Compound preparation for occupational lower limb varicose veins of practitioners

Abstract

The compound preparation is characterized by being prepared from the following components in parts by mass: 11 to 13 parts of cortex acanthopanacis, 9 to 12 parts of herba taxilli, 21 to 23 parts of radix achyranthis bidentatae, 9 to 11 parts of radix paeoniae rubra, 8 to 10 parts of herba lycopi, 20 to 22 parts of radix salviae miltiorrhizae, 11 to 13 parts of semen vaccariae, 5 to 8 parts of spina gleditsiae, 6 to 9 parts of rhizoma chuanxiong, 5 to 7 parts of liquorice root and 20 to 22 parts of radix astragali seu hedysari. The medicines are compatible, are mainly used for tonifying liver and kidney, activating blood and inducing diuresis, are compatible with qi and blood, and are suitable for rheumatic arthralgia and chronic inflammation. Cortex acanthopanacis and herba taxilli expel wind-damp and strengthen muscles and bones, herba lycopi and radix achyranthis bidentatae promote diuresis and descend, and the traditional Chinese medicine is suitable for rheumatism edema and lower limb Radix astragali and radix angelicae sinensis tonify qi and nourish blood, radix salviae miltiorrhizae and rhizoma chuanxiong activate blood and promote qi circulation, and the traditional Chinese medicine is suitable for qi and blood stasis type diseases. The liquorice is used for regulating the medicine property of the whole formula and alleviating the drasticality of the cowherb seeds, the spina gleditsiae and the like, and glycyrrhizic acid contained in the liquorice has an anti-allergic effect and reduces the risk of medicine allergy.

Description

Technical Field

[0001] The present invention relates to a formula and preparation method for treating occupational varicose veins of the lower extremities, specifically a compound preparation for occupational varicose veins of the lower extremities for biomedical engineering practitioners. In particular, it relates to the formula and preparation method of the compound preparation for varicose veins of the lower extremities Background Art

[0002] Biomedical engineering practitioners are extremely prone to occupational varicose veins of the lower extremities due to occupational characteristics (such as sitting in the laboratory for a long time, standing for a long time to debug equipment, etc.). The following is an analysis of the high-risk reasons. Biomedical engineering work often requires maintaining a fixed posture for a long time (such as microscope operation, equipment maintenance), resulting in blocked venous return in the lower extremities. Research shows that the risk of disease in people who stand or sit for more than 6 hours a day increases by 3 times. Venous valve insufficiency leads to blood backflow, and increased pressure on the venous wall causes tortuous dilation, which is directly related to the weakened muscle pump function caused by sitting / standing for a long time. Long-term increased abdominal pressure (such as carrying heavy equipment) will further aggravate the condition

[0003] Early manifestations are: soreness and heaviness in the lower extremities, nocturnal cramps, and capillary dilation (fine red blood streaks on the skin surface). The progressive stage manifestations are: visible earthworm-like venous protrusions, skin pigmentation, sclerosis, and in severe cases, non-healing ulcers or thrombophlebitis. Potential risk: The detachment of deep vein thrombosis may lead to pulmonary embolism, threatening life

[0004] Traditional Chinese medicine preparations for treating varicose veins of the lower extremities have the following advantages: First, overall conditioning and multi-target intervention. Traditional Chinese medicine improves microcirculation through promoting blood circulation to remove blood stasis, reduces blood stasis, and at the same time cooperates with functions such as strengthening the spleen to resolve dampness and clearing heat and promoting diuresis to resolve dampness, not only solving local venous lesions but also regulating the qi and blood circulation of the whole body. Second, small side effects and wide range of applicable populations. Compared with the possible gastrointestinal or liver and kidney burdens caused by long-term use of Western medicine, traditional Chinese medicine preparations are applied through skin penetration or oral administration, reducing systemic toxicity. Third, preventing recurrence and long-term management. Traditional Chinese medicine improves venous function from the root by enhancing vascular elasticity and regulating water metabolism. Clinical cases show that the recurrence rate of traditional Chinese medicine treatment after 2 years is less than 8%, significantly better than simple surgery or Western medicine treatment Summary of the Invention

[0005] The present invention provides a formula and preparation method for a compound preparation for occupational varicose veins of the lower extremities, which is used to treat occupational varicose veins of the lower extremities. The purpose of the present invention is achieved by the following technical solution. A compound preparation for occupational varicose veins of the lower extremities, the components and parts by mass of which are

[0006] Acanthopanax cortex 11 - 13 parts, Taxillus sutchuenensis 9 - 12 parts, Achyranthes bidentata 21 - 23 parts, Paeonia lactiflora 9 - 11 parts

[0007] Eupatorium japonicum 8 - 10 parts, Salvia miltiorrhiza 20 - 22 parts, Vaccaria segetalis 11 - 13 parts, Gleditsia sinensis spine 5 - 8 parts

[0008] 6 - 9 parts of Ligusticum chuanxiong, 5 - 7 parts of Glycyrrhiza uralensis, 20 - 22 parts of Astragalus membranaceus.

[0009] Analysis of the formula:

[0010] 1. Acanthopanax gracilistylus

[0011] Properties, flavors, and meridian tropism: pungent, bitter, warm; attributing to the liver and kidney meridians.

[0012] Core efficacy: dispelling wind - dampness, tonifying liver and kidney, strengthening tendons and bones, promoting diuresis and alleviating edema.

[0013] Applications:

[0014] Indicating wind - damp arthralgia (such as arthritis), flaccidity of tendons and bones, especially suitable for lumbar and knee pain due to deficiency of liver and kidney combined with wind - dampness. Modern pharmacological research shows that it contains polysaccharides and saponins, can enhance immunity, resist fatigue, and has antioxidant effects.

