Low-temperature crushing preparation process and application of traditional Chinese medicine composition

Abstract

The invention relates to the field of modern processing of traditional Chinese medicines, and particularly provides a low-temperature crushing preparation process and application of a traditional Chinese medicine composition. According to the process, medicinal materials are pre-frozen at the temperature of-40 DEG C to-30 DEG C to be subjected to glassy transition, and the synergistic effect of vortex airflow crushing and a high-frequency ultrasonic field under the protection of liquid nitrogen is combined, so that the crushing temperature is controlled to be less than or equal to-30 DEG C, and the ultrafine particle size D90 is less than or equal to 15 microns. Meanwhile, a three-stage gradient cold trap (-80 DEG C,-120 DEG C and-196 DEG C) is adopted to recover volatile components, and a surface modifier is immediately added after crushing to inhibit powder agglomeration. The process solves the problems of degradation of thermosensitive components, dissipation of volatile components, overlarge particle size and the like in traditional crushing, so that the retention rate of the thermosensitive components is greater than or equal to 95%, the volatile loss rate is less than or equal to 3%, and the dissolution rate is increased by 2.8 times or more. The obtained powder can be directly applied to acupoint application, powder inhalation and transdermal preparations, and the requirements of a novel drug delivery system are met.

Description

Technical Field

[0001] This invention relates to the field of modern processing technology of traditional Chinese medicine, specifically to a preparation process and application of low-temperature pulverization of a traditional Chinese medicine composition. Background Technology

[0002] Traditional Chinese medicine (TCM) pulverization technology is a crucial step in the modernization of TCM formulations, directly impacting the retention of active ingredients and the bioavailability of the preparations. The localized high temperatures (>60℃) generated during traditional mechanical pulverization easily lead to the degradation of heat-sensitive components such as glycosides, terpenes, and volatile oils. Simultaneously, a large amount of volatile components escapes during pulverization, disrupting the compatibility balance of the compound formulation. Furthermore, conventional methods struggle to reduce particle size to below 20μm, limiting drug dissolution rates and the development of novel drug delivery systems.

[0003] While existing cryogenic pulverization technologies have partially alleviated the problem of heat damage, they still have significant drawbacks: liquid nitrogen impregnation consumes as much as 3-5 kg / kg of medicinal material, making it prohibitively expensive; cryogenic grinding causes ice crystal growth due to phase separation, damaging the cell structure of the medicinal material; and some technologies fail to reach the glass transition temperature of the medicinal material, resulting in a retention rate of less than 85% for heat-sensitive components. Therefore, there is an urgent need for a green and efficient pulverization process that balances cryogenic protection, volatile component recovery, and ultrafine particle size control. Summary of the Invention

[0004] The purpose of this section is to outline some aspects of embodiments of the present invention and to briefly describe some preferred embodiments. Simplifications or omissions may be made in this section, as well as in the abstract and title of this application, to avoid obscuring the purpose of these documents; however, such simplifications or omissions should not be construed as limiting the scope of the invention.

[0005] In view of the problems existing in the prior art, the inventors have proposed the present invention.

[0006] Therefore, the purpose of this invention is to overcome the shortcomings of the prior art and provide a preparation process and application of low-temperature pulverization of traditional Chinese medicine compositions.

[0007] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a preparation process for low-temperature pulverization of a traditional Chinese medicine composition, comprising the following steps:

[0008] (a) Slice the Chinese herbal raw materials to a thickness of 0.5 to 2 mm, pre-freeze them at -40°C to -30°C for 2 to 4 hours, and confirm that the glass transition has been achieved by DSC detection with a loss factor tanδ≤0.05;

[0009] (b) The mixture is pulverized under liquid nitrogen protection using a vortex airflow pulverizer with a liquid nitrogen flow rate of 80-120 L / min (medicinal material ratio 1:1-1.5:1), an airflow pressure of 0.8-1.2 MPa, a vortex rotation speed of 12000-18000 rpm, and a pulverization chamber temperature maintained at -35℃ to -25℃.

[0010] (c) A high-frequency ultrasonic field is applied simultaneously during the pulverization process, with a frequency of 28-40 kHz and a power density of 0.5-2 W / cm³. 3 ;

[0011] (d) Volatile components are recovered through a three-stage cold trap, with the cold trap temperatures set at -80℃, -120℃, and -196℃, respectively;

[0012] (e) Immediately after pulverization, add a surface modifier accounting for 0.1-0.5% of the powder weight, wherein the surface modifier is a lecithin-trehalose complex (mass ratio 1:3-1:5) or a β-cyclodextrin-mannitol complex (mass ratio 1:2).

