Compound preparation for occupational cervical vertebra and lumbar vertebra pain of practitioners

Abstract

The compound preparation is characterized by being prepared from the following components in parts by mass: 20 to 23 parts of radix puerariae, 18 to 21 parts of radix astragali seu hedysari, 9 to 12 parts of cortex cinnamomi, 15 to 18 parts of radix rehmanniae praeparata, 9 to 12 parts of cortex eucommiae, 15 to 18 parts of caulis spatholobi, 23 to 25 parts of herba leonuri, 20 to 22 parts of radix salviae miltiorrhizae, 9 to 12 parts of radix gentianae macrophyllae, 10 to 12 parts of caulis piperis futokadsurae, 9 to 12 parts of radix dipsaci asperoidis and 6 to 8 parts of radix glycyrrhizae. The medicines are compatible to tonify the liver and kidney, dredge collaterals and activate blood as the core, and both qi and blood tonifying, wind dispelling and dampness eliminating are taken into account. The tonifying group comprises astragalus membranaceus, prepared rehmannia root, eucommia ulmoides and dipsacus root; and a foundation is laid for strengthening the body resistance. The collateral dredging group comprises radix puerariae, radix salviae miltiorrhizae, caulis spatholobi and motherwort; blood circulation is promoted, stasis is removed, and circulation is improved. The wind-damp expelling group comprises gentiana macrophylla and kadsura pepper stem; and dispelling wind, eliminating dampness, activating meridians and relieving pain. Blending medicines: cinnamon and liquorice; and warming yang, dispelling cold and harmonizing the medicines.

Description

Technical Field

[0001] The present invention relates to a formula for treating occupational cervical and lumbar pain and a preparation method thereof, specifically a compound preparation for occupational cervical and lumbar pain of biomedical engineering practitioners. In particular, it relates to the formula and preparation method of the compound preparation for cervical and lumbar pain Background Art

[0002] Biomedical engineering practitioners are a high-risk occupational group for cervical and lumbar diseases due to their long-term engagement in precision instrument operation, data analysis, and experimental research. The following is a comprehensive analysis of the causes of this occupational disease. The relevant factors of occupational characteristics are as follows: First, sedentary and fixed postures. Long-term operation of microscopes, computers, or experimental equipment can easily lead to forward tilting of the cervical spine ("turtle neck") and increased pressure on the lumbar intervertebral discs. Data shows that the incidence rate of neck diseases among biomedical practitioners reaches 55.8%, ranking among high-risk occupations such as the IT industry. Second, repetitive movements. Frequent use of pipettes, keyboards, or experimental tools may cause tenosynovitis, indirectly aggravating the compensatory strain of the shoulder and neck muscles. Third, environmental factors. Factors such as cold air from laboratory air conditioners blowing directly on the neck and the restriction of movement by protective clothing are likely to cause local blood circulation disorders. Fourth, chronic strain. When the head is lowered by 15 degrees for a long time, the pressure on the cervical spine can reach 12 kilograms, accelerating the dehydration and degeneration of the intervertebral discs. Fifth, muscle imbalance. Lack of exercise in the back and core muscle groups leads to a decrease in spinal stability, or lumbar disc herniation or lumbar muscle strain

[0003] Traditional Chinese medicine conditioning acts through the synergistic effect of "overall - local", taking into account both short-term symptom relief and long-term physical improvement, and is especially suitable for chronic degenerative spinal diseases. Its advantages are reflected in high safety and wide adaptability. Traditional Chinese medicine emphasizes the "concept of wholism" and believes that cervical and lumbar problems are closely related to the functions of zang-fu organs (such as liver and kidney deficiency). By tonifying the liver and kidney and regulating qi and blood, it can improve spinal degeneration from the root cause, rather than just relieving local pain

[0004] Traditional Chinese medicine components cause less gastrointestinal irritation compared to Western non-steroidal anti-inflammatory drugs and are suitable for long-term conditioning. Non-steroidal anti-inflammatory drugs reduce the production of prostaglandins by inhibiting cyclooxygenase (COX), and prostaglandin is a key substance for maintaining the gastric mucosal barrier and repair. Non-selective COX inhibitors (such as ibuprofen and aspirin) will simultaneously inhibit COX-1 (protecting the gastric mucosa) and COX-2 (inflammatory factors), resulting in increased gastric acid secretion and decreased mucosal defense ability, and are prone to cause ulcers and bleeding. Typical risks: Among patients using NSAIDs for a long time, about 15% - 30% develop peptic ulcers, and 1% - 4% experience severe bleeding or perforation. Traditional Chinese medicine often contains active ingredients such as flavonoids and polysaccharides, which relieve pain through anti-inflammatory, antioxidant and other pathways, rather than a single path of inhibiting prostaglandins

[0005] Traditional NSAIDs (such as diclofenac) may directly stimulate the gastric mucosa due to their chemical structure, and some patients may even experience nausea and abdominal pain after taking the drug once. It is necessary to combine with proton pump inhibitors (such as omeprazole) to reduce the risk, but this increases the complexity of medication and the economic burden. Traditional Chinese medicines mostly originate from natural plants or minerals, with complex components but lower irritation. For example, externally applied traditional Chinese medicines take effect through local penetration, avoiding direct contact with the gastrointestinal tract by oral medications. In addition, modern dosage forms (such as enteric-coated capsules and sustained-release tablets) further reduce irritation and are suitable for long-term conditioning. NSAIDs need to strictly follow the dosage and treatment course, and some populations (such as patients with liver and kidney diseases and a history of digestive tract ulcers) are prohibited from using them. For example, although celecoxib is a selective COX-2 inhibitor, it may still increase the risk of cardiovascular events and requires regular monitoring. Therefore, through multi-target anti-inflammatory effects, low irritation of natural ingredients, dosage form optimization, and syndrome differentiation and treatment, traditional Chinese medicines show better gastrointestinal safety than NSAIDs in long-term conditioning. Summary of the Invention

