions for mixing three different excipients—lactose, β-cyclodextrin, and corn starch—in pairs at the same ratio, and for mixing β-cyclodextrin and lactose in different ratios. The drug loading of the latter was optimized, and comparative experiments were conducted on excipients from different manufacturers. Finally, the prototype of the final product was determined. This product has a brownish-yellow appearance, uniform color and particle size, a sweet aroma, and exhibits no moisture absorption, softening, clumping, or deliquescence. It has good solubility, flowability, and molding rate, and is not easily hygroscopic. Gallic acid, a marker component of clove, and psoralen, a marker component of five-finger peach, were successfully detected by HPLC gradient elution.

[0008] Preferably, the mass ratio of the five-finger peach and clove is 6:1.

[0009] Clove, a traditional Chinese medicine, is the dried flower bud of *Eugenia caryophllata* Thunb., a plant in the Myrtaceae family. It contains various chemical substances, including volatile oils, flavonoids, steroids, triterpenoids, and tannins, and exhibits significant in vitro anti-H. pylori effects. The main active ingredient is eugenol from the volatile oil. Its water extract, hydro-alcohol extract, and alcohol extract all demonstrate in vitro antibacterial effects, with a minimum inhibitory concentration (MIC) between 160-320 μg / ml. The main mechanism involves altering the morphology and ultrastructure of *H. pylori*, downregulating the expression of its virulence genes, and thus affecting the tricarboxylic acid cycle and pyruvate metabolism pathway.

[0010] Five-finger fig (Ficus hirta Vahl) is the dried root of the Ficus hirta Vahl plant, a member of the Moraceae family, named for its five-finger-shaped leaves. It contains coumarins, amino acids, volatile oils, sugars, and steroidal components. Five-finger fig has been shown to improve the decreased expression of tight junction protein, adhesion junction protein, and transcription factor SOX2 in the gastric mucosa of indomethacin-induced rat models, thus it can be used to prevent and treat gastric mucosal damage, thereby playing an auxiliary role in combating Helicobacter pylori infection.

[0011] Preferably, the excipients are selected from a combination of lactose and cyclodextrin, and the mass ratio of the extract to the excipients is 1:4.8 or 1:4.

[0012] Preferably, the excipients are selected from those produced by Solarbio.

[0013] Preferably, the excipients also include the flavoring agent steviol glycosides.

[0014] Preferably, the amount of the flavoring agent steviol glycoside added to the granules does not exceed 0.1666 g / kg. -1 .

[0015] Preferably, the size of the granules is 10-80 mesh.

[0016] Preferably, the concentration standard of the extract is: 1.04-1.07g per 1000ul of liquid.

[0017] Preferably, after mixing the five-finger peach and cloves, add 10 times the amount of water, heat and reflux at 100°C for 1 hour, and then concentrate to prepare an extract.

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

[0019] This invention discloses a preparation process for fragrant peach granules. Five-finger peach and clove are mixed, heated under reflux for extraction, and concentrated to obtain an extract. This extract is then combined with any two excipients selected from lactose, corn starch, and β-cyclodextrin to form granules. When the excipients are a lactose-cyclodextrin (2:1) combination, and the extract-mixed excipients are granulated in a (1:4.8) or (1:4) ratio, uniform brownish-yellow granules are obtained. These granules are completely soluble in hot water within 5 minutes, with repose angles of 21.34° and 21.76°, respectively. The forming rates are 98.13% and 98.33%, respectively, and the moisture absorption rates within 24 hours are 0.749% and 0.754%, respectively. Gallic acid and psoralen are detected in the final product after adding the flavoring agent steviol glycosides using HPLC. This demonstrates that the preparation process of the present invention can yield peach-flavored granules with appearance and solubility meeting pharmacopoeia requirements, good flowability, high molding rate, and low moisture absorption using both of the above formulations, and the preparation method is stable and feasible. Attached Figure Description

[0020] Figure 1 This is a mixed standard HPLC chromatogram;

[0021] Figure 2 The HPLC chromatogram is for a sample with a mass ratio of extract to excipients of 1:4.8.

