Preparation method for improving pilot-scale test efficiency of yang-strengthening and heart-strengthening decoction

Abstract

The invention discloses a yang-strengthening and heart-strengthening decoction granular preparation and a preparation method thereof, and belongs to the technical field of traditional Chinese medicine preparations. The invention aims to solve the problems of single dosage form, unstable quality control and the like of yang-strengthening and heart-strengthening decoction in the prior art. According to the technical scheme, the method comprises the following steps: adding 8-12 times by weight of water into raw medicinal materials, and extracting twice for 1-2 hours each time; combining the extracting solutions, and concentrating under reduced pressure to obtain clear paste with the relative density of 1.10-1.20; drying the clear paste under reduced pressure to obtain dry paste powder; and mixing the dry paste powder with dextrin according to a weight ratio of 5: 2-5: 5, granulating by using an 80-90% ethanol solution as a wetting agent, and drying to obtain the product. According to the method, key process parameters such as the extraction times and the auxiliary material ratio are systematically optimized, so that the optimal process range is determined. The preparation method has the beneficial effects that the preparation method is stable in process, clear in parameter, good in reproducibility and extremely small in batch-to-batch difference (RSDlt: 2.0%); the prepared granules are good in forming and good in flowability, and the quality uniformity of products and the safety and effectiveness of clinical medication are effectively guaranteed.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, specifically to a preparation method for improving the pilot-scale efficiency of Fuyang Qiangxin Decoction. Background Technology

[0002] Fuyang Qiangxin Decoction is a classic formula in Traditional Chinese Medicine (TCM) used to treat heart failure and related cardiac diseases caused by deficiency of heart yang. Its definite effects of warming yang, tonifying qi, promoting blood circulation, and eliminating water retention have led to its widespread clinical application and recognition. Currently, in clinical practice, this formula is mainly used by patients in the traditional form of a decoction. The physician prescribes the medicine based on syndrome differentiation, and the patient prepares the herbs themselves, decocts them at home, and then drinks the decoction.

[0003] However, this traditional form of decoction application has unavoidable inherent drawbacks. The process of patients preparing the decoction themselves is not only cumbersome and time-consuming, but more importantly, many process parameters affecting the dissolution of medicinal components, such as the amount of water added, the heat, and the duration, rely entirely on personal experience, making precise and standardized control difficult. This arbitrariness in the preparation process easily leads to significant fluctuations in the content of effective components between different batches, different operators, and even different doses from the same decoction, directly affecting the stability and predictability of clinical efficacy.

[0004] Meanwhile, the inherent drawbacks of traditional decoctions—large volume, bitter taste, and inconvenience in carrying and storing—significantly reduce patient medication adherence, especially for patients with chronic heart failure who require long-term, regular medication to control their condition. These shortcomings collectively limit the further promotion and modernization of this classic formula, making it difficult to fully adapt to modern fast-paced lifestyles and the stringent requirements for drug quality uniformity. Therefore, developing a new dosage form of Fuyang Qiangxin Decoction that overcomes the aforementioned drawbacks of traditional decoctions, achieving accurate dosage, stable and controllable quality, and convenient administration and carrying, has become an urgent technical problem to be solved in this field. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a preparation method that improves the pilot-scale efficiency of Fuyang Qiangxin Decoction, solving the technical problems of the single dosage form of existing Fuyang Qiangxin Decoction and the unstable quality, inconvenient administration, and difficulty in guaranteeing clinical efficacy caused by the non-standardized preparation process of traditional decoctions.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a preparation method for improving the pilot-scale efficiency of Fuyang Qiangxin Decoction, comprising the following steps: Step S1: Provide raw medicinal materials according to the prescription ratio of Fuyang Qiangxin Decoction, and pre-treat the special medicinal materials contained therein; Step S2: Add water to the processed medicinal materials and decoct twice, each time adding water at a volume of 8 to 12 times the weight of the medicinal materials, and extracting for 1 to 2 hours. Combine the decoctions and filter to obtain the extract. Step S3: Concentrate the extract under reduced pressure at 60-80°C to a relative density of 1.10-1.20 (measured at 60°C) to obtain a concentrated extract; Step S4: Dry the ointment under reduced pressure at 60-80°C until constant weight to obtain dry ointment powder; Step S5: After pulverizing and sieving the dry powder, mix it with the excipient dextrin at a weight ratio of 5:2 to 5:5, add an appropriate amount of 80-90% ethanol to moisten and granulate, dry and granulate to obtain the Fuyang Qiangxin Decoction granule preparation.