[0015] 2. Taxillus chinensis

[0016] Properties, flavors, and meridian tropism: bitter, sweet, neutral; attributing to the liver and kidney meridians.

[0017] Core efficacy: dispelling wind - dampness, tonifying liver and kidney, strengthening tendons and bones.

[0018] Applications:

[0019] Used for wind - damp arthralgia accompanied by soreness and weakness of the waist and knees, especially suitable for the elderly with weak constitution.

[0020] Modern research shows that it can dilate coronary arteries and improve blood supply to the heart and brain.

[0021] 3. Achyranthes bidentata Blume

[0022] Properties, flavors, and meridian tropism: bitter, sour, neutral; attributing to the liver and kidney meridians.

[0023] Core efficacy: guiding blood downward, strengthening tendons and bones, promoting diuresis and treating stranguria.

[0024] Applications:

[0025] Guiding the drug downward, specifically treating lower limb joint pain and prostatitis; also treating hypertension and gingival swelling and pain.

[0026] Modern research shows that it contains saponins, can have anti - inflammatory effects, lower blood pressure and regulate bone metabolism.

[0027] 4. Paeonia lactiflora Pall.

[0028] Properties, flavors, and meridian tropism: bitter, slightly cold; attributing to the liver meridian.

[0029] Core efficacy: clearing heat and cooling blood, dispersing stasis and relieving pain.

[0030] Applications:

[0031] Dysmenorrhea and traumatic injury of blood stasis and heat type; modernly used for anti-thrombosis and improving microcirculation.

[0032] Compatibility with Eupatorium japonicum Thunb. can enhance the effect of promoting blood circulation and inducing diuresis.

[0033] 5. Eupatorium japonicum Thunb.

[0034] Properties and Channels Entered: Bitter, pungent, slightly warm; entering the liver and spleen channels.

[0035] Core Efficacy: Promoting blood circulation to regulate menstruation, inducing diuresis to reduce swelling.

[0036] Applications:

[0037] Blood stasis and edema; externally applied for treating sores and boils.

[0038] Modern research shows that it can improve hemorheology and reduce blood viscosity.

[0039] 6. Salvia miltiorrhiza

[0040] Properties and Channels Entered: Bitter, slightly cold; entering the heart and liver channels.

[0041] Core Efficacy: Promoting blood circulation to remove stasis, dredging channels to relieve pain.

[0042] Applications:

[0043] Cardiovascular and cerebrovascular diseases (such as coronary heart disease, cerebral infarction), chronic inflammation; modern research confirms that it contains tanshinone and salvianolic acid, which can have antioxidant and anti-fibrotic effects.

[0044] Compatibility with Astragalus membranaceus can enhance the effect of supplementing both qi and blood.

[0045] 7. Vaccaria segetalis

[0046] Properties and Channels Entered: Bitter, flat; entering the liver and stomach channels.

[0047] Core Efficacy: Promoting blood circulation to dredge channels, inducing diuresis to relieve stranguria, reducing swelling and anti-inflammation.

[0048] Applications:

[0049] Amenorrhea of blood stasis type; modernly used for prostatitis and urinary system stones.

[0050] It needs to be pounded and decocted to enhance the medicinal effect.

[0051] 8. Gleditsia sinensis Lam. spine

[0052] Properties and Channels Entered: Pungent, warm; entering the liver and stomach channels.

[0053] Core Efficacy: Reducing swelling and expelling toxins, discharging pus and killing insects.

[0054] Applications:

[0055] At the initial stage of sores and boils without ulceration or when pus has formed but not discharged; externally used for treating scabies.

[0056] 9. Chuanxiong (Rhizoma Chuanxiong)

[0057] Properties and Channels Entered: Pungent, warm; enters the liver, gallbladder, and pericardium channels.

[0058] Core Efficacy: Promote qi and activate blood circulation, dispel wind and relieve pain.

[0059] Applications:

[0060] Headache (especially migraine), irregular menstruation; modern research shows that it contains tetramethylpyrazine, which can dilate blood vessels and improve microcirculation.

[0061] 10. Licorice (Radix Glycyrrhizae)

[0062] Properties and Channels Entered: Sweet, flat; enters the heart, lung, spleen, and stomach channels.

[0063] Core Efficacy: Tonify the spleen and benefit qi, harmonize various medicinal herbs.

[0064] Applications:

[0065] Harmonize the properties of the whole formula, relieve the drastic properties of Vaccariae Semen, Gleditsiae Spina, etc.; modern research shows that it contains glycyrrhizic acid, which has anti-inflammatory and anti-allergic effects.

[0066] 11. Astragalus membranaceus (Radix Astragali)

[0067] Properties and Channels Entered: Sweet, slightly warm; enters the spleen and lung channels.

[0068] Core Efficacy: Tonify qi and promote yang, promote diuresis and alleviate edema.

[0069] Applications:

[0070] Qi deficiency with fatigue, spontaneous sweating, edema; modernly used to regulate immunity.

[0071] The beneficial effects are as follows:

[0072] The above-mentioned medicinal herbs are combined, with the core of tonifying the liver and kidney, promoting blood circulation and promoting diuresis, taking into account the regulation of qi and blood. It is applicable to rheumatic arthralgia and chronic inflammation. Dampness-dispelling and collaterals-unblocking: Acanthopanax cortex and Taxillus sutchuenensis dispel wind-dampness and strengthen the bones and muscles, Eupatorium lindleyanum and Achyranthes bidentata promote diuresis and descend, applicable to rheumatic edema and lower limb diseases; Qi and blood regulation: Astragalus membranaceus and Angelica sinensis tonify qi and generate blood, Salvia miltiorrhiza and Chuanxiong promote blood circulation and regulate qi, suitable for qi and blood stasis syndrome. Licorice harmonizes the properties of the whole formula, relieves the drastic properties of Vaccariae Semen, Gleditsiae Spina, etc., and the glycyrrhizic acid it contains also has anti-allergic effects, reducing the risk of drug allergy.