[0013] As a preferred embodiment of the low-temperature pulverization preparation process of the traditional Chinese medicine composition described in this invention, the pre-freezing in step (a) adopts a stepped cooling method, first maintaining at -25℃ for 2 hours, and then lowering to -40℃ and maintaining for 1.5 to 2 hours to avoid ice crystal growth that could damage cell structure.

[0014] As a preferred embodiment of the low-temperature pulverization process for the traditional Chinese medicine composition described in this invention, in step (b), the vortex airflow pulverizer is equipped with an online laser diffractometer to monitor the particle size in real time and dynamically adjust the airflow pressure to ensure that D50 = 3-5 μm, D90 ≤ 15 μm, and specific surface area ≥ 8 m². 2 / g.

[0015] As a preferred embodiment of the low-temperature pulverization preparation process of the traditional Chinese medicine composition described in this invention, the ultrasonic field in step (c) is applied in pulse mode with a working cycle of 30s ultrasound / 5s intermittent, thereby reducing local heat accumulation.

[0016] As a preferred embodiment of the low-temperature pulverization preparation process of the traditional Chinese medicine composition of the present invention, wherein: the surface modifier in step (e) is injected in situ at the end of pulverization by a spraying device, the spraying pressure is 0.2-0.5MPa, and the atomized particle size is 10-20μm.

[0017] The traditional Chinese medicine composition powder prepared by the low-temperature pulverization process of the traditional Chinese medicine composition described in this invention has the following characteristics: volatile component retention rate ≥97%, heat-sensitive component degradation rate ≤3%, angle of repose ≤30°, and compression molding tensile strength ≥2.5MPa.

[0018] A traditional Chinese medicine powder composition is prepared for use in the preparation of acupoint patches, wherein: the powder is applied to the skin and absorbed through the skin to achieve a therapeutic effect.

[0019] The application of a traditional Chinese medicine powder composition in the preparation of an inhaled powder, wherein: the powder is mixed with a lactose carrier (particle size 80-100μm) at a ratio of 1:9, the fine particle fraction (FPF) is ≥75%, and the aerodynamic particle size (MMAD) is 1-5μm.

[0020] The application of a traditional Chinese medicine powder composition in the preparation of transdermal drug delivery formulations, wherein: the powder is dispersed in a sodium carboxymethyl cellulose gel matrix at a concentration of 5-10 wt%, and the transdermal permeation rate constant is ≥0.15 h⁻¹.

[0021] A low-temperature pulverization system for a low-temperature pulverization preparation process of a traditional Chinese medicine composition includes:

[0022] Pre-freezing compartment with temperature control accuracy of ±1℃, equipped with DSC online monitoring module;

[0023] Liquid nitrogen circulating vortex pulverizer, integrating an ultrasonic generator and temperature sensor;

[0024] The three-stage gradient cold trap consists of an -80℃ cold trap to capture large molecular volatiles, a -120℃ cold trap to condense medium molecular components, and a -196℃ liquid nitrogen cold trap to capture small molecular volatiles.

[0025] The laser diffractometer provides real-time feedback on particle size to the pulverizer control system.

[0026] Surface modifier spraying device, atomization pressure 0.2-0.5MPa.

[0027] Beneficial effects of this invention: This process reduces the molecular diffusion coefficient to 10 by precisely controlling the glass transition of medicinal materials (tanδ≤0.05). -14 cm 2 At the / s level, it achieves a dual effect of "low-temperature embrittlement" and "molecular locking." The synergistic effect of vortex airflow pulverization and ultrasonic field reduces energy consumption by 40% while increasing cell wall disruption rate to over 95%, with a stable D90 particle size ≤15μm and a specific surface area of ​​8–12m². 2 / g, significantly accelerating dissolution kinetics. A three-stage gradient cold trap system fractionally captures volatile components with different boiling points, achieving a recovery rate of ≥97%, solving the problem of imbalanced principal, assistant, and adjuvant components in traditional compound powder pulverization. In-situ surface modification technology forms a nano-protective film on the surface of newly formed powder through a lecithin-trehalose complex, inhibiting oxidation and agglomeration, resulting in a powder repose angle ≤30°, meeting the requirements for direct tableting. This process provides highly active raw materials for innovative dosage forms such as acupoint patches and inhaled powder inhalers. Detailed Implementation

[0028] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the examples in the specification.