[0007] The innovation and beneficial effects of this invention are mainly reflected in the systematic optimization and precise definition of key process steps: Firstly, in the raw material pretreatment step S1, this invention clarifies the processing method for special medicinal materials. Specifically, pulverizing *Lepidium apetalum* seeds to pass through a No. 2 sieve helps improve the dissolution of its active ingredients; soaking *Aconitum carmichaelii* slices for approximately 30 minutes followed by pre-decocting for about 1 hour, and then combining the pre-decocted liquid with the subsequent extract for concentration. This method ensures that the toxic components of *Aconitum carmichaelii* slices are removed under controlled conditions, guaranteeing the safety of the formulation during scale-up production.

[0008] Secondly, in step S2 of the herbal extraction process, this invention simplifies the traditional extraction process, which may require multiple steps, to two. Furthermore, it optimizes and determines more specific process parameters: the water addition ratio is 10 times the weight of the herbal material, and the extraction time is 1.5 hours. This parameter combination significantly shortens the production cycle while ensuring the extraction rate. Specifically, the water addition ratio... It can be calculated using the following formula: ; in, The volume of water added is in liters (L). The total weight of the medicinal materials (kg) The preferred value for the water addition ratio is 10.

[0009] Furthermore, in the concentration and drying steps S3 and S4, this invention broadens the parameter range of the process operation. The vacuum concentration temperature is set to 60–80°C, preferably 60–70°C, and the vacuum drying temperature is set to 60–80°C (but not higher than 80°C). This wider temperature range enhances the process's adaptability to pilot-scale production equipment and improves operational flexibility. Simultaneously, by adjusting the relative density at the concentration endpoint… Precisely controlled within the range of 1.10 to 1.20 (measured at 60°C), that is: ; This ensures that the concentrated extract has a suitable viscosity, which facilitates subsequent transfer and drying, and avoids material loss due to excessive viscosity.

[0010] Finally, in the granulation step S5, this invention optimized the excipient ratio and granulation conditions. The weight ratio of the dry extract powder to the excipient dextrin was specified to be within the range of 5:2 to 5:5, meaning the amount of dextrin used was not less than 28.6% of the weight of the dry extract powder. Simultaneously, the wetting binder was defined as an 80%–90% concentration (v / v) ethanol solution, and its dosage was further specified as approximately 30–50 mL per 100 g of the mixed powder of dry extract powder and dextrin. This combination of parameters solved the problem of controlling the soft material state during pilot-scale production, ensuring the stability of the granulation process and a high particle formation rate.

[0011] This invention provides a preparation method for improving the pilot-scale efficiency of Fuyang Qiangxin Decoction. It has the following beneficial effects: 1. The preparation method of this invention, through precise control of the extraction process—specifically, limiting the amount of water to 8-12 times, extracting twice, and each time for 1-2 hours—ensures that the effective components in the medicinal materials are fully and evenly dissolved. This series of clearly defined parameterized operations eliminates the randomness and reliance on experience in traditional home decoction, guaranteeing the stability and uniformity of the medicinal material basis from the source.

[0012] 2. Concentrating the extract to a clear paste with a specific relative density, and further drying it under reduced pressure into a dry powder, is a key technological turning point in the standardization of this invention. This step not only effectively removes excess moisture and improves the stability of the intermediate, but more importantly, it transforms the fluid extract into a stable, easily measured solid powder, thus fundamentally solving the problem of inaccurate single-dose administration caused by uneven concentration or volume errors when dispensing traditional decoctions.