[0022] Figure 3 The image shows the HPLC chromatogram of a sample with a mass ratio of extract to excipients of 1:4. Detailed Implementation

[0023] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0024] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0025] (I) Preparation and quality inspection of Peach Delight Granules

[0026] 1. Medicinal materials and reagents

[0027] Five-finger peach (ordered from Qingyuan Municipal Hospital of Traditional Chinese Medicine); clove (Sichuan Qianfang Pharmaceutical Co., Ltd., batch number 202106068); α-lactose monohydrate (Macklin, HPLC grade, ≥99.5%); β-cyclodextrin (Macklin, 98%); corn starch (Macklin, reagent grade); lactose (Solarbio); β-cyclodextrin (Solarbio); ammonium sulfate (produced by Xilong Scientific Co., Ltd., AR); methanol (produced by SIMARK, HPLC grade); acetonitrile (produced by SIMARK, HPLC grade); phosphoric acid (Tianjin Zhiyuan Chemical Reagent Co., Ltd., AR); double-distilled water (prepared by an integrated ultrapure water and pure water system); psoralen standard (produced by PSoralen, batch number PS0554-0025MG); gallic acid standard (developed by Chengdu Manster Biotechnology Co., Ltd. and Chengdu Institute of Biology, Chinese Academy of Sciences, HPLC grade, ≥99.97%).

[0028] 2. Experimental Methods

[0029] 2.1 Pretreatment methods for medicinal materials

[0030] Pre-treatment method of Five-Finger Peach: Take its hard, dried roots, cut them into small sections of 3-7cm using a chaff cutter, put them into a multi-functional grinder and grind them thoroughly to a particle size of 50-300 mesh, collect the ground product, seal it and store it in a cool, dry place for later use.

[0031] Pre-treatment method for cloves: Take the dried flower buds and put them directly into a multi-functional grinder to grind them thoroughly. The particle size should be 50-300 mesh. Collect the ground product, seal it and store it in a cool and dry place for later use.

[0032] 2.2 Extract Preparation Method

[0033] Take the pre-treated medicinal materials and mix them with cloves at a mass ratio of 6:1. Place the mixture in a dry, clean round-bottom flask and add 10 times the amount (by mass) of double-distilled water. Set the water bath temperature to 100℃ and heat under reflux for extraction. Start timing 1 hour from the first drop of reflux. Filter the extract while it is still hot. Repeat this extraction method 3 times and combine the filtrates. Concentrate the extract by rotary evaporation until the liquid mass per 1000ul is 1.04-1.07g. Store in the upper part of a refrigerator at 4℃.

[0034] 2.3 Particle Preparation Method

[0035] 1) Weigh the premixed excipients and extract according to the prescription precisely, mix them thoroughly in a mortar and pestle to make a soft material. The soft material should be able to be formed into a ball when squeezed in the hand and easily dispersed when pressed.

[0036] 2) Place the soft material in a hand-cranked granulator (the inner diameter of the sieve hole is 1.5 mm, which is between the standard No. 1 sieve and the standard No. 2 sieve specified in the pharmacopoeia, i.e., between 2000±70μm and 850±29μm) and granulate it.

[0037] 3) Remove the remaining soft material from the hand-cranked pellet mill and extrude it through the No. 1 sieve to form pellets.

[0038] 4) For the fine powder that has passed through the No. 5 sieve, add an appropriate amount of double-distilled water to make it fully aggregate and form, and then granulate it through the No. 1 sieve.

[0039] 5) Combine the particles obtained in steps 2), 3), and 4), dry them at 55℃ for 1 hour, and then granulate them using a double sieve method. Retain particles of 10-80 mesh and remove particles coarser than 10 mesh and finer powders finer than 80 mesh to obtain the sample.