[0029] Many specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways different from those described herein, and those skilled in the art can make similar extensions without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0030] Secondly, the term "an embodiment" or "embodiment" as used herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in different places throughout this specification does not necessarily refer to the same embodiment, nor is it a single embodiment or an embodiment selectively excluded from other embodiments.

[0031] Example 1

[0032] This embodiment provides a preparation process and application of low-temperature pulverization of a traditional Chinese medicine composition, specifically, the preparation of Angelica sinensis-Ligusticum chuanxiong compound powder.

[0033] As one implementation method, Angelica sinensis (volatile oil content ≥0.8%) and Ligusticum chuanxiong (ligustrazine content ≥0.2%) are selected and combined in a mass ratio of 3:2.

[0034] Preferably, the preprocessing steps include:

[0035] The medicinal materials were sliced ​​to a thickness of 1.0±0.2 mm and placed in a pre-freezing chamber at -38℃ for step-freezing (first maintained at -25℃ for 2 hours, then cooled to -38℃ at a rate of 5℃ / min and maintained for 3 hours).

[0036] The loss factor tanδ = 0.03 (≤0.05) was confirmed to have reached the glass transition state (elastic modulus ≥1.2×10⁻⁶) by online monitoring using differential scanning calorimetry (DSC). 9 Pa).

[0037] The specific grinding parameters for the grinding process are as follows:

[0038] A liquid nitrogen circulating vortex pulverizer was used, with a liquid nitrogen flow rate of 100 L / min (medicinal material ratio of 1.2:1), an air pressure of 1.0 MPa, and a vortex rotation speed of 15000 rpm.

[0039] Simultaneous application of a high-frequency ultrasonic field: frequency 35kHz, power density 1.5W / cm² 3 The preferred pulse mode is 30s working and 5s intermittent, with the grinding chamber temperature maintained at -30±2℃;

[0040] By dynamically adjusting the pulverization parameters using an online laser diffractometer, the particle size distribution was made to achieve D50 = 4.1 μm and D90 = 12.3 μm.

[0041] Volatile component recovery is further achieved using a three-stage gradient cold trap system:

[0042] First-stage -80℃ cold trap: traps large molecular volatiles (such as angelica lactone, boiling point >150℃);

[0043] Secondary -120℃ cold trap: Condensation of boiling point components (such as tetramethylpyrazine, boiling point 80-120℃);

[0044] Three-stage -196℃ liquid nitrogen cold trap: captures small molecule aldehydes and ketones (boiling point <80℃).

[0045] Surface modification: Immediately after pulverization, 0.3% surface modifier (lecithin-trehalose complex, mass ratio 1:4) was injected via a spray device at a pressure of 0.3 MPa and atomized particle size of 15 ± 5 μm. The resulting powder had a specific surface area of ​​11.7 m². 2 / g, angle of repose 28°.

[0046] Performance Verification and Application

[0047] index result Test methods Ferulic acid retention rate 97.2％ HPLC Dissolution rate of tetramethylpyrazine in 5 minutes 92％ Dissolution method in the 2020 edition of the Chinese Pharmacopoeia

[0048] Application: Mix 80wt% of this powder with 15wt% mannitol and 5wt% croscarmellose sodium, and compress directly into tablets (pressure 8kN), with a tablet weight of 100mg.

[0049] Example 2

[0050] This embodiment provides a preparation process and application of low-temperature pulverization of a traditional Chinese medicine composition, specifically, the preparation of Astragalus membranaceus-Ophiopogon japonicus compound powder.

[0051] To address the high thermosensitivity of astragaloside A (decomposition temperature 60℃) and ophiopogonin D (thermal isomerization), the following optimized process was adopted:

[0052] Raw material processing: Astragalus membranaceus and Ophiopogon japonicus (1:1) were sliced ​​to 0.5 mm and pre-frozen at -40℃ for 3.5 h (tanδ=0.02);

[0053] Grinding parameters adjusted: Ultrasonic power density increased to 2.0 W / cm³. 3 With broken fiber structure;

[0054] Surface modifier replacement: β-cyclodextrin-mannitol complex (1:2) was used, with an addition amount of 0.4%.

[0055] Key process control: The gas flow pressure is dynamically adjusted to 0.9 MPa to maintain D50 = 4.0 μm by using an online laser diffractometer to provide real-time feedback of particle size data.

[0056] As a preferred option, the -120℃ stage in the three-stage cold trap is used to focus on capturing Ophiopogon japonicus saponins (boiling point 210-230℃).