[0013] 3. This invention, through the selection and proportioning of granulation excipients and wetting agents, maintains a systematically screened weight ratio of dry extract powder to dextrin of 5:2 to 5:5, and uses 80%–90% ethanol as a wetting agent, thus obtaining a soft material with moderate viscosity and suitable hardness. This directly contributes to the final granules' high sphericity, uniform particle size, and excellent flowability, which not only facilitates automated dispensing but also avoids moisture absorption and clumping problems caused by poor granule formation, significantly improving the shelf-life stability of the formulation.

[0014] 4. Finally, the Fuyang Qiangxin Decoction, which traditionally requires long-term decoction, has been successfully transformed into a modern granule that can be instantaneously brewed and drunk. This brings great convenience to patients, completely eliminating the cumbersome preparation process. The design of single-dose packaging ensures the accuracy and safety of medication, while the dry and small-volume form completely solves the problems of carrying and storage, significantly enhancing the medication compliance of chronic disease patients who need to take long-term medication, thereby maximizing the clinical value of this classical famous prescription. Brief Description of the Drawings

[0015] Figure 1 It is a process flow diagram for the preparation of the Fuyang Qiangxin Decoction granule preparation of the present invention. Detailed Embodiments

[0016] Next, in conjunction with the drawings of the present invention specification, the technical solutions in the embodiments of the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0017] Please refer to the attached Figure 1 , the embodiment of the present invention provides a preparation method for improving the pilot production efficiency of the Fuyang Qiangxin Decoction, including the following steps: First, in the stage of raw material preparation and pretreatment of Chinese medicinal materials, all the required raw material Chinese medicinal materials are accurately weighed according to the prescription ratio of the Fuyang Qiangxin Decoction. Targeted pretreatment is carried out on the special Chinese medicinal materials: put the semen lepidii into a pulverizing device and pulverize it until its particles can pass through a No. 2 sieve; place the processed aconite root slices in a container, add an appropriate amount of water and soak for about 30 minutes, and then pre-decoct them together with the soaking solution for about 1 hour. After this pre-decoction step is completed, separate and collect the obtained decoction from the decoction device for later use, and the aconite root slices residue after decoction are combined with other Chinese medicinal materials.

[0018] Next, enter the stage of Chinese medicinal material extraction. Put the aconite root slices residue after pretreatment and all other Chinese medicinal materials together into an extraction device. Add purified water into the extraction device, and the amount of water added is calculated according to the following formula based on the total weight of the Chinese medicinal materials:

[0019] Among them, represents the volume of purified water required to be added, with the unit of liter (L); represents the total weight of the Chinese medicinal materials put into the extraction device, with the unit of kilogram (kg); The water addition ratio ranges from 8 to 12. The extraction process is then initiated, involving two heating and decoction extractions, each lasting 1 to 2 hours. After both extractions, the extracts are combined and thoroughly mixed with the pre-decoction of Aconitum carmichaelii collected in the preceding steps to form a combined extract. This combined extract is then filtered through a filtration device to remove dregs and insoluble matter, yielding a clear extract.

[0020] Subsequently, the clarified extract was pumped into a vacuum concentration apparatus for concentration. The extract was concentrated by vacuum evaporation at a temperature of 60–80°C. During this process, the physical properties of the concentrate were continuously monitored until its relative density was determined. The target range is to be reached, which is defined by the following formula:

[0021] in, This represents the relative density of the concentrate measured at 60°C. When the relative density reaches this range, concentration is stopped to obtain a homogeneous concentrated extract.

[0022] After obtaining the concentrated extract, it is removed from the concentration equipment and evenly spread on a tray of a vacuum drying device. The concentrated extract is then dried under reduced pressure at a temperature range of 60–80°C. The drying process continues until the extract reaches a constant weight, indicating that the moisture has been fully removed, at which point a dry, solid powder is obtained.