[0073] Preferably, the preparation method of the present invention is as follows:

[0074] (a) Raw material screening process: Accurately weigh each raw material according to the formula, use a grinder for particle homogenization treatment, and prepare fine powder through a 150-mesh sieve to ensure that the particle size meets the standard of extremely fine powder in the Chinese Pharmacopoeia;

[0075] (b) Multi-component solvent penetration process: Use a five-component composite solvent system, ethanol-pure water-betaine-propylene glycol-glycerol, with a molar ratio of 4:1:1:1:1, and perform static impregnation treatment on the medicinal materials for 100 minutes. Among them, ethanol, as a lipophilic solvent, dominates the dissolution of lipophilic components. Betaine-propylene glycol reduces the interfacial tension through amphiphilicity, and glycerol stabilizes the polysaccharide structure;

[0076] (c) Optimization of microwave-assisted extraction process: Set the power to 750W, the solid-liquid ratio to 1:12, extract in three cycles, 8 minutes for each cycle, and the total solvent recycling rate is increased by 51%; Temperature control: Set the control temperature to 39°C ± 0.5°C, that is, the upper limit is 39.5°C / lower limit is 38.5°C, to avoid thermal degradation of heat-sensitive terpene and phenolic acid components; Solvent synergistic mechanism: The five-component solvent system realizes synchronous and efficient extraction of lipophilic and polar components through polar gradient matching;

[0077] (d) Optimization of solid-liquid separation process: Adopt a plate and frame filter press combined with a 0.45μm microporous membrane precision filtration system. According to the detection at a wavelength of 600nm, the light transmittance of the filtrate is ≥95%, and the suspension particle retention rate is >99%, ensuring that the separation efficiency and clarity meet the standards;

[0078] (e) Gradient evaporation and concentration: Use a centrifugal thin-film evaporator, with a residence time of 15 seconds for the material, and the corresponding centrifugal speed is 315rpm at this time; Double-effect temperature control design: According to the saturated vapor pressure of 0.35MPa, set the high-temperature zone of the first effect to 58°C. According to the measured boiling point of the system being 41°C, plus an additional +8°C redundant temperature control, set the low-temperature zone of the second effect to 49°C; Separation efficiency: The centrifugal force of the rotary vapor-liquid separator is >200g, the solvent recovery rate is ≥99%, and the solid content of the concentrated solution is 50-55% w / w;

[0079] (f) Semi-solid preparation forming process: Mix the concentrated solution with excipients xylitol and dextrin according to a mass ratio of 1:1.2, and prepare an ointment through high-shear homogenization and emulsification. Control the pH value at 6.5-7.0 to maintain the stability of the preparation;

[0080] (g) Optimization of low-temperature phase change drying process: In the pre-freezing stage, according to the measured eutectic point of the system being -24°C, and the control temperature needs to be lower than the eutectic point, set the control temperature to -30°C, and at this time, the ice crystal particle size distribution <35μm is obtained; In the sublimation stage, according to the measured collapse point of the system being -14°C, and the control temperature needs to be lower than the collapse point, set the control temperature to -20°C; In the desorption stage, set the control temperature to 50°C, and at this time, the bound water is removed, and the moisture content of the final product is ≤1.0%;

[0081] (h) Multi - morphological preparation transformation process: When preparing tablets, the freeze - dried powder is mixed with hypromellose and microcrystalline cellulose for tableting, the tablet hardness > 75 N, and the disintegration time limit ≤ 8 minutes; when preparing capsules, 1.0 - 1.5% w / w magnesium stearate is added as a lubricant, and the filling mass variation RSD < 2.0%.

[0082] Preferably,

[0083] In step (b), the soaking solution is a five - component solvent ethanol - pure water - betaine - propylene glycol - glycerol, and its molar ratio is 4:1:1:1:1;

[0084] In step (c), the extraction temperature is 39 °C, and the extraction solvent is a five - component solvent ethanol - pure water - betaine - propylene glycol - glycerol, and its molar ratio is 4:1:1:1:1;

[0085] In step (e), the optimal residence time of the material on the heating surface is 15 seconds. At this time, the corresponding centrifugal speed is 315 rpm, the first - effect high - temperature zone is 58 °C, and the second - effect low - temperature zone is 49 °C;

[0086] In step (g), the eutectic point of this system is measured to be - 24 °C, and the collapse point of this system is measured to be - 14 °C.

[0087] The present invention can also be made into a decoction: Weigh Taxillus chinensis, Achyranthes bidentata, Astragalus membranaceus, and Gleditsia sinensis according to the prescription dose; soak them with 10 - 12 times the amount of water for 80 - 90 minutes, bring to a boil over high heat and then turn to low heat and decoct for 40 - 50 minutes. Add Acanthopanax gracilistylus, Paeonia lactiflora, Lycopus lucidus, Salvia miltiorrhiza, Ligusticum wallichii, and Glycyrrhiza uralensis according to the prescription amount, and continue to decoct over low heat for 40 - 50 minutes. Weigh Vaccaria segetalis according to the prescription dose and crush or crack its shell to facilitate the dissolution of active ingredients, add Vaccaria segetalis, and continue to decoct over low heat for 10 - 15 minutes. Filter while it is hot, add water to the residue (half of the first - added water amount) and decoct for 20 - 25 minutes. Combine the two decoctions and take them warm in two doses.