[0040] 2.4 Quality Research Methods

[0041] 2.4.1 Appearance Evaluation

[0042] Granules should be kept dry, with uniform particle size and consistent color. Furthermore, granule samples should possess a certain degree of stability and should not exhibit moisture absorption, softening, clumping, or deliquescence. The appearance of the granules prepared in the experiment should be evaluated using the above standards.

[0043] 2.4.2 Evaluation of solubility

[0044] Accurately weigh 0.5g of each pre-designed granule into a 15ml Corning centrifuge tube with a minimum graduation of 0.5ml. Use a pipette to precisely add 10ml of 70℃-80℃ hot water, shake vigorously for 5ml, and observe immediately. The granules should be completely dissolved or the solution should become slightly turbid.

[0045] 2.4.3 Liquidity Assessment

[0046] Draw a circle of radius R in the center of a dry, clean 17cm × 25cm graph paper. Adjust the height H of the bottom of a 90mm diameter glass funnel placed on a funnel stand from the paper surface to a suitable height, ensuring that the particles falling from the funnel do not hinder their free accumulation nor cause them to leave the paper surface. Align the funnel's circular opening with the center of the circle on the graph paper and fix the funnel in place. Slowly pour the sample until the edge of its cone covers the edge of the circle on the graph paper. Measure the height h of the cone and calculate the angle of repose using the formula θ = arctan(h / R). Perform three parallel measurements for each batch of samples and calculate the arithmetic mean as the final result for that batch.

[0047] Within a certain range, increasing powder particle size leads to increased flowability, while decreasing particle size leads to decreased flowability. In addition, surface forces (such as friction) on powders also significantly affect flowability. For example, moisture adsorbed on the powder surface increases its bulk density and decreases its porosity, thereby increasing interparticle adhesion and reducing flowability.

[0048] 2.4.4 Molding Rate Evaluation

[0049] Accurately weigh 5g of granular sample and place it on the top of sieve No. 1. The bottom of sieve No. 5 is connected to a sealed receiving container. Keep the sample horizontal and sieve it back and forth for 3 minutes while sieving and tapping. Combine the coarse particles that cannot pass through sieve No. 1 and the fine powder that can pass through sieve No. 5 and weigh them. The total should not exceed 15%. Calculate the molding rate (%) = mass of particles that can pass through sieve No. 1 but not sieve No. 5 / total mass of weighed particles × 100%. Perform three parallel tests on each batch of samples and take the arithmetic mean as the final result.

[0050] When evaluating the molding rate, a higher viscosity of the soft material will make the originally irregular particle size closer to the sieve opening, and the overall sample particle size will be higher, thus increasing the probability that the particles cannot pass through the No. 1 sieve. A lower viscosity of the soft material will make the particles loose and easy to break, and the overall sample particle size will be lower, thus increasing the probability that the particles will pass through the No. 5 sieve. Both will reduce the molding rate. The most suitable soft material state can make the particle molding rate reach the highest level. This state is defined as the "ideal state".

[0051] 2.4.5 Hygroscopicity Evaluation

[0052] Use a dry, stoppered glass weighing bottle of the same size. One day before the test, place it in a suitable constant temperature desiccator. Prepare an appropriate amount of saturated ammonium sulfate solution and add it to an open glass dish. Place the dish at the bottom of the desiccator to ensure more uniform moisture absorption of the granules. Accurately weigh the mass m1. Accurately weigh 1g of fully dried granules (pre-dried in an electric constant temperature incubator at 50℃ for 3 hours under mild conditions), spread it evenly in the weighing bottle, making the sample thickness approximately 1mm. Accurately weigh the mass m2 of the weighing bottle containing the sample. Leave the weighing bottle with the sample open and place it under constant temperature and humidity conditions for 24 hours, along with the cap. Close the cap and accurately weigh the weighing bottle containing the moisture-absorbing sample. Moisture absorption rate (%) = (m3-m2) / (m2-m1)×100%. Perform three parallel tests for each batch of samples and take the arithmetic mean as the final result. The hygroscopicity of the drug was evaluated in this section according to the requirements of the 2020 edition of the Chinese Pharmacopoeia, as detailed in Table 1:

[0053] Table 1. Definition of Hygroscopic Weight Gain

[0054]

[0055] 2.4.6 Evaluation by High Performance Liquid Chromatography

[0056] Accurately weigh 2 mg of the national standard substances psoralen and gallic acid into a brown volumetric flask, and dilute to the mark with anhydrous methanol. Filter a small amount of the diluted solution through a 0.22 μm organic phase filter and add it to a sample vial for HPLC analysis. Accurately weigh 4 g of a specific group of granule samples into a regular volumetric flask, add an appropriate amount of 50% methanol-water solution, sonicate at maximum power for 20 min until fully dissolved, and dilute to the mark with 50% methanol-water solution. Filter a small amount (approximately 2 ml) of the diluted solution through a 0.22 μm organic phase filter and add it to a sample vial for HPLC gradient elution to determine its main components. Identify and determine the content of psoralen and gallic acid from the medicinal materials *Ficus hirta* and clove, respectively, in the selected granule samples.

[0057] (II) Quality Evaluation Results and Discussion of Peach Delight Granules

[0058] 1. Evaluation Results and Discussion of Granule Properties

[0059] 1.1 Screening of different excipient mixtures

[0060] Lactose monohydrate, β-cyclodextrin, and corn starch were paired in pairs according to the formulation ratio shown in Table 2, and sufficient granule samples were prepared according to the method in Part (I) 2.3. All tests except "high performance liquid chromatography evaluation" in Part (I) 2.4 were performed.

[0061] Ultimately, when lactose and cyclodextrin (Macklin) were combined, the excipient mass ratio was 1:1, and the extract to excipient mass ratio was 1:4.8, the appearance met the pharmacopoeia requirements, the solubility was good, the flowability was optimal, the hygroscopicity was weakest, and the molding rate was excellent.

[0062] 1.2 Optimization Study of Formulation

[0063] For the combination of lactose and cyclodextrin (Macklin), the mass ratio of Macklin lactose and β-cyclodextrin was adjusted appropriately (1:1, 1:2, 2:1), the extract density range was controlled to be 1.04-1.07, and the extract-excipient mass ratio was kept constant (1:4.8). All evaluation tests except for "high performance liquid chromatography evaluation" in Part (I) 2.4 were carried out.

[0064] Ultimately, the combination of lactose and cyclodextrin (Macklin), with an excipient mass ratio of 2:1 and an extract-to-excipient mass ratio of 1:4.8, resulted in the best flowability, the highest molding rate, and the weakest hygroscopicity.

[0065] 1.3 Research on Improving Drug Loading

[0066] Although the granules with lactose and β-cyclodextrin (2:1) combination already have good properties, they still have the defect of insufficient drug loading. The drug loading in the formulation was increased (other conditions remained unchanged, and lactose and β-cyclodextrin were still produced by Macklin). The mass ratio of extract to excipients was adjusted to two groups of 1:4.8 and 1:4. All evaluation tests except "high performance liquid chromatography evaluation" in Part (I) 2.4 were carried out.

[0067] Ultimately, after increasing the drug loading (i.e., adjusting the extract-excipient mass ratio to 1:4), the quality performance decreased to some extent, but still remained at a good level.

[0068] 1.4 Comparative Test of Auxiliary Materials from Different Manufacturers

[0069] Granule formulations prepared using Macklin excipients at extract-excipient mass ratios of 1:4.8 and 1:4 have yielded granules with superior properties. To verify these experimental results, Solarbio's β-cyclodextrin and lactose were used in accordance with the same formulations (A5, A6) and experimental methods, and all evaluation tests in Part (I) 2.4, excluding "High Performance Liquid Chromatography Evaluation", were performed.