[0023] Finally, the formulation stage is carried out. The obtained dry extract powder is pulverized and sieved to form a fine powder with uniform particle size. Then, the dry extract powder is mixed with dextrin as an excipient in a mixing device, with the weight ratio of dry extract powder to dextrin controlled within the range of 5:2 to 5:5. In the uniformly mixed powder, an 80% to 90% (v / v) ethanol solution is slowly added as a wetting and binding agent, and stirring is continued until a soft material with suitable moisture content is formed, which can be formed into a ball by hand and crumbles easily when lightly pressed. This soft material is granulated into wet granules through a granulation device, and then the wet granules are transferred to a drying device for final drying. After drying, the granules are classified by particle size using a granulation device to obtain the final Fuyang Qiangxin Decoction granule formulation.

[0024] For the extraction process of medicinal materials, this invention employs orthogonal experimental design to screen the optimal combination of process parameters. In this study, three factors significantly affecting the extraction effect were selected: factor A is the water addition ratio, factor B is the single extraction time, and factor C is the number of extractions. Each factor was investigated at three different levels. The experimental arrangement followed an L9(3^4) orthogonal array, focusing on the extraction transfer rate of key active ingredients. As the final evaluation indicator, this indicator directly reflects the efficiency of the transfer of active ingredients from medicinal materials to the extract.

[0025] Analysis of the orthogonal experimental results revealed that, within the set range, the water addition ratio and extraction time significantly affected the extraction transfer rate. The impact of [the factor] is not the most significant. In contrast, the number of extractions is the primary factor affecting extraction efficiency. Further comparisons reveal that increasing the number of extractions from two to three, while [the number of extractions] increases the extraction transfer rate... There was a slight improvement, but the difference between the two was not statistically significant, while production time costs and energy consumption increased significantly. Considering both the sufficiency of extraction and the economic benefits of pilot production, the optimal extraction process of this invention was determined to be a combination of two extractions, adding 10 times the amount of water, and extracting for 1.5 hours.

[0026] In establishing the granulation process, this invention meticulously screened the proportions of excipients and the parameters of the wetting agent. First, a series of comparative experiments were conducted to determine the appropriate weight ratio of the dry extract powder to the excipient dextrin. The dry extract powder... With dextrin According to different weight ratios ( The mixture was granulated, and the final particle size distribution, sphericity, and flowability were used as evaluation criteria. Experimental results showed that the granulation process was smooth and the resulting particles exhibited the best physical properties when the weight ratio of the dry extract powder to dextrin was between 5:2 and 5:5. If the dextrin content was below this range, the particles were prone to crumbling, resulting in a low particle size distribution; if it was above this range, the proportion of excipients in the formulation was high, affecting the drug loading per unit dose.

[0027] After determining the appropriate ratio of dry extract powder to dextrin, the concentration of the wetting agent ethanol was further adjusted. Optimization was performed. Ethanol solutions of different volume concentrations were used as wetting binders to investigate their effects on the granulation process and particle quality. The evaluation mainly included the viscoelasticity and plasticity of the soft material, as well as the hardness and melting time of the particles after final drying. The study found that when the concentration of the ethanol solution... When the concentration is between 80% and 90% (v / v), the resulting soft material has moderate viscosity, easily passes through a sieve to form uniform particles, and the final particles have good mechanical strength and solubility characteristics that meet pharmacopoeia requirements. If the concentration is too low, the soft material becomes too sticky, easily leading to granulation failure; if the concentration is too high, the wettability deteriorates, making it difficult to form the soft material. Therefore, this invention uses an 80% to 90% ethanol solution as the wetting agent.

[0028] In an embodiment of the present invention, in order to comprehensively evaluate the final product quality of the Fuyang Qiangxin Decoction granules prepared by the above method, and to verify the stability and reproducibility of the process during pilot-scale amplification, a systematic quality test was conducted on three batches of pilot-scale products produced continuously.

[0029] First, the routine physical properties of the three batches of samples were tested. The tests included appearance, particle size distribution, moisture content, solubility characteristics, and the difference in dosage per unit dose. All tests were conducted according to the relevant regulations and methods for granules in the Chinese Pharmacopoeia. The results showed that all three batches of products were brownish-yellow granules, with odor and taste meeting the requirements; their particle size distribution was concentrated, and the moisture content and other indicators were within the standard limits, indicating that the preparation method described in this invention can stably produce granule formulations that meet the basic requirements of the Pharmacopoeia.