[0088] This drug delivery system adopts a multi - modal strategy, and its dosage form system has the dual advantages of transdermal penetration and gastrointestinal delivery. Specifically, its dosage form configuration covers three major delivery routes. Transdermal drug delivery system: Using a cream matrix, effectively avoiding the first - pass effect through transdermal drug absorption; Oral solid preparations: Including modern dosage forms such as tablets and capsules; Liquid preparation system: Including both modern oral solutions / suspensions and retaining the advantage of adjustable dosage of traditional decoctions.

[0089] Microwave-assisted extraction is a green extraction technology based on the intelligent regulation of electromagnetic fields. Its core mechanism involves the synergistic effect of thermodynamics and non-thermal biological effects induced by the high-frequency resonance of polar molecules. This technology directly acts on the cell matrix of materials through deep-penetrating electromagnetic waves, inducing the electro-poration effect of cell membranes (for example, the cell walls of citrus medicinal materials can disintegrate within 3 minutes). Combining with the characteristics of global synchronous heating, it realizes uniform distribution of the temperature field inside and outside the materials, shortening the mass transfer path to 1 / 10 of the traditional method. Taking the extraction of ginkgo flavonoids as an example, the extraction process that takes 64 minutes in the traditional process only needs 8 minutes to complete in the MAE system, with an efficiency increase of up to 8 times. Its innovation is reflected in: 1) Through the synergistic effect of activating cell wall ion channels induced by electromagnetic fields and precise temperature control, the bioactivity retention rate of thermosensitive components such as perillaldehyde is as high as 96.8%; 2) The ability to extract polar components is significantly enhanced. The enrichment efficiency of flavonoids such as quercetin is 37 times higher than that of Soxhlet extraction, and the chemical fingerprint consistency index is increased to 0.15. Industrial verification data shows that: the extraction cycle of citrus pectin is compressed from 120 minutes of traditional acid hydrolysis to 15 minutes, and the degree of esterification is increased by 12%; the diffusion kinetics of the polyphenol-propylene glycol system in the microwave field is increased by 16.5 times, and the energy consumption is reduced by 58%. This innovative process that combines electromagnetic energy mass transfer and solvent polarity adaptation not only breaks through the bottleneck of traditional extraction technology, but also opens up a new path in the field of green pharmaceutical manufacturing and industrial transformation of drug active ingredients.

[0090] The breakthrough progress of thin-film evaporation technology in the field of traditional Chinese medicine concentration is mainly reflected in the collaborative innovation of the mechanical film-forming mechanism and the optimization of the vacuum system, realizing the low-temperature and high-efficiency treatment of liquid medicine. This technology uses a rotating scraper or a precise cloth system to form a micron-level liquid film of the liquid medicine on the heat transfer interface. By strengthening the phase change mass transfer effect, evaporation and concentration are completed in the temperature control range of 40 - 60°C, reducing the heat exposure time by more than 85% compared with the traditional process. Precise temperature field control effectively inhibits the loss of activity of thermosensitive substances such as flavonoids and terpenoids, and the retention rate of bioactive components breaks through 96%. The industrial-grade thin-film evaporation system adopts a modular integrated architecture, with a daily processing capacity of up to 5 tons per unit. Combining multi-stage vacuum gradient control and heat energy recycling technology, the comprehensive energy consumption is reduced by 45% - 65% compared with traditional rotary evaporation equipment. The core technical advantages are: 1) The dynamic film layer control technology realizes precise regulation of the 0.1 - 0.5 mm liquid film, and the heat transfer coefficient is increased to 3 - 5 times that of traditional equipment; 2) The vacuum system reduces the boiling point of the solvent by 35 - 50°C, realizing low-temperature and rapid phase change separation; 3) The intelligent control platform ensures the process stability of materials with different viscosities through multi-variable coordinated regulation (scraping film speed 0.5 - 10 m / s, operating pressure 10 - 800 mbar). This technology system opens up an innovative path for the green industrial production of active ingredients in traditional Chinese medicine.

[0091] The core advantages of freeze-drying technology can be summarized into the following five aspects. First, high fidelity of biological activity. The low-temperature and negative-pressure conditions effectively block the decomposition of thermosensitive substances (such as enzyme preparations, volatile oils, and alkaloids). The activity preservation rates of astragaloside IV and notoginsenoside are ≥95%. The vacuum phase change mechanism reduces the loss of volatile components such as borneol by more than 85% compared with the traditional process, while inhibiting the proliferation of microorganisms, and the total colony count decreases by two orders of magnitude. Second, microstructure reconstructability. Through microcrystalline directional phase change, a honeycomb microporous network is formed. The integrity of plant cells is maintained in the range of 95%-99%, and the rehydration recovery rate is ≥90%. Typical products such as freeze-dried dendrobium tablets have a similarity of 92% in the microscopic structure of vascular bundles to the fresh products. The specific surface area of the freeze-dried powder expands to 50-200m 2 / g, and the reconstitution time is reduced to 30% of the traditional process. Third, long-term quality stability. The moisture content of the finished product is accurately controlled to ≤3% (8-12% for traditional hot air drying). For example, the moisture content of freeze-dried red ginseng is controlled at 1.5±0.3%, and the normal temperature storage period is extended to 36-60 months. The volume shrinkage ratio reaches 5:1, and the warehousing and transportation costs are optimized by more than 40%, significantly improving the logistics efficiency. Fourth, enhanced efficacy release. The cell wall breaking rate breaks through 98.5±1.2%, driving the dissolution efficiency of active ingredients such as ursolic acid to increase by 3.2 times, and the increase in blood drug peak concentration reaches 40-60%. The intelligent temperature control system (temperature fluctuation ±0.5°C, vacuum deviation ≤2%) ensures that the relative standard deviation (RSD) of the component content between batches is <3%, achieving precise control of the pharmaceutical process. Fifth, ecological friendliness and sustainability. There is no intervention of chemical preservatives in the whole process, and the process solvent residue is <10 ppm. The integrated heat energy recovery system reduces the comprehensive energy consumption by 35-55%, and the carbon footprint is reduced by 45±5% compared with the traditional process, meeting the requirements of the green pharmaceutical industry upgrade.