[0057] Stability and formulation performance

[0058] Accelerated test: After 3 months of storage at 40℃ / 75%RH, the retention rate of astragaloside A was 95.3%;

[0059] Inhalation performance: Powder and lactose carrier (80-100μm) were mixed at a ratio of 1:9. The new generation impactor test showed an FPF of 82.3% and a MMAD of 3.1μm.

[0060] Transdermal gel penetration rate: 0.18h -1 .

[0061] Furthermore, the glassy molecular locking mechanism increases the activation energy of thermal degradation to 152 kJ / mol (molecular dynamics simulation), and the inclusion effect of β-cyclodextrin inhibits saponin isomerization.

[0062] Example 3

[0063] This embodiment provides a preparation process and application of low-temperature pulverization of a traditional Chinese medicine composition, specifically, the preparation of Rehmannia glutinosa-Polygonatum sibiricum compound powder.

[0064] An innovative process for high-viscosity materials: Rehmannia glutinosa (35% polysaccharide) and Polygonatum sibiricum (28% polysaccharide) are mixed in a 2:1 ratio. The following steps are used to solve the problem of material sticking to the wall:

[0065] Pre-freezing treatment: Immersion in a 10% ethanol-dry ice mixture (-70℃) to reduce viscoelasticity;

[0066] Pulsed liquid nitrogen injection: every 30 seconds of pulverization is followed by a 5-second pause to reduce localized temperature rise;

[0067] Add flow aid: 0.1% nano silica (particle size 50nm).

[0068] Staged cold trap design:

[0069] A -120℃ stage is added to the three-stage cold trap to capture the iridoid glycosides of Rehmannia glutinosa (boiling point 185℃);

[0070] The recovery rate of iridoid glycosides was 95.6% as determined by HPLC.

[0071] Comprehensive performance test

[0072]

[0073]

[0074] Furthermore, when the powder was dispersed in 5 wt% sodium carboxymethyl cellulose gel, Franz diffusion cell experiments on isolated porcine skin showed a transdermal permeation rate constant of 0.18 h⁻¹. -1 .

[0075] The core breakthrough of this process lies in the first-ever organic integration of four key technical elements: glass transition control, vortex-ultrasonic synergistic pulverization, gradient cold trap recovery, and in-situ surface modification, forming a comprehensive protection mechanism for multi-component systems of traditional Chinese medicine. During the pre-freezing stage, by precisely controlling the medicinal materials to be below the glass transition temperature, the molecular motion energy barrier in the amorphous regions within the materials is significantly enhanced. At the pulverization kinetics level, the energy coupling between the vortex airflow field and the ultrasonic field creates a unique cell-wall breaking mode. Crucially, the pulsed ultrasonic working mode (30s on / 5s off) dissipates accumulated strain energy through a periodic relaxation process, strictly controlling the pulverization hotspot temperature below -30℃.

[0076] The innovation of the gradient cold trap system lies in the boiling point-adaptive trapping of volatile components. The three temperature zones (-80℃ / -120℃ / -196℃) essentially construct a molecular weight-selective condensation field: in the -80℃ region, high-boiling-point macromolecules such as angelica lactone are preferentially adsorbed due to enhanced van der Waals forces; in the -120℃ medium-temperature region, by reducing molecular kinetic energy, the Brownian motion radius of moderately volatile components such as tetramethylpyrazine is contracted to the range of the trap; and in the -196℃ liquid nitrogen region, the rotational freedom of small molecule aldehydes and ketones is completely frozen by ultra-low temperature.

[0077] This process breaks through the traditional single-temperature control approach of cryogenic pulverization, establishing a systematic solution encompassing "state transition - energy transfer - component recovery - interface engineering." Compared to existing technologies, its innovation is prominently reflected in three dimensions: At the thermodynamic level, glassy state control increases the molecular diffusion activation energy from the 80 kJ / mol level to the 150 kJ / mol level, achieving a qualitative leap in component protection from "delay" to "near-blocking"; at the kinetic level, the ultrasonic-vortex synergistic field reduces cell wall disruption energy consumption by 42%, resolving the contradiction between ultrafine pulverization and maintaining low temperatures; at the formulation level, in-situ modified powders directly meet the physical property requirements of novel drug delivery systems, shortening the process chain from raw materials to dosage form. This multi-dimensional innovation provides a scientifically sound and practical technological platform for the modernization of traditional Chinese medicine.

[0078] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A low-temperature pulverization process for preparing a traditional Chinese medicine composition, characterized in that: Includes the following steps: (a) Slice the Chinese herbal raw materials to a thickness of 0.5 to 2 mm, pre-freeze them at -40°C to -30°C for 2 to 4 hours, and confirm that the glass transition has been achieved by DSC detection of loss factor tanδ≤0.05; (b) The mixture is pulverized under liquid nitrogen protection using a vortex airflow pulverizer with a liquid nitrogen flow rate of 80-120 L / min (medicinal material ratio 1:1-1.5:1), an airflow pressure of 0.8-1.2 MPa, a vortex rotation speed of 12000-18000 rpm, and a pulverization chamber temperature maintained at -35℃ to -25℃. (c) A high-frequency ultrasonic field is applied simultaneously during the pulverization process, with a frequency of 28-40 kHz and a power density of 0.5-2 W / cm³. 3 ; (d) Volatile components are recovered through a three-stage cold trap, with the cold trap temperatures set at -80℃, -120℃, and -196℃, respectively; (e) Immediately after pulverization, add a surface modifier accounting for 0.1% to 0.5% of the powder weight, wherein the surface modifier is a lecithin-trehalose complex (mass ratio 1:3-1:5) or a β-cyclodextrin-mannitol complex (mass ratio 1:2).

2. The preparation process of a low-temperature pulverization of a traditional Chinese medicine composition as described in claim 1, characterized in that: The pre-freezing in step (a) adopts a step-by-step cooling method, first maintaining at -25℃ for 2 hours, and then lowering to -40℃ for 1.5 to 2 hours to avoid ice crystal growth that could damage cell structure.

3. The preparation process of a low-temperature pulverization of a traditional Chinese medicine composition as described in claim 2, characterized in that: The vortex airflow pulverizer in step (b) is equipped with an online laser diffractometer to monitor particle size in real time and dynamically adjust the airflow pressure to ensure D50 = 3-5 μm, D90 ≤ 15 μm, and specific surface area ≥ 8 m². 2 / g.

4. The preparation process of a low-temperature pulverization of a traditional Chinese medicine composition as described in claim 1, characterized in that: The ultrasonic field in step (c) is applied in pulse mode with a working cycle of 30s ultrasound / 5s interval to reduce local heat accumulation.

5. The preparation process of a low-temperature pulverization of a traditional Chinese medicine composition as described in claim 1, characterized in that: The surface modifier in step (e) is injected in situ at the end of the pulverization process using a spraying device, with a spraying pressure of 0.2-0.5 MPa and an atomized particle size of 10-20 μm.

6. The traditional Chinese medicine composition powder prepared by the low-temperature pulverization process according to any one of claims 1-5 is characterized in that: The volatile component retention rate is ≥97%, the heat-sensitive component degradation rate is ≤3%, the angle of repose is ≤30°, and the compression molding tensile strength is ≥2.5MPa.

7. The application of the traditional Chinese medicine composition powder as described in claim 6 in the preparation of acupoint patches, characterized in that: Apply the powder to the skin; it will be absorbed through the skin to achieve a therapeutic effect.

8. The application of the traditional Chinese medicine composition powder as described in claim 6 in the preparation of inhalation powder, characterized in that: The powder and lactose carrier (particle size 80-100μm) are mixed at a ratio of 1:9, with a fine particle fraction (FPF) ≥75% and an aerodynamic particle size (MMAD) of 1-5μm.

9. The application of the traditional Chinese medicine composition powder as described in claim 6 in the preparation of transdermal drug delivery formulations, characterized in that: The powder was dispersed in a sodium carboxymethyl cellulose gel matrix at a concentration of 5-10 wt%, with a transdermal permeation rate constant ≥0.15 h. -1 .

10. A low-temperature pulverizing system for preparing a traditional Chinese medicine composition according to any one of claims 1-5, characterized in that: include: Pre-freezing compartment with temperature control accuracy of ±1℃, equipped with DSC online monitoring module; Liquid nitrogen circulating vortex pulverizer, integrating an ultrasonic generator and temperature sensor; The three-stage gradient cold trap consists of an -80℃ cold trap to capture large molecular volatiles, a -120℃ cold trap to condense medium molecular components, and a -196℃ liquid nitrogen cold trap to capture small molecular volatiles. The laser diffractometer provides real-time feedback on particle size to the pulverizer control system. Surface modifier spraying device, atomization pressure 0.2-0.5MPa.

Images