[0030] To further evaluate the batch-to-batch consistency of the process of this invention, high-performance liquid chromatography (HPLC) was used to accurately determine the content of key indicator components in three batches of samples. The relative standard deviation (RSD) of the content determination results for the three batches of samples was calculated to quantitatively evaluate the uniformity of product quality. The formula for calculating the relative standard deviation is as follows:

[0031] in,

[0032] In this formula, Representing the Measured content of key components in batch samples; This represents the average content of key components across all batches of samples. The standard deviation; The number of sample batches tested. The calculated RSD value is within the reasonable range allowed by pharmaceutical quality control. This result strongly demonstrates that the preparation method described in this invention has excellent process reproducibility and can ensure a high degree of consistency in the intrinsic quality of products between different batches.

[0033] Finally, to investigate the stability of the granule formulation prepared by this invention, an accelerated stability test was conducted on one batch of samples. The samples were placed in a constant temperature and humidity environment of 40°C and 75% for continuous observation. Samples were taken at preset time points, and a series of quality indicators, including appearance, moisture content, solubility characteristics, and content of key components, were monitored. The test results showed that after being placed under accelerated conditions, no significant adverse changes were observed in any of the sample's indicators, preliminarily confirming that the granule formulation prepared by the method of this invention has good stability.

[0034] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A preparation method for improving the efficiency of the trial of Fuyangqiangxin Decoction, characterized in that, The method comprises the following steps: Step S1: providing raw medicinal materials according to the prescription of Fuyang Qiangxin Decoction, and pretreating special medicinal materials contained therein; Step S2: boiling and extracting the pretreated medicinal materials twice, each time adding water in an amount of 8-12 times the weight of the medicinal materials, and extracting for 1-2 hours, and then combining and filtering to obtain an extract; Step S3: concentrating the extract at 60-80°C under reduced pressure to a relative density of 1.10-1.20 (measured at 60°C) to obtain a concentrated clear paste; Step S4: drying the clear paste at 60-80°C under reduced pressure to a constant weight to obtain a dry paste powder; Step S5: crushing and sieving the dry paste powder, mixing it with a bulking agent dextrin at a weight ratio of 5:2-5:5, adding an appropriate amount of 80-90% ethanol to wet granulation, drying and granulating to obtain Fuyang Qiangxin Decoction granules.

2. The method of claim 1, wherein, The pretreatment of special medicinal materials in step S1 comprises: crushing Semen Platycladi to pass through a No. 2 sieve; soaking Heishun Pian for about 30 minutes and pre-boiling for about 1 hour, and the liquid obtained by pre-boiling is combined with the extract for common concentration.

3. The method of claim 1, wherein, The water addition multiple in step S2 is 10 times the weight of the medicinal materials, and the extraction time is 1.5 hours.

4. The method of claim 1, wherein, The amount of water V added in step S2 W This is calculated according to the following formula: V W = k × W H ; Wherein, V W L, W H As the total weight of medicinal materials kg, k is the water multiple, The value is 10.

5. The method of claim 1, wherein, The temperature for reduced-pressure concentration in step S3 is 60-70°C.

6. The method of claim 1, wherein, Relative density R of the end point of the concentration in step S3 D Control between 1.10 and 1.20, and measured at 60°C: R D ∈ [1.10, 1.20] (at 60 °C).

7. The method of claim 1, wherein the method is performed in a single step. The temperature for reduced-pressure drying in step S4 is not higher than 80°C.

8. The method of claim 1, wherein, The bulking agent in step S5 is dextrin, and the amount thereof is not less than 28.6% of the weight of the dry paste powder, i.e., the weight ratio of the dry paste powder to dextrin is not higher than 5:

2.

9. The method of claim 1, wherein, The wetting and binding agent in step S5 is an ethanol solution with a concentration of 80%-90% v / v.

10. The method of claim 1, wherein, About 30-50 mL of the 80%-90% ethanol solution is added to 100 g of the mixture of the dry paste powder and dextrin for wet granulation.

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