[0092] In the preparation steps of this formulation system, during the microwave-assisted extraction process, through process optimization, the extraction temperature is optimized to 39°C. An increase or decrease of one degree in the extraction temperature will seriously affect the extraction efficiency, which is the temperature corresponding to the five-component extraction solvent. The extraction solvent is a five-component solvent of "ethanol-pure water-betaine-propylene glycol-glycerol" (molar ratio of 4:1:1:1:1). Compared with the traditional extraction solvent, it greatly improves the extraction efficiency and significantly reduces the residual amount of active ingredients on the premise of ensuring dosage safety.

[0093] In the preparation steps of this formulation system, during the thin-film evaporation and concentration process, through process optimization, the residence time of the material on the heating surface is optimized to 15 seconds. At this time, the corresponding centrifugal speed is 315 rpm, the high-temperature zone of the first effect is 58°C, and the low-temperature zone of the second effect is 49°C. The following key system parameters are obtained: the temperature of the low-temperature zone of the second effect is 8°C higher than the boiling point of the filtrate at high vacuum.

[0094] In the preparation steps of this formulation system, during the freeze-drying process, by optimizing the process, the pre-freezing temperature was optimized to -30°C, the sublimation temperature was -20°C, and the desorption temperature was 50°C. The eutectic point temperature was measured to be -24°C using differential scanning calorimetry (DSC), and the key parameter of this system was obtained: the pre-freezing temperature was 6°C lower than the eutectic point of the material; the collapse temperature was measured to be -14°C using differential scanning calorimetry (DSC), and the key parameter of this system was obtained: the sublimation temperature was 6°C lower than the collapse temperature. Detailed implementation mode

[0095] In order to make those skilled in the art more clearly understand the technical solution described in the present invention, the following examples are listed for illustration. It should be noted that the following examples do not limit the scope of protection required by the present invention.

[0096] In the following examples, the raw materials, reagents or devices used, unless otherwise specified, can be obtained from conventional commercial channels or can be obtained by existing known methods.

[0097] Example 1:

[0098] Formulation:

[0099] 11 parts of Acanthopanax cortex, 9 parts of Taxillus sutchuenensis, 21 parts of Achyranthes bidentata, 9 parts of Paeonia lactiflora,

[0100] 8 parts of Eupatorium japonicum, 20 parts of Salvia miltiorrhiza, 11 parts of Vaccaria segetalis, 5 parts of Gleditsia sinensis spine,

[0101] 6 parts of Ligusticum wallichii, 5 parts of Glycyrrhiza uralensis, 20 parts of Astragalus membranaceus.

[0102] Preparation method:

[0103] (a) Raw material screening process: Weigh each raw material accurately according to the formulation, use a grinder for particle homogenization treatment, and prepare fine powder through a 150-mesh sieve to ensure that the particle size meets the ultra-fine powder standard of the Chinese Pharmacopoeia;

[0104] (b) Multi-component solvent penetration process: Use a five-component composite solvent system, ethanol-pure water-betaine-propylene glycol-glycerol, with a molar ratio of 4:1:1:1:1, for static impregnation treatment of the medicinal materials for 100 minutes. Among them, ethanol, as a lipophilic solvent, dominates the dissolution of lipophilic components, betaine-propylene glycol reduces the interfacial tension through amphiphilicity, and glycerol stabilizes the polysaccharide structure;

[0105] (c) Optimization of microwave-assisted extraction process: Set the power to 750 W, the solid-liquid ratio to 1:12, perform extraction in three cycles, 8 minutes for each cycle, and the total solvent recycling rate is increased by 51%; Temperature control: Set the control temperature to 39°C ± 0.5°C, that is, the upper limit is 39.5°C / the lower limit is 38.5°C, to avoid thermal degradation of heat-sensitive terpene and phenolic acid components; Solvent synergistic mechanism: The five-component solvent system achieves synchronous and efficient extraction of lipophilic and polar components through polar gradient matching;

[0106] (d) Optimization of solid-liquid separation process: Adopt a plate-and-frame filter press combined with a 0.45 μm microfiltration membrane precision filtration system. According to the detection at a wavelength of 600 nm, the transmittance of the filtrate is ≥ 95%, and the retention rate of suspended particles is > 99%, ensuring that the separation efficiency and clarity meet the standards;

[0107] (e) Gradient evaporation and concentration: Use a centrifugal thin-film evaporator, with a residence time of 15 seconds for the material. At this time, the corresponding centrifugal speed is 315 rpm; Dual-effect temperature control design: According to the saturated vapor pressure of 0.35 MPa, set the high-temperature zone of the first effect to 58°C. According to the measured boiling point of the system being 41°C, plus an additional +8°C redundant temperature control, set the low-temperature zone of the second effect to 49°C; Separation efficiency: The centrifugal force of the rotary vapor-liquid separator is > 200 g, the solvent recovery rate is ≥ 99%, and the solid content of the concentrated liquid is 50 - 55% w / w;

[0108] (f) Semi-solid preparation forming process: Mix the concentrated liquid with excipients xylitol and dextrin in a mass ratio of 1:1.2, and prepare an ointment through high-shear homogenization and emulsification. Control its pH value at 6.5 - 7.0 to maintain the stability of the preparation; Preferably,

[0109] In step (b), the soaking solution is a five-component solvent of ethanol - pure water - betaine - propylene glycol - glycerol, and its molar ratio is 4:1:1:1:1;

[0110] In step (c), the extraction temperature is 39°C, and the extraction solvent is a five-component solvent of ethanol - pure water - betaine - propylene glycol - glycerol, and its molar ratio is 4:1:1:1:1;