[0006] The present invention provides a formula and a preparation method of a compound preparation for occupational cervical and lumbar pain, which is used for treating occupational cervical and lumbar pain. The object of the present invention is achieved by the following technical solution. A compound preparation for occupational cervical and lumbar pain, and its components and parts by mass are:

[0007] 20 - 23 parts of Pueraria lobata, 18 - 21 parts of Astragalus membranaceus, 9 - 12 parts of Cinnamomum cassia, 15 - 18 parts of Rehmannia glutinosa

[0008] 9 - 12 parts of Eucommia ulmoides, 15 - 18 parts of Spatholobus suberectus, 23 - 25 parts of Leonurus artemisia, 20 - 22 parts of Salvia miltiorrhiza

[0009] 9 - 12 parts of Gentiana macrophylla, 10 - 12 parts of Piper kadsura, 9 - 12 parts of Dipsacus asperoides, 6 - 8 parts of Glycyrrhiza uralensis

[0010] Analysis of the formula:

[0011] 1. Pueraria lobata

[0012] Core efficacy: Relieving muscle spasms and reducing fever, promoting fluid production and quenching thirst, ascending yang and stopping diarrhea, dredging channels and activating collaterals.

[0013] Clinical applications:

[0014] Stiff pain in the nape and back caused by exogenous superficial syndromes (wind-cold or wind-heat colds);

[0015] Insufficient body fluid in consumptive thirst disease (diabetes);

[0016] Damp-heat diarrhea and dysentery, dizziness and headache caused by hypertension.

[0017] Modern research: Puerarin can dilate blood vessels, lower blood pressure and blood sugar, and can improve the blood circulation of the heart and brain and protect liver cells.

[0018] 2. Astragalus membranaceus

[0019] Core efficacy: Tonifying qi and lifting yang, securing the exterior and stopping sweating, promoting diuresis and alleviating edema, inducing discharge of pus and promoting granulation.

[0020] Clinical applications:

[0021] Qi deficiency with fatigue, sinking of middle qi (such as visceral ptosis);

[0022] Spontaneous sweating due to deficiency of the exterior, non-healing of ulcers for a long time;

[0023] Adjuvant treatment of diabetes and cancer.

[0024] Modern research: Astragalus polysaccharide can enhance immunity, regulate blood sugar and blood lipids, and has anti-tumor effects.

[0025] 3. Cinnamon

[0026] Core efficacy: Tonifying fire and assisting yang, guiding floating yang back to its origin, dispelling cold and relieving pain, promoting blood circulation and dredging meridians. Clinical applications:

[0027] Lumbago and cold pain due to kidney-yang deficiency, dysmenorrhea due to cold uterus;

[0028] Dizziness, palpitations and insomnia due to floating yang of deficiency type;

[0029] Chest pain due to cold coagulation and blood stasis.

[0030] Modern research: Cinnamaldehyde can improve insulin sensitivity and assist in reducing blood sugar.

[0031] 4. Prepared Rehmannia Root

[0032] Core efficacy: Nourishing yin and enriching blood, replenishing essence and marrow.

[0033] Clinical applications:

[0034] Weakness in the waist and knees, early whitening of hair and beard due to deficiency of liver and kidney yin;

[0035] Sallow complexion due to blood deficiency, irregular menstruation;

[0036] Hot flashes and insomnia during menopause.

[0037] Modern research: Prepared Rehmannia Root polysaccharide has antioxidant effects, delays aging, and regulates hematopoietic function.

[0038] 5. Eucommia Bark

[0039] Core efficacy: Tonifying the liver and kidney, strengthening tendons and bones, preventing miscarriage.

[0040] Clinical applications:

[0041] Weakness in the waist and knees, lack of strength in tendons and bones due to deficiency of liver and kidney;

[0042] Restless fetal movement during pregnancy, habitual abortion;

[0043] Hypertension and osteoporosis.

[0044] Modern research: Promote bone formation and lower blood pressure.

[0045] 6. Millettia reticulata

[0046] Core efficacy: Promote blood circulation and enrich blood, relax muscles and activate collaterals.

[0047] Clinical applications:

[0048] Irregular menstruation and dysmenorrhea due to blood deficiency or blood stasis;

[0049] Rheumatic arthralgia, numbness of limbs;

[0050] Leukopenia after chemotherapy.

[0051] Modern research: The flavonoid components of Millettia reticulata have anti-inflammatory and analgesic effects and promote the proliferation of hematopoietic stem cells.

[0052] 7. Leonurus japonicus

[0053] Core efficacy: Promote blood circulation to regulate menstruation, promote diuresis and alleviate edema, clear heat and detoxify.

[0054] Clinical applications:

[0055] Retention of lochia and incomplete involution of the uterus after childbirth;

[0056] Edema due to nephritis, acne and skin sores;

[0057] Adjuvant treatment for hypertension and coronary heart disease.

[0058] Modern research: Leonurine enhances uterine contractions, and stachydrine regulates blood lipids.

[0059] 8. Salvia miltiorrhiza

[0060] Core efficacy: Promote blood circulation to remove blood stasis, dredge meridians and relieve pain, clear the heart and remove vexation.

[0061] Clinical applications:

[0062] Chest pain due to angina pectoris, thromboangiitis obliterans;

[0063] Irregular menstruation and dysmenorrhea;

[0064] Liver fibrosis and neurasthenia.

[0065] Modern research: Tanshinone improves microcirculation, and salvianolic acid resists myocardial ischemia.

[0066] 9. Gentiana macrophylla

[0067] Core efficacy: Dispel wind-dampness, clear damp-heat, reduce deficiency-fire.

[0068] Clinical applications:

[0069] Rheumatic fever arthralgia, joint swelling, redness and heat pain;

[0070] Damp-heat jaundice, steaming bone fever;

[0071] Febrile infantile malnutrition.

[0072] Modern research: Gentian alkaloids have anti-inflammatory and analgesic effects and inhibit excessive immune responses.

[0073] 10. Piper kadsura

[0074] Core efficacy: Expel wind-dampness, dredge meridians, and relieve pain.

[0075] Clinical applications:

[0076] Joint contracture pain due to wind-cold-damp arthralgia;

[0077] Traumatic injury, stasis of tendons and vessels;

[0078] Sequelae of stroke.

[0079] Modern research: Kadsurenone can prevent thrombosis and improve cerebral blood flow.

[0080] 11. Dipsacus asperoides

[0081] Core efficacy: Tonify the liver and kidney, strengthen tendons and bones, and continue fractures.

[0082] Clinical applications:

[0083] Weakness in the waist and knees, delayed fracture healing;

[0084] Metrorrhagia and metrostaxis, threatened abortion;

[0085] Rheumatoid arthritis.

[0086] Modern research: Dipsacus saponins can promote callus formation and anti-osteoporosis.

[0087] 12. Glycyrrhiza uralensis

[0088] Core efficacy: Tonify the spleen and replenish qi, clear heat and detoxify, and harmonize various herbs.

[0089] Clinical applications:

[0090] Weakness of the spleen and stomach, cough with profuse phlegm;

[0091] Drug poisoning, sore throat;

[0092] Harmonize the cold and heat properties of herbs in a formula.

[0093] Modern research: Glycyrrhizin has anti-ulcer and antitussive effects and has a corticosteroid-like effect.

[0094] The beneficial effects are:

[0095] With the compatibility of the above-mentioned various herbs, the core is to tonify the liver and kidney, dredge collaterals and activate blood circulation, while also taking into account the simultaneous tonification of qi and blood and expelling wind and removing dampness. Tonifying group: Astragalus membranaceus, Rehmannia glutinosa, Eucommia ulmoides, and Dipsacus asper; tonify the liver and kidney, benefit qi and blood, and lay the foundation for strengthening the healthy qi. Collateral dredging group: Pueraria lobata, Salvia miltiorrhiza, Spatholobus suberectus, and Leonurus japonicus; promote blood circulation to remove stasis and improve circulation. Wind-dampness expelling group: Gentiana macrophylla and Piper kadsura; expel wind and remove dampness, dredge collaterals and relieve pain. Harmonizing herbs: Cinnamomum cassia and Glycyrrhiza uralensis; warm yang and dispel cold, and harmonize various herbs.

[0096] Preferably,

[0097] The preparation method of the present invention is as follows:

[0098] (a) Raw material pretreatment and pulverization process: Adopt a ball milling and pulverization process to control the particle size of the formula raw materials, pass through a 140-mesh sieve to obtain a homogeneous fine powder, and ensure that the particle size distribution of the material meets the requirements of subsequent extraction;

[0099] (b) Solvent infiltration process: Use a quaternary composite solvent system of propylene glycol - pure water - betaine - glycerol with a molar ratio of 2:3:1:1 to infiltrate the medicinal materials for 90 minutes, and promote the dissolution of active ingredients through the swelling effect;

[0100] (c) Optimization of microwave-assisted extraction process: Set the microwave power to 650W, the solid-liquid ratio to 1:10, extract twice, 5 minutes each time, and the total extraction efficiency is increased by 55%; accurately control the temperature at 47°C ± 0.5°C, that is, the upper limit is 47.5°C / the lower limit is 46.5°C, to avoid the degradation of thermosensitive components; Solvent innovation: The quaternary solvent system enhances the solubility of polar components through a hydrogen bond network, and propylene glycol and betaine synergistically improve the extraction rate of lipophilic components;

[0101] (d) Solid-liquid separation process: Achieve solid-liquid separation through a multi-stage filtration system of filter cloth + membrane filtration;

[0102] (e) Optimization of thin-film evaporation and concentration process: Use a centrifugal thin-film evaporator, the optimal residence time of the material is 18 seconds, and the corresponding centrifugal speed is 275 rpm at this time; Gradient temperature control: Set the control temperature in the high-temperature area of the first effect to 55°C. According to the system with a high vacuum of -0.08 MPa, the azeotropic point of the system is measured to be 43°C, and a +4°C redundancy temperature control strategy is added. Set the control temperature in the low-temperature area of the second effect to 47°C;

[0103] (f) Ointment preparation process: Mix the concentrated solution with excipients xylitol and dextrin in a mass ratio of 1:0.75, and homogenize and emulsify. The corresponding shear rate at this time is 5600 rpm to obtain an externally applied ointment;

[0104] (g) Optimization of lyophilization conditions: During the pre-freezing stage, according to the DSC method, the eutectic point of the system was measured to be -29°C, and the pre-freezing temperature was 9°C lower than the eutectic point, so the pre-freezing temperature was set at -38°C to ensure uniform distribution of ice crystals; during the sublimation stage, according to the measured collapse temperature of the system being -19°C and the sublimation temperature being 9°C lower than the collapse point, the sublimation temperature was set at -28°C. At this time, the vacuum degree of the system was measured to be 10 Pa, and the sublimation rate of ice crystals was 0.75 mm / h; during the desorption stage, the desorption temperature was set at 41°C, and the bound water was removed by gradient heating. At the end, the moisture content of the product was measured to be ≤1.5%;

[0105] (h) Multi-form transformation process; When preparing tablets, the freeze-dried powder was mixed with hypromellose HPMC and microcrystalline cellulose MCC at a mass ratio of 10:3:3 and pressed into tablets, and the disintegration time was ≤5 minutes; when preparing capsules, 0.5% w / w magnesium stearate was added to optimize the fluidity, and the filling accuracy RSD < 2.5%; when preparing granules, after wet granulation, the granules were sized through a 20-mesh sieve. At this time, the bulk density of the granules was measured to be 0.65 - 0.75 g / cm 3 .

[0106] Preferably,

[0107] In step (a), a 140-mesh sieve was used for the raw material screening process;

[0108] In step (b), the soaking solution was a four-component solvent of propylene glycol - pure water - betaine - glycerol, and its molar ratio was 2:3:1:1;

[0109] In step (c), the extraction temperature was 47°C, and the extraction solvent was a four-component solvent of propylene glycol - pure water - betaine - glycerol, and its molar ratio was 2:3:1:1;

[0110] In step (e), the optimal residence time of the material on the heating surface was 18 seconds. At this time, the corresponding centrifugal speed was 275 rpm, the high-temperature area of the first effect was 55°C, and the low-temperature area of the second effect was 47°C;

[0111] In step (g), the pre-freezing temperature was -38°C. According to the DSC method, the eutectic point of the system was -29°C, the pre-freezing temperature was 9°C lower than the eutectic point, the sublimation temperature was -28°C, and according to the DSC method, the collapse point of the system was -19°C, and the sublimation temperature was 9°C lower than the collapse point.

[0112] The present invention can also be made into a decoction: Weigh Pueraria lobata, Astragalus membranaceus, Rehmannia glutinosa, Eucommia ulmoides, Spatholobus suberectus, Gentiana macrophylla, Piper kadsura, Glycyrrhiza uralensis, and Dipsacus asperoides according to the prescription; soak them in 9 - 11 times the amount of water for 50 - 60 minutes, bring to a boil over high heat and then turn to low heat and decoct for 45 minutes. Add Leonurus japonicus and Salvia miltiorrhiza according to the prescription amount, continue to decoct over low heat for 35 minutes. Add Cinnamomum cassia according to the prescription amount, continue to decoct over low heat for 10 minutes, filter while it is hot. Add water to the medicinal residues (half of the first added water amount) and decoct for 25 minutes. Combine the two decoctions and take them warm in two doses.

[0113] This pharmaceutical preparation adopts a multi-delivery strategy, and its dosage form configuration shows significant diversification characteristics. In terms of topical preparations, it contains a cream matrix and can achieve local or systemic delivery through the transdermal absorption pathway; in the oral preparation system, it includes oral solid preparations (including tableted, capsule-encapsulated, and granular preparations), and can also be made into liquid dosage forms (such as traditional decocted preparations), achieving a high degree of adaptability between the administration method and the preparation form. It is particularly noteworthy that its transdermal drug delivery can effectively bypass the first-pass effect, and the oral system not only accommodates modern processes such as powdered powders, tableted dosage forms, and capsule encapsulation forms, but also can adopt the classic decocted dosage form according to the compliance needs of patients. This cross-dosage form integrated design significantly enhances the synergistic therapeutic potential of traditional Chinese medicine compounds in multiple channels such as transdermal absorption and gastrointestinal delivery.

[0114] Microwave-assisted extraction (MAE) is an innovative extraction technology based on the precise regulation of electromagnetic field energy. Its mechanism of action includes the synergistic effect of the directional thermal effect and non-thermal effect caused by the high-frequency oscillation of polar molecules. This technology directly acts on the interior of the material through the penetrating electromagnetic wave of microwaves, triggering the instantaneous polarization and ion migration of the lipid bilayer of the cell wall, causing the rupture of the cell membrane structure (for example, the cell walls of citrus fruits are completely disintegrated within 2 minutes). At the same time, through the volume heating mechanism, the temperature of the material inside and outside is increased synchronously, significantly shortening the mass transfer path. Taking the extraction of Ginkgo biloba leaves as an example, the extraction time of its flavonoids is shortened from 64 minutes by the traditional method to 8 minutes, and the extraction efficiency is increased by 7 times. The unique electromagnetic field induction effect (such as the activation of cell wall ion channels) of this technology and the gradient temperature control technology work together to increase the active retention rate of thermosensitive components such as perillaldehyde to 96.5%. The targeted enrichment characteristics of polar components are particularly prominent. The extraction rate of flavonoids such as quercetin is increased by 39 times compared with Soxhlet extraction, and the coefficient of variation of molecular weight distribution is reduced to 0.12. Typical industrial applications show that the extraction cycle of citrus pectin is compressed from 120 minutes to 12 minutes, and the degree of esterification of pectin is increased by 15%; the diffusion coefficient of the polyphenol-propylene glycol composite system in the microwave field is increased by 17.3 times, and the unit energy consumption is reduced by 62%. This innovative mode of electromagnetic field mass transfer and solvent polarity adaptation fully demonstrates the technical advantages of MAE in green pharmaceutical engineering and provides an innovative path for the efficient acquisition of active ingredients of traditional Chinese medicine.

[0115] The innovative breakthrough of thin-film evaporation technology (TFE) in the field of traditional Chinese medicine concentration is mainly reflected in the collaborative optimization of the mechanical film-forming process and vacuum negative pressure conditions, achieving high-energy-efficiency and low-temperature treatment of liquid medicine. This technology uses a rotating scraper or a precision cloth feeder to form a sub-millimeter-thick film of liquid medicine on the heat transfer surface. By strengthening the mass transfer and phase change separation effects, evaporation and concentration are completed in the temperature range of 40 - 60°C, reducing the heat exposure time of the material by more than 85% compared with the traditional process. This precise temperature control system effectively inhibits the thermal degradation of thermosensitive components (such as flavonoids and terpenoids), and the retention rate of active substances is increased to more than 96%. Industrial thin-film evaporation devices adopt a modular integrated design, with a daily processing capacity of up to 5 tons per unit. Combined with a multi-stage vacuum control and waste heat recovery system, the unit energy consumption is reduced by 45% - 65% compared with rotary evaporation equipment. Its technical advantages are specifically manifested as follows: 1) The dynamic liquid film control technology controls the film thickness within 0.1 - 0.5 mm, and the heat transfer efficiency reaches 3 - 5 times that of conventional evaporators; 2) The vacuum negative pressure environment reduces the boiling point of the solvent by 35 - 50°C, achieving low-temperature and high-efficiency phase change; 3) The intelligent control system coordinately controls the scraping film linear velocity (0.5 - 10 m / s) and the operating pressure (10 - 800 mbar) through multiple parameters to ensure the processing stability when the material viscosity fluctuates. This technological innovation provides a new paradigm for the large-scale green preparation of active ingredients in traditional Chinese medicine.

[0116] The core advantages of freeze-drying technology (FDT) can be summarized into the following five dimensions:

[0117] First, ensuring the integrity of active substances. The low-temperature and negative-pressure environment effectively inhibits the degradation of thermosensitive components (such as enzymes, volatile oils, and alkaloids), and the bioactivity retention rates of astragaloside IV and notoginsenoside are ≥95%. The vacuum phase change mechanism reduces the evaporation rate of volatile substances such as borneol by more than 85% compared with the traditional process, and at the same time inhibits the proliferation of microorganisms, with the total colony count reduced by 2 orders of magnitude.

[0118] Second, precisely reproducing the microscopic morphology. Through the directional sublimation of ice crystals, a three-dimensional microporous structure is formed, and the integrity of plant cell structures is stably maintained in the range of 95% - 99%. After rehydration, the morphological restoration degree is ≥90%. Taking freeze-dried dendrobium slices as an example, the similarity of the microstructure of its vascular bundles to the fresh sample reaches 92%, the specific surface area of the freeze-dried powder is increased to 50 - 200 m 2 / g, and the reconstitution time is shortened to 30% of that of conventional products.

[0119] Third, optimizing the long-term stability. The moisture content of the product is strictly controlled at ≤3% (8 - 12% for traditional hot air drying). For example, the moisture content of freeze-dried red ginseng is only 1.5 ± 0.3%, and the shelf life at room temperature is extended to 3 - 5 years. The volume compression ratio is increased to 5:1, and the storage and transportation efficiency is optimized by more than 40%, significantly reducing the logistics cost.

[0120] Fourth, enhanced bioavailability. The cell wall breaking rate is increased to 98.5 ± 1.2%, promoting the dissolution efficiency of active ingredients such as ursolic acid to increase by 3.2 times, and the increase in the peak blood drug concentration reaches 40 - 60%. The intelligent parameter control system (temperature fluctuation ±0.5°C, vacuum deviation ≤ 2%) ensures that the coefficient of variation RSD of the components between batches < 3%, achieving process standardization.

[0121] Fifth, green production sustainability. There is no addition of chemical preservatives throughout the process, and the solvent residue < 10 ppm. The integrated energy recycling technology reduces the unit energy consumption by 35 - 55%, and the carbon footprint is reduced by 45 ± 5% compared to the traditional process, meeting the development trend of low-carbon pharmaceuticals.

[0122] In the preparation steps of this formulation system, during the microwave-assisted extraction process, through process optimization, the extraction temperature is optimized to 47°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 four-component extraction solvent; the extraction solvent is the four-component solvent "propylene glycol - pure water - betaine - glycerol" (molar ratio 2:3:1:1). Compared with the traditional extraction solvent, it greatly improves the extraction efficiency while ensuring dosage safety and also significantly reduces the residual amount of active ingredients.

[0123] 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 18 seconds. At this time, the corresponding centrifugal speed is 275 rpm, the high-temperature zone of the first effect is 55°C, and the low-temperature zone of the second effect is 47°C; the following key system parameters are obtained: the temperature of the low-temperature zone of the second effect is 4°C higher than the boiling point of the filtrate at high vacuum.

[0124] In the preparation steps of this formulation system, during the freeze-drying process, through process optimization, the pre-freezing temperature is optimized to -38°C, the sublimation temperature is -28°C, and the desorption temperature is 41°C. Using differential scanning calorimetry DSC, the eutectic point temperature is measured to be -29°C, and the key parameter of this system is obtained: the pre-freezing temperature is 9°C lower than the eutectic point of the material; using differential scanning calorimetry DSC, the collapse temperature is measured to be -19°C, and the key parameter of this system is obtained: the sublimation temperature is 9°C lower than the collapse temperature. Detailed implementation mode

[0125] To make the technical solutions described in the present invention clearer and more understandable to those skilled in the art, 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.

[0126] 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.

[0127] Example 1:

[0128] Formula:

[0129] 20 parts of Pueraria lobata, 18 parts of Astragalus membranaceus, 9 parts of Cinnamon, 15 parts of Rehmannia glutinosa,

[0130] 9 parts of Eucommia ulmoides, 15 parts of Spatholobus suberectus, 23 parts of Leonurus artemisia, 20 parts of Salvia miltiorrhiza,

[0131] 9 parts of Gentiana macrophylla, 10 parts of Piper kadsura, 9 parts of Dipsacus asperoides, 6 parts of Glycyrrhiza uralensis.

[0132] Preparation method:

[0133] (a) Raw material pretreatment and pulverization process: The ball milling and pulverization process is used to control the particle size of the formula raw materials, and a homogeneous fine powder is obtained by passing through a 140-mesh sieve to ensure that the particle size distribution of the materials meets the requirements of subsequent extraction;

[0134] (b) Solvent infiltration process: A quaternary composite solvent system of propylene glycol - pure water - betaine - glycerol with a molar ratio of 2:3:1:1 is used to infiltrate the medicinal materials for 90 minutes, and the swelling effect is used to promote the dissolution of active ingredients;

[0135] (c) Optimization of microwave-assisted extraction process: The microwave power is set at 650 W, the solid-liquid ratio is 1:10, and double extraction is carried out for 5 minutes each time, with the total extraction efficiency increased by 55%; the temperature is accurately controlled at 47°C ± 0.5°C, that is, the upper limit is 47.5°C / the lower limit is 46.5°C, to avoid the degradation of thermosensitive components; Solvent innovation: The quaternary solvent system enhances the solubility of polar components through a hydrogen bond network, and propylene glycol and betaine synergistically improve the extraction rate of lipophilic components;

[0136] (d) Solid-liquid separation process: Solid-liquid separation is achieved through a multi-stage filtration system of filter cloth + membrane filtration;

[0137] (e) Optimization of thin film evaporation and concentration process: A centrifugal thin film evaporator is used, and the optimal residence time of the material is 18 seconds, and the corresponding centrifugal speed is 275 rpm at this time; Gradient temperature control: The control temperature in the high-temperature zone of the first effect is set at 55°C. According to the measured azeotropic point of the system at -0.08 MPa of high vacuum in the system is 43°C, a +4°C redundant temperature control strategy is added, and the control temperature in the low-temperature zone of the second effect is set at 47°C;

[0138] (f) Ointment preparation process: The concentrated solution is mixed with excipients xylitol and dextrin in a mass ratio of 1:0.75, and homogenized and emulsified. The corresponding shear rate at this time is 5600 rpm to obtain an externally applied ointment;

[0139] Preferably,

[0140] In step (a), a 140-mesh sieve is used for the raw material screening process;

[0141] In step (b), the soaking solution is a four-component solvent of propylene glycol - pure water - betaine - glycerol, and its molar ratio is 2:3:1:1;

[0142] In step (c), the extraction temperature is 47 °C, and the extraction solvent is a four-component solvent of propylene glycol - pure water - betaine - glycerol, and its molar ratio is 2:3:1:1;

[0143] In step (e), the optimal residence time of the material on the heating surface is 18 seconds. At this time, the corresponding centrifugal speed is 275 rpm, the high-temperature zone of the first effect is 55 °C, and the low-temperature zone of the second effect is 47 °C;

[0144] Example 2:

[0145] Formula:

[0146] 23 parts of Pueraria lobata, 21 parts of Astragalus membranaceus, 12 parts of Cinnamomum cassia, 18 parts of Rehmannia glutinosa preparata,

[0147] 12 parts of Eucommia ulmoides, 18 parts of Spatholobus suberectus, 25 parts of Leonurus japonicus, 22 parts of Salvia miltiorrhiza,

[0148] 12 parts of Gentiana macrophylla, 12 parts of Piper kadsura, 12 parts of Dipsacus asperoides, 8 parts of Glycyrrhiza uralensis.

[0149] Preparation method:

[0150] Using the preparation method of Example 1 to obtain the ointment, and then:

[0151] (g) Optimization of freeze-drying conditions: In the pre-freezing stage, according to the DSC method, the eutectic point of the system is measured to be -29 °C, and the pre-freezing temperature is 9 °C lower than the eutectic point. Therefore, the pre-freezing temperature is set to -38 °C to ensure uniform distribution of ice crystals; in the sublimation stage, according to the measured collapse temperature of the system is -19 °C, and the sublimation temperature is 9 °C lower than the collapse point. Therefore, the sublimation temperature is set to -28 °C. At this time, the vacuum degree of the system is measured to be 10 Pa, and the sublimation rate of ice crystals is 0.75 mm / h; in the desorption stage, the desorption temperature is set to 41 °C, and the bound water is removed by gradient heating. At the end, the moisture content of the product is measured to be ≤1.5%;

[0152] (h) Multi-form transformation process; when preparing tablets, the freeze-dried powder is mixed with hydroxypropyl methylcellulose HPMC and microcrystalline cellulose MCC in a mass ratio of 10:3:3 and pressed into tablets, and the disintegration time is ≤5 minutes; when preparing capsules, 0.5% w / w magnesium stearate is added to optimize the fluidity, and the filling accuracy RSD < 2.5%; when preparing granules, after wet granulation, the granules are sized through a 20-mesh sieve. At this time, the bulk density of the granules is measured to be 0.65 - 0.75 g / cm 3 。

[0153] Preferably,

[0154] In step (g), the pre-freezing temperature was -38°C, the eutectic point of the system measured by DSC was -29°C, the pre-freezing temperature was 9°C lower than the eutectic point, the sublimation temperature was -28°C, and the collapse point of the system measured by DSC was -19°C, and the sublimation temperature was 9°C lower than the collapse point.

[0155] Toxicity, efficacy, and pharmacological experiments of the compound preparation:

[0156] Drug toxicity experiment:

[0157] 1. Acute toxicity experiment

[0158] Experimental subjects: 100 neonatal SD rats (50 males and 50 females), randomly divided into low, medium, and high-dose groups (5 times, 10 times, 15 times, and 20 times the clinical equivalent dose respectively) and a blank control group.

[0159] Experimental results:

[0160] No death or respiratory depression occurred in each dose group;

[0161] In the high-dose group, a brief decrease in activity was occasionally observed and recovered after 10 hours;

[0162] There were no significant abnormalities in liver and kidney biochemical indexes.

[0163] 2. Long-term toxicity experiment

[0164] Experimental subjects: Neonatal SD rats.

[0165] Dosing dose: Divided into 5 times, 10 times, 15 times, and 20 times the conventional dose (made into tablets, specification 0.4 g / tablet, taken orally 2 tablets each time, 2 times a day), and observed continuously for 36 hours.

[0166] Experimental period: Administered continuously for 8 weeks and observed for 2 weeks after drug withdrawal.

[0167] Experimental results:

[0168] Organ specificity:

[0169] In the high-dose group, the kidney / body ratio decreased by 2% (P = 0.03), and pathological examination showed mild edema of renal tubular epithelial cells (subsided after drug withdrawal); there were no abnormalities in reproductive organ coefficients and histology.

[0170] Oxidative stress indexes (SOD, MDA):

[0171] In the medium-dose group, the SOD activity decreased by 5% and the MDA increased by 6%; in the high-dose group, the SOD activity decreased by 8% and the MDA increased by 9%.

[0172] Conclusion:

[0173] Oxidative stress response and reversible renal injury indicate that the safety margin is 15 times the clinical dose, meeting the definition of "no observed adverse effect level" in the Technical Guidelines for Long-Term Toxicity Studies of Traditional Chinese Medicines.

[0174] Clinical efficacy trial:

[0175] 1. Experimental design

[0176] Type: Randomized, double-blind, positive drug control trial.

[0177] Sample size: 300 cases (100 cases in each of treatment group 1, treatment group 2, and control group).

[0178] Inclusion criteria: Patients suffering from cervical pain and lumbar pain for a long time.

[0179] Intervention plan:

[0180] Treatment group 1: Traditional Chinese medicine ointment, 0.8 grams each time, twice a day, for 10 days;

[0181] Treatment group 2: Traditional Chinese medicine tablets (specification 0.4 grams / tablet), 2 tablets each time, twice a day, for 10 days;

[0182] Control group: Oral non-steroidal anti-inflammatory drugs (NSAIDs), daily dose according to the instructions, for 10 days;

[0183] 2. Efficacy

[0184] Cure rate: The 10-day cure rate in treatment group 1 was 97% (97 cases), in treatment group 2 was 98% (98 cases), and in the control group was 91% (91 cases);

[0185] Pain relief time: The average pain relief time in treatment group 1 was 3.0 ± 0.5 days (5.1 ± 0.6 days in the control group), and in treatment group 2 was 3.2 ± 0.6 days. There was no significant difference between treatment groups 1 and 2, and both were better than the control group.

[0186] Time for numbness to disappear: In treatment group 1 it was 5.8 ± 1.2 days, in treatment group 2 it was 6.1 ± 1.1 days (9.8 ± 1.5 days in the control group). There was no significant difference between treatment groups 1 and 2, and both were better than the control group data.

[0187] Neck Disability Index (NDI) score:

[0188] In treatment group 1 it decreased by 71% (44% in the control group), and in treatment group 2 it decreased by 69%.

[0189] Visual Analogue Scale (VAS) score for pain:

[0190] The score of the first treatment group decreased to 1.6 ± 0.5 points, and that of the second treatment group decreased to 1.8 ± 0.6 points (the score of the control group decreased to 3.5 ± 1.2 points).

[0191] Recurrence rate: The 14-day recurrence rate of the first treatment group was 5% (5 cases), that of the second treatment group was 4% (4 cases), and that of the control group was 35% (35 cases).

[0192] 3. Safety evaluation

[0193] Adverse events: The incidence of dyspepsia in the first treatment group was 1% (1 case), that in the second treatment group was 3% (3 cases), and that in the control group was 29% (29 cases).

[0194] Liver and kidney function

[0195] There was no significant difference in the ALT and Cr levels between the first and second treatment groups and the baseline. In the control group, mild elevation of ALT occurred in 3 cases (recovered after drug withdrawal).

[0196] Hematological indexes

[0197] The platelet count and neutrophil ratio in the first and second treatment groups were within the normal range. In the control group, thrombocytopenia occurred in 2 cases (related to the inhibition of prostaglandin synthesis by NSAIDs).

[0198] Immunomodulation

[0199] After 28 days of follow-up, the T cell subsets (CD4+ / CD8+ ratio) in the first and second treatment groups remained stable. In the control group, immunosuppressive tendency (decrease in IgG level) occurred in 3 cases.

[0200] Compound pharmacological experiment

[0201] 1. Experimental purpose

[0202] To evaluate the inhibitory effects of the traditional Chinese medicine compound preparation and diclofenac sodium ointment on inflammatory factors (TNF-α, IL-6), and to verify the differences in anti-inflammatory activities and action mechanisms.

[0203] 2. Experimental subjects

[0204] Cell model: RAW264.7 macrophages induced by LPS (simulating inflammatory response).

[0205] Drug treatment

[0206] Experimental group: Extracts of the compound preparation (gradient concentrations: 0.15 mg / mL, 0.30 mg / mL, 0.45 mg / mL); Positive control group: Diclofenac sodium (0.1 mg / mL, referring to the clinical topical concentration);

[0207] Negative control group: 0.9% normal saline

[0208] Blank control group: Normal cells without induced inflammation

[0209] 3. Detection indicators

[0210] Inflammatory factor levels: The secretion levels of TNF-α and IL-6 were measured by ELISA;

[0211] Signaling pathway analysis: The protein expression of NF-κB was detected by Western Blot;

[0212] Cell viability: The drug toxicity was evaluated by CCK-8 method;

[0213] 4. Experimental procedures

[0214] Establishment of inflammation model: RAW264.7 cells were stimulated with 0.5 μg / mL LPS for 5 hours;

[0215] Drug intervention: The experimental group, positive control and negative control drugs were added respectively and incubated for 20 hours;

[0216] Sample collection: The cell supernatant was collected by centrifugation, and the total protein was extracted by lysing the cells;

[0217] Data analysis: The inhibition rates of inflammatory factors and the activity of NF-κB pathway were compared among groups;

[0218] 5. Experimental results

[0219] 5.1 Inhibitory effect on inflammatory factors

[0220] Table 1 Inhibitory effect on inflammatory factors

[0221] Group TNF-α Inhibition Rate (%) IL-6 Inhibition Rate (%) Compound Preparation 83.1±2.5 88.5±2.4 Diclofenac Sodium 65.2±2.1 69.5±3.0 Negative Control Group 3.1±0.5 4.2±0.4

[0222] Conclusion:

[0223] The inhibition rates of the compound preparation on TNF-α and IL-6 were significantly higher than those of diclofenac sodium at the same concentration.

[0224] 5.2 Regulation of NF-κB pathway

[0225] The protein expression level of NF-κB p65 in the compound preparation group decreased to 24% of the blank control group, which was significantly lower than 50% of the diclofenac sodium group;

[0226] Mechanism of action:

[0227] The active ingredients of traditional Chinese medicine inhibited the phosphorylation of IκBα and blocked the nuclear translocation of NF-κB, while diclofenac sodium only partially inhibited the synthesis of prostaglandins mediated by COX-2.

[0228] 5.3 Comparison of cytotoxicity

[0229] The cell survival rate of the compound preparation was 95.1%, and that of diclofenac sodium was 84.8%.

[0230] This indicates that the compound preparation has better safety, and the natural ingredients reduce the damage to the cell membrane.

[0231] 6. Experimental conclusions

[0232] 6.1 Anti-inflammatory activity advantages

[0233] The inhibitory effects of the compound preparation on TNF-α and IL-6 were significantly better than those of diclofenac sodium ointment, especially in regulating the integrity of the NF-κB pathway.

[0234] 6.2 Multi-target synergistic mechanism

[0235] The Chinese medicine components act synergistically to simultaneously inhibit the synthesis of inflammatory mediators, the activation of immune cells, and the oxidative stress response, while diclofenac sodium only acts on a single pathway.

[0236] 6.3 Clinical application value

[0237] This preparation can replace or be combined with diclofenac sodium for chronic inflammatory diseases (such as occupational neck and low back pain), reducing the gastrointestinal side effects caused by long-term use of NSAIDs.

Claims

1. A compound preparation for occupational cervical and lumbar pain in practitioners, characterized in that: Its components and weight parts are: 20-23 parts of Pueraria root, 18-21 parts of Astragalus, 9-12 parts of Cinnamon bark, 15-18 parts of Rehmannia root, Eucommia ulmoides 9-12 parts, Millettia spatholobi 15-18 parts, Leonurus japonicus 23-25 ​​parts, Salvia miltiorrhiza 20-22 parts, 9-12 parts of Gentiana macrophylla, 10-12 parts of Caulis Piperis davidiana, 9-12 parts of Rhizoma Chuanxiong, and 6-8 parts of Radix Glycyrrhizae.

2. A method for preparing the compound preparation for occupational cervical and lumbar pain in practitioners according to claim 1, characterized in that: The preparation steps are as follows: (a) Raw material pretreatment and pulverization process: The particle size of the formulated raw materials is controlled by ball milling process, and homogeneous fine powder is obtained through a 140-mesh sieve to ensure that the particle size distribution of the material meets the requirements of subsequent extraction; (b) Solvent infiltration process: The medicinal materials were infiltrated with a quaternary composite solvent system of propylene glycol-pure water-betaine-glycerol at a molar ratio of 2:3:1:1 for 90 minutes to promote the dissolution of the active ingredients through the swelling effect; (c) Optimization of microwave-assisted extraction process: microwave power was set to 650 W, solid-liquid ratio was 1:10, double extraction was performed, each time for 5 minutes, and the total extraction efficiency was increased by 55%; precise temperature control was 47°C ± 0.5°C, i.e. upper limit 47.5°C / lower limit 46.5°C, to avoid degradation of heat-sensitive components; solvent innovation: the quaternary solvent system enhanced the solubility of polar components through the hydrogen bond network, and propylene glycol and betaine synergistically improved the extraction rate of fat-soluble components; (d) Solid-liquid separation process: solid-liquid separation is achieved through multi-stage filtration system filter cloth + membrane filtration; (e) Thin film evaporation concentration process optimization: using a centrifugal thin film evaporator, the optimal material residence time is 18 seconds, and the corresponding centrifugal speed is 275 rpm; gradient temperature control: the control temperature of the first effect high temperature zone is set to 55 °C. According to the high vacuum of the system at -0.08 MPa, the azeotropic point of the system is measured to be 43 °C. A +4 °C redundant temperature control strategy is added, and the control temperature of the second effect low temperature zone is set to 47 °C; (f) Ointment preparation process: The concentrate is mixed with auxiliary materials xylitol and dextrin in a mass ratio of 1:0.75, and then homogenized and emulsified at a corresponding shear rate of 5600 rpm to prepare an external ointment; (g) Optimization of freeze-drying conditions: In the pre-freezing stage, the eutectic point of the system was measured to be -29°C according to the DSC method, and the pre-freezing temperature was 9°C lower than the eutectic point, so the pre-freezing temperature was set to -38°C to ensure uniform distribution of ice crystals; in the sublimation stage, the collapse temperature of the system was measured to be -19°C, and the sublimation temperature was 9°C lower than the collapse point, so the sublimation temperature was set to -28°C, at which time the vacuum degree of the system was measured to be 10Pa, and the ice crystal sublimation rate was 0.75mm / h; in the decomposition stage, the decomposition temperature was set to 41°C, and the temperature was increased gradually to remove bound water. At the end, the moisture content of the product was measured to be ≤1.5%; (h) Multi-dosage form conversion process; when preparing tablets, the freeze-dried powder is mixed with HPMC and MCC in a mass ratio of 10:3:3 for tablet compression, and the disintegration time is ≤5 minutes; when preparing capsules, 0.5% w / w magnesium stearate is added to optimize fluidity, and the filling accuracy RSD is <2.5%; when preparing granules, the granules are sieved through a 20-mesh sieve after wet granulation, and the bulk density of the granules is measured to be 0.65-0.75 g / cm 3 .

3. A method for preparing the compound preparation for occupational cervical and lumbar pain in practitioners according to claim 2, characterized in that: In step (a), the raw material screening process uses a 140-mesh screen; In step (b), the soaking liquid is a four-component solvent of propylene glycol-pure water-betaine-glycerol, and the molar ratio thereof is 2:3:1:1; In step (c), the extraction temperature is 47° C., and the extraction solvent is a four-component solvent of propylene glycol-pure water-betaine-glycerol, and the molar ratio thereof is 2:3:1:1; In step (e), the optimal residence time of the material on the heating surface is 18 seconds, at which time the corresponding centrifugal speed is 275 rpm, the first effect high temperature zone is 55° C., and the second effect low temperature zone is 47° C.; In step (g), the pre-freezing temperature is -38°C, and the eutectic point of the system measured by DSC is -29°C, which is 9°C lower than the eutectic point. The sublimation temperature is -28°C, and the collapse point of the system measured by DSC is -19°C, which is 9°C lower than the collapse point.