[0070] Ultimately, it was found that Solarbio's excipients outperformed Macklin's when the excipient groups were the same. Furthermore, it was demonstrated that simply increasing the amount of extract to improve drug loading would lead to a certain decrease in the quality level of the granules, but the quality level would still remain good.

[0071] 1.5 Determination of the final product formulation

[0072] In addition to extract (dry extract powder) and fillers, flavoring agents, coloring agents, disintegrants, etc. can be added to granules to improve their performance. Granules prepared with the Peach Delight formula have a natural brownish-yellow or yellowish-brown color, and there is no need to change the appearance color; its solubility meets the requirements, so the addition of disintegrants is not considered; the Peach Delight formula has no obvious bitter or sour taste, so the final product of this experiment only added the flavoring agent steviol glycosides (stevia, ribobadiol A, ribobadiol B, ribobadiol C, ribobadiol D, ribobadiol F, durqueside A, stevia glycoside, steviol disaccharide) to enhance the sweetness.

[0073] Therefore, the limit for steviol glycosides in GB2760 is adopted, namely, the maximum usage is 0.2 g / kg. -1 (Based on steviol equivalents). Research has shown that the Peach & Delight formula already possesses sufficient sweetness; therefore, the amount of flavoring agent added to the final product is set at "1 mg steviol glycoside per 6 g of filler," ensuring that the amount of sample granules added does not exceed 0.1666 g / kg. -1 .

[0074] 2. HPLC Results and Discussion

[0075] HPLC was performed on granules prepared using lactose and cyclodextrin (2:1, Solarbio) as the combination, with an excipient mass ratio of 2:1, an extract-to-excipient mass ratio of 1:4.8 and 1:4, and a steviol glycoside-to-excipient mass ratio of 1:6000. The gradient elution chromatogram of the sample is shown below. Figure 1-3 As shown in Table 2, the elution time and peak area of ​​each chromatographic peak are shown in Table 2.

[0076] Table 2 summarizes the chromatographic information of two types of particles with extract-to-excipient mass ratios of 1:4.8 and 1:4.

[0077]

[0078] Based on the above data, psoralen and gallic acid peaks were observed in samples 1:4.8 and 1:4. The theoretical plate number for this method, calculated based on gallic acid, is ≥5000. Slight tailing was observed in individual peaks (T>1.05), but this did not affect quantification. Resolution was greater than 1.5 when present. Experiments demonstrate that both 1:4.8 and 1:4 samples contain gallic acid and psoralen, and the content of gallic acid and psoralen in the 1:4 formulation is higher than that in the 1:4.8 formulation, indicating that increasing the amount of extract successfully improved the drug loading of the granules.

[0079] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and these variations still fall within the protection scope of the present invention.

Claims

1. A preparation process for peach-flavored refreshing granules, characterized in that, After mixing five-finger peach and clove, add 10-20 times the amount of water, heat and reflux at 90-110℃ for 1-3 hours to extract, then concentrate to make an extract, and then make granules together with excipients. The mass ratio of the five-finger peach and clove is 6:

1. The excipient is selected from a combination of α-lactose and β-cyclodextrin, the mass ratio of α-lactose to β-cyclodextrin is 2:1, and the mass ratio of the extract to the excipient is 1:4.8 or 1:

4.

2. The preparation process of the peach-flavored refreshing granules according to claim 1, characterized in that, The excipients are selected from those produced by Solarbio.

3. The preparation process of the peach-flavored refreshing granules according to claim 1, characterized in that, The size of the granules is 10-80 mesh.

4. The preparation process of the peach-flavored refreshing granules according to claim 1, characterized in that, The concentration standard of the extract is: 1.04-1.07g per 1000ul of liquid.

5. The preparation process of the peach-flavored refreshing granules according to claim 1, characterized in that, After mixing the five-finger peach and cloves, add 10 times the amount of water, heat and reflux at 100℃ for 1 hour, and then concentrate to prepare an extract.

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