A traditional Chinese medicine composition for treating knee osteoarthritis, a preparation method and application thereof

Abstract

This invention discloses a traditional Chinese medicine composition for treating knee osteoarthritis, its preparation method, and its application, belonging to the field of traditional Chinese medicine preparation technology. The composition, by weight, comprises 7-12 parts of Fangji (Stephania tetrandra), 17-23 parts of Huangqi (Astragalus membranaceus), 7-12 parts of Huangbai (Phellodendron chinense), 8-15 parts of Baizhu (Atractylodes macrocephala), 7-12 parts of Cangzhu (Atractylodes lancea), 16-24 parts of Yiyiren (Coix lacryma-jobi), 7-12 parts of Chuanniuxi (Achyranthes bidentata), 4-8 parts of Shengjiang (Zingiber officinale), 4-8 parts of Dazao (Ziziphus jujuba), and 4-8 parts of Zhigancao (Glycyrrhiza uralensis). Baizhu is prepared by honey-processing and wheat bran-frying, and Yiyiren is prepared by wheat bran-frying. During preparation, each raw material is decocted with water 2-3 times, the extracts are combined, and then concentrated at low temperature, vacuum dried, and pulverized to prepare the corresponding preparation. The composition can be used to prepare a drug for treating knee osteoarthritis of the Qi deficiency and dampness obstruction type. It can invigorate Qi and strengthen the body, tonify the spleen and kidneys, clear heat and remove dampness, and relieve pain. It addresses both the root cause of Qi deficiency and the symptoms of dampness obstruction, and has the advantages of definite curative effect, high safety, convenient administration and controllable quality.

Description

Technical Field

[0001] This invention belongs to the technical field of traditional Chinese medicine compositions and preparations, specifically relating to a traditional Chinese medicine composition for treating knee osteoarthritis, its preparation method, and its application. Background Technology

[0002] Knee osteoarthritis is a chronic degenerative joint disease characterized by degeneration of the knee cartilage, changes in the subchondral bone, and inflammation of the synovium. It commonly manifests as knee pain, swelling, stiffness, limited range of motion, and difficulty climbing stairs or walking. The risk of developing knee osteoarthritis increases with age, joint strain, and weight gain. The disease typically has a long course, is prone to recurrence, and significantly impacts patients' daily activities and quality of life.

[0003] Currently, treatment options for knee osteoarthritis mainly include exercise and weight management, oral or topical medications, intra-articular injections, and surgery. While medication can alleviate pain and inflammation to some extent, long-term or inappropriate use may pose risks to the gastrointestinal tract, cardiovascular system, or kidneys. The effectiveness of intra-articular injections varies from person to person, and surgery is invasive and has limitations in its application. Therefore, there remains a real need to provide appropriate treatment plans tailored to different disease stages and syndrome characteristics.

[0004] In Traditional Chinese Medicine (TCM), knee osteoarthritis falls under the categories of "knee obstruction" or "bone obstruction," and its occurrence is usually related to factors such as insufficient vital energy (Qi), invasion of external pathogens, and obstruction of meridians. Knee osteoarthritis often has a prolonged and recurring course and is more common in middle-aged and elderly people. With increasing age and the duration of the disease, the Qi of the spleen and kidneys gradually weakens. Qi deficiency leads to impaired fluid metabolism, resulting in the internal generation of dampness. Prolonged dampness can stagnate and transform into heat, which descends and obstructs the meridians, hindering the flow of Qi and blood, leading to symptoms such as knee pain, swelling, heaviness, and difficulty in flexion and extension. Simultaneously, the lingering damp-heat can further deplete vital energy, gradually forming a mixed state of deficiency and excess, with Qi deficiency as the root cause and damp-heat obstruction as the manifestation.

[0005] Current traditional Chinese medicine formulas for treating knee osteoarthritis are mostly formulated to tonify the liver and kidneys, strengthen tendons and bones, promote blood circulation, and dispel wind and dampness. Different treatment methods are applicable to different syndromes such as liver and kidney deficiency, qi stagnation and blood stasis, and cold-dampness obstruction. However, for syndromes of qi deficiency combined with damp-heat obstruction, focusing only on clearing heat, removing dampness, and unblocking the meridians may not be enough to address the underlying qi deficiency; while focusing only on tonification may not be sufficient to improve the swelling, heaviness, and limited mobility caused by local dampness obstruction in the joint.