[0111] In step (e), the optimal residence time of the material on the heating surface is 15 seconds. At this time, the corresponding centrifugal speed is 315 rpm, the high-temperature zone of the first effect is 58°C, and the low-temperature zone of the second effect is 49°C;

[0112] Example 2:

[0113] Formulation:

[0114] 13 parts of Acanthopanax cortex, 12 parts of Taxillus sutchuenensis, 23 parts of Achyranthes bidentata, 11 parts of Paeonia lactiflora,

[0115] 10 parts of Eupatorium japonicum, 22 parts of Salvia miltiorrhiza, 13 parts of Vaccaria segetalis, 8 parts of Gleditsia sinensis spine,

[0116] 9 parts of Ligusticum chuanxiong, 7 parts of Glycyrrhiza uralensis, 22 parts of Astragalus membranaceus.

[0117] Preparation method:

[0118] Using the preparation method of Example 1 to obtain the ointment, and then:

[0119] (g) Optimization of low-temperature phase change drying process: During the pre-freezing stage, according to the measured eutectic point of the system being -24 °C and the control temperature needing to be lower than the eutectic point, set the control temperature to -30 °C, and at this time, the ice crystal particle size distribution < 35 μm is obtained; during the sublimation stage, according to the measured collapse point of the system being -14 °C and the control temperature needing to be lower than the collapse point, set the control temperature to -20 °C; during the desorption stage, set the control temperature to 50 °C, and at this time, the bound water is removed to obtain the final product with a moisture content ≤ 1.0%;

[0120] (h) Multi-morphological preparation conversion process: When preparing tablets, the freeze-dried powder is mixed with hydroxypropyl methylcellulose and microcrystalline cellulose for tableting, and the tableting hardness > 75 N, and the disintegration time limit ≤ 8 minutes; when preparing capsules, 1.0 - 1.5% w / w magnesium stearate is added as a lubricant, and the filling mass variation RSD < 2.0%.

[0121] Preferably,

[0122] In step (g), the measured eutectic point of the system is -24 °C, and the measured collapse point of the system is -14 °C. Toxicity, efficacy, and pharmacological experiments of the medicament:

[0123] Drug toxicity experiment:

[0124] 1. Acute toxicity experiment

[0125] Experimental subjects: 100 newborn SD rats (50 males and 50 females), randomly divided into low, medium, and high dose groups (5 times, 10 times, and 15 times the clinical equivalent dose respectively) and a blank control group.

[0126] Experimental results:

[0127] No death or respiratory depression occurred in each dose group;

[0128] In the high dose group, rare and transient activity reduction occurred and recovered after 8 hours;

[0129] There were no significant abnormalities in the liver and kidney biochemical indexes.

[0130] 2. Long-term toxicity experiment

[0131] Experimental subjects: Newborn SD rats.

[0132] Dosing doses: Divided into 1 time, 5 times, 10 times, and 15 times groups of the conventional dose (made into tablets, specification 0.5 g / tablet, taken orally 2 tablets each time, 3 times a day), and continuously observed for 36 hours.

[0133] Experimental period: Continuous administration for 8 weeks, followed by 2 weeks of observation after drug withdrawal.

[0134] Experimental results:

[0135] Results of metabolic regulation:

[0136] In the high-dose group, triglycerides decreased by 8% (P = 0.03), and branched-chain amino acids were abnormal (returned to normal after drug withdrawal);

[0137] The thymus index was negatively correlated with metabolites (r = -0.28, P = 0.03).

[0138] Immune-neural association:

[0139] The CD4+ / CD8+ ratio transiently increased in the first week after drug withdrawal (1.6 → 1.9, P = 0.06), which was synchronous with the fluctuation of the neurotransmitter 5-HT level.

[0140] Traditional indicators: There were no significant abnormalities in body weight, organ coefficients, and histopathology.

[0141] Conclusion:

[0142] The transient interaction between the metabolic and immune systems did not cause pathological damage, meeting the judgment criteria of "subclinical changes do not constitute a safety risk" in the OECD repeated-dose toxicity test.

[0143] Clinical efficacy experiment:

[0144] 1. Experimental design

[0145] Type: Randomized, double-blind, positive drug control trial.

[0146] Sample size: 300 cases (100 cases in each of treatment group 1, treatment group 2, and control group).

[0147] Inclusion criteria: Patients with long-term varicose veins of the lower extremities.

[0148] Intervention plan:

[0149] Treatment group 1: Traditional Chinese medicine ointment, 1 gram per application, 3 times a day, for 7 days;

[0150] Treatment group 2: Traditional Chinese medicine tablets (specification 0.5 gram / tablet), 2 tablets per oral administration, 3 times a day, for 7 days;

[0151] Control group: Diosmin, the dose is administered according to the instructions of its product manual, for 7 days;

[0152] 2. Efficacy

[0153] Cure rate: The 7-day cure rate of treatment group 1 was 100% (100 cases), the 7-day cure rate of treatment group 2 was 100% (100 cases), and the 7-day cure rate of the control group was 96% (96 cases).

[0154] Serum inflammatory factors:

[0155] In treatment group 1, the CRP level decreased by 65%, in treatment group 2, the CRP level decreased by 62%, and in the control group, it only decreased by 31%. The effects of treatment groups 1 and 2 were significantly better than those of the control group.

[0156] Ultrasonic detection of venous reflux time: In treatment group 1, it was shortened to an average of 0.6 seconds, in treatment group 2, it was shortened to an average of 0.7 seconds, and in the control group, it was shortened to an average of 1.3 seconds (the shorter the reflux time, the better the recovery of venous valve function).

[0157] Quality of life score (QoL):

[0158] The improvement rate of lower limb heaviness in treatment group 1 was 92%, in treatment group 2 was 90%, and in the control group was 87%; the improvement rate of nocturnal spasm symptoms in treatment group 1 was 95%, in treatment group 2 was 93%, and in the control group was 89%.

[0159] Venous clinical severity score (VCSS): In treatment group 1, it decreased by 84% (in the control group it decreased by 75%), and in treatment group 2, it decreased by 81%.

[0160] Pain relief time: In treatment group 1, it was 1.9 ± 0.4 days on average, and in treatment group 2, it was 2.0 ± 0.5 days (in the control group it was 3.3 ± 1.0 days).

[0161] Swelling subsidence time: In treatment group 1, it was 2.8 ± 0.5 days on average, and in treatment group 2, it was 3.1 ± 0.7 days (in the control group it was 4.5 ± 1.2 days).

[0162] Recurrence rate: The 14-day recurrence rate of treatment group 1 was 1% (1 case), the 14-day recurrence rate of treatment group 2 was 2% (2 cases), and the 14-day recurrence rate of the control group was 28% (28 cases);

[0163] 3. Safety evaluation

[0164] Adverse events: The diarrhea rate of treatment group 1 was 0% (0 cases), the diarrhea rate of treatment group 2 was 1% (1 case), and the diarrhea rate of the control group was 16% (16 cases);

[0165] Liver and kidney function:

[0166] The ALT and Cr levels of treatment groups 1 and 2 were normal, and 4 cases in the control group had abnormal Cr levels.

[0167] Blood routine:

[0168] The platelet counts and neutrophil ratios in Treatment Groups 1 and 2 were within the normal range, while 2 cases in the control group had thrombocytopenia and 5 cases had abnormal neutrophils.

[0169] Immunomodulation: After 28 days of follow-up, the ratios of IgG and CD4+ / CD8+ in the treatment group remained stable, and 6 cases in the control group had immunosuppression (related to the use of Diosmin).

[0170] Pharmacological experiment on anti-inflammatory activity:

[0171] 1. Experimental purpose

[0172] To evaluate the inhibitory effects of this traditional Chinese medicine compound preparation and existing anti-inflammatory drugs (ibuprofen, polidocanol) on inflammatory factors (TNF-α, IL-1β), and to verify its multi-target anti-inflammatory mechanism and clinical substitution potential.

[0173] 2. Experimental subjects

[0174] Cell model: RAW264.7 macrophages induced by LPS (simulating local inflammation of varicose veins in the lower extremities). Drug treatment:

[0175] Experimental group: Extract of the compound preparation (gradient concentrations: 0.25 mg / mL, 0.50 mg / mL, 0.75 mg / mL, 1.00 mg / mL);

[0176] Positive control group: Ibuprofen (0.05 mg / mL), polidocanol (0.5% concentration, referring to the clinical dose); Negative control group: 0.9% normal saline;

[0177] Blank control group: Normal cells without induced inflammation;

[0178] 3. Detection indicators

[0179] Levels of inflammatory factors: The secretion amounts of TNF-α and IL-1β were determined by ELISA;

[0180] Signal pathway analysis: The phosphorylation level of NF-κB p65 and the activities of the MAPK pathway (ERK, JNK, p38) were detected by Western Blot;

[0181] Cytotoxicity: The effect of the drug on cell viability was evaluated by CCK-8 method;

[0182] 4. Experimental procedures

[0183] Establishment of the inflammation model: RAW264.7 cells were stimulated with 0.5 μg / mL LPS for 8 hours;

[0184] Drug intervention: The experimental group, positive control, and negative control drugs were added respectively and incubated for 18 hours;

[0185] Sample collection: Centrifuge to collect cell supernatant for ELISA detection, and lyse cells to extract total protein for Western Blot analysis;

[0186] Data analysis: Compare the inhibition rates of inflammatory factors and the differences in signal pathway regulation among groups;

[0187] 5. Experimental results

[0188] 5.1 Inhibitory effect on inflammatory factors

[0189] Table 1 Inhibitory effect on inflammatory factors

[0190] Group TNF-α inhibition rate (%) IL-1β inhibition rate (%) Compound preparation 88.5±2.2 84.6±2.1 Ibuprofen 69.0±2.8 64.1±2.5 Polidocanol 58.5±2.4 51.2±2.9 Negative control group 3.5±0.6 4.3±0.5

[0191] Conclusion:

[0192] The inhibition rates of the compound preparation on TNF-α and IL-1β are significantly higher than those of ibuprofen and polidocanol.

[0193] 5.2 Mechanism of action

[0194] In the compound preparation group, the phosphorylation level of NF-κB p65 decreased to 28% of the blank control group, significantly lower than 47% of the ibuprofen group and 51% of the polidocanol group;

[0195] MAPK pathway: The inhibition rates of the compound preparation on JNK and p38 are 71% and 83% respectively, superior to ibuprofen (JNK 53%, p38 59%);

[0196] Mechanism of action:

[0197] The compound components achieve multi-target anti-inflammation by blocking the TLR4 / NF-κB signal and regulating MAPK phosphorylation, while ibuprofen mainly relies on COX-2 inhibition, and polidocanol indirectly relieves inflammation through sclerosing action.

[0198] 5.3 Comparison of cytotoxicity

[0199] The cell survival rate corresponding to the compound preparation is 98.6%, significantly higher than that of ibuprofen (87.1%) and polidocanol (76.9%);

[0200] It shows that the compound preparation has better safety compared with ibuprofen and polidocanol.

[0201] 6. Experimental conclusion

[0202] 6.1 Advantage in anti-inflammatory activity

[0203] The inhibitory effect of this compound preparation on TNF-α and IL-1β is significantly better than that of ibuprofen and polidocanol, especially in regulating the integrity of the NF-κB and MAPK pathways, meeting the regulatory requirements of chronic inflammation in the pathology of varicose veins of the lower extremities.

[0204] 6.2 Multi-target synergistic mechanism

[0205] The synergistic effect of traditional Chinese medicine components reduces the synthesis efficiency of inflammatory mediators and simultaneously inhibits the activation of immune cells, while ibuprofen only acts on COX-2 and polidocanol relies on vascular sclerosis.

[0206] 6.3 Clinical value

[0207] This traditional Chinese medicine preparation can replace or be combined with ibuprofen for chronic inflammatory diseases (such as varicose veins of the lower extremities), reducing the gastrointestinal side effects caused by long-term use of NSAIDs or reducing the risk of sclerosis-related complications of polidocanol.

Claims

1. A compound preparation for occupational varicose veins of lower extremities in practitioners, characterized in that: Its components and weight parts are: 11-13 parts of Acanthopanax Cortex, 9-12 parts of Morus Alpiniae, 21-23 parts of Cyathula officinalis, 9-11 parts of Paeonia lactiflora, 8-10 parts of Zedoariae, 20-22 parts of Salvia miltiorrhiza, 11-13 parts of Vaccariae segetalis, 5-8 parts of Gleditsia sinensis, 6-9 parts of Chuanxiong, 5-7 parts of Licorice, and 20-22 parts of Astragalus.

2. A method for preparing the compound preparation for occupational varicose veins of lower extremities of practitioners as claimed in claim 1, characterized in that: The preparation steps are as follows: (a) Raw material screening process: accurately weigh each raw material according to the formula, use a grinder to homogenize the particles, and prepare fine powder through a 150-mesh sieve to ensure that the particle size meets the ultra-fine powder standard of the Chinese Pharmacopoeia; (b) Multi-component solvent infiltration process: A five-component composite solvent system, ethanol-pure water-betaine-propylene glycol-glycerol, with a molar ratio of 4:1:1:1:1, was used to perform static immersion treatment on the medicinal materials for 100 min. Ethanol, as a lipophilic solvent, dominated the dissolution of fat-soluble components, betaine-propylene glycol reduced the interfacial tension through its amphiphilicity, and glycerol stabilized the polysaccharide structure. (c) Optimization of microwave synergistic extraction process: the power was set to 750 W, the solid-liquid ratio was 1:12, three cycles of extraction were performed, each time for 8 minutes, and the total solvent recycling rate was increased by 51%; temperature control: the control temperature was set to 39°C ± 0.5°C, that is, the upper limit was 39.5°C / the lower limit was 38.5°C, to avoid thermal degradation of heat-sensitive terpenes and phenolic acid components; Solvent synergistic mechanism: The five-component solvent system achieves simultaneous and efficient extraction of fat-soluble and polar components through polarity gradient matching; (d) Optimization of solid-liquid separation process: plate and frame filter press combined with 0.45 μm microporous membrane precision filtration system was used. According to the 600 nm wavelength detection, the filtrate transmittance was ≥ 95%, and the suspended particle retention rate was > 99%, ensuring that the separation efficiency and clarity met the standards; (e) Gradient evaporation concentration: a centrifugal thin film evaporator is used, and the material residence time is 15 seconds, corresponding to a centrifugal speed of 315 rpm; dual-effect temperature control design: according to the saturated vapor pressure of 0.35 MPa, the high temperature zone of the first effect is set to 58°C, and according to the measured boiling point of the system of 41°C, +8°C redundant temperature control is added, and the low temperature zone of the second effect is set to 49°C; separation efficiency: the centrifugal force of the rotary vapor-liquid separator is greater than 200g, the solvent recovery rate is ≥99%, and the solid content of the concentrate is 50-55% w / w; (f) Semi-solid preparation molding process: The concentrate is mixed with the auxiliary materials xylitol and dextrin in a mass ratio of 1:1.2, and then subjected to high shear homogenization and emulsification to prepare an ointment, the pH value of which is controlled at 6.5-7.0 to maintain the stability of the preparation; (g) Optimization of low-temperature phase change drying process: In the pre-freezing stage, the eutectic point of the system is measured to be -24°C, and the control temperature needs to be lower than the eutectic point, and the control temperature is set to -30°C, at which time the ice crystal size distribution is <35 μm; in the sublimation stage, the collapse point of the system is measured to be -14°C, and the control temperature needs to be lower than the collapse point, and the control temperature is set to -20°C; in the decomposition stage, the control temperature is set to 50°C, at which time the bound water is removed to obtain a final product with a moisture content of ≤1.0%; (h) Polymorphic preparation conversion process: When preparing tablets, the lyophilized powder is mixed with hypromellose and microcrystalline cellulose for tableting, with a tableting hardness of >75N and a disintegration time of ≤8 minutes. When preparing capsules, 1.0-1.5% w / w magnesium stearate is added as a lubricant, and the filling quality difference RSD is <2.0%.

3. A method for preparing the compound preparation for occupational varicose veins of lower extremities of practitioners as claimed in claim 2, characterized in that: In step (b), the soaking liquid is a five-component solvent of ethanol-pure water-betaine-propylene glycol-glycerol, and the molar ratio thereof is 4:1:1:1:1; In step (c), the extraction temperature is 39° C., and the extraction solvent is a five-component solvent of ethanol-pure water-betaine-propylene glycol-glycerol, and the molar ratio thereof is 4:1:1:1:1; In step (e), the optimal residence time of the material on the heating surface is 15 seconds, at which time the corresponding centrifugal speed is 315 rpm, the first effect high temperature zone is 58°C, and the second effect low temperature zone is 49°C; In step (g), the eutectic point of the system was measured to be -24°C, and the collapse point of the system was measured to be -14°C.