[0006] Chinese patent application CN120053572A discloses a traditional Chinese medicine preparation for treating gout and rheumatoid arthritis, and its preparation method. This preparation consists of Fangji (Stephania tetrandra), Jiubiying (Saussurea involucrata), Jiang Houpu (Magnolia officinalis), Rendongteng (Lonicera japonica), Walengzi (Ostrea gigas), Cheqianzi (Plantago asiatica), Yiyiren (Coix lacryma-jobi), Laifuzi (Radix Raphanus sativus), Shenjincao (Herba Lycopi), Mianbixie (Herba Dimoides), Pugongying (Herba Taraxaci), Mudanpi (Cortex Moutan), and Fengxian Tougucao (Herba Impatiens). It is prepared through steps including soaking the herbs, two decoctions, combining the liquids, and heating and concentrating. It is mainly used to promote uric acid excretion and exert diuretic, anti-edema, heat-clearing, detoxifying, and wind-dispelling effects. However, this patent mainly focuses on the formulation and efficacy descriptions related to high uric acid and gout, without proposing a specific treatment plan for the syndrome characteristics of knee osteoarthritis due to qi deficiency and dampness obstruction. Furthermore, its preparation method mainly relies on decoction in containers and liquid concentration, leaving room for improvement in terms of ease of administration, industrial-scale preparation, and batch-to-batch quality consistency.

[0007] Chinese patent application CN122057030A discloses a traditional Chinese medicine composition based on a ternary carrier and a quaternary formula, and its preparation method. The composition consists of a ternary carrier comprising 30% by weight and a quaternary formula comprising 70% by weight. The ternary carrier includes silicified microcrystalline cellulose, fumed silica, and hydroxypropyl methylcellulose. The quaternary formula is formulated according to the principles of principal, assistant, adjuvant, and guiding herbs. The patent lists various four-herb combinations suitable for different diseases, including a combination of Phellodendron bark, Atractylodes lancea, Achyranthes bidentata, and Coix seed for gout and synovitis. It also discloses dosage forms such as gels, ointments, poultices, granules, capsules, and tablets, as well as extraction, spray drying, and overall mixing and molding processes. The technical solution of this patent mainly focuses on the ternary carrier system, the fixed quaternary compatibility structure, and the universal compatibility of various prescriptions and dosage forms. The different combinations of the four ingredients listed correspond to different diseases. The diagnosis of knee osteoarthritis cases listed in the specification is liver and kidney deficiency and cold-dampness obstruction. It has not yet proposed a special prescription scheme that takes into account both the qi deficiency and dampness obstruction in knee osteoarthritis with qi deficiency and dampness obstruction.

[0008] Furthermore, traditional Chinese medicine decoctions typically require on-site preparation, which presents problems such as time-consuming preparation, inconvenience in carrying and taking them; different decoction, concentration, and drying conditions may also affect batch consistency. Existing general-purpose formulation carriers or widely listed Chinese medicine compatibility schemes cannot automatically replace specialized formulation schemes developed for specific TCM syndromes, specific joint diseases, and corresponding quality control requirements.

[0009] Therefore, how to provide a traditional Chinese medicine composition and its preparation suitable for knee osteoarthritis with qi deficiency and dampness obstruction syndrome, so as to solve or overcome the technical problems of existing treatments that are insufficient in addressing both the root cause of qi deficiency and the symptoms of damp-heat obstruction, lack of targeted syndrome differentiation, inconvenience of traditional decoction preparations, and the need to improve the consistency of preparation quality, and achieve synergistic improvement of knee joint swelling, pain, and limited mobility related to qi deficiency and damp-heat obstruction syndrome, is an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0010] To address the deficiencies in the existing technologies, this invention provides a traditional Chinese medicine composition for treating knee osteoarthritis, its preparation method, and its application. The aim is to address the pathogenesis of knee osteoarthritis characterized by "qi deficiency as the root cause and damp-heat obstruction as the manifestation," by combining herbs that tonify qi, clear heat, dispel dampness, and promote joint mobility, thus balancing the root cause of qi deficiency with the manifestation of dampness obstruction. Furthermore, by controlling the proportions of raw materials, processing methods, extraction and concentration conditions, formulation technology, and quality indicators, the formulation applicability and quality controllability of the traditional Chinese medicine composition are improved.

[0011] In a first aspect, the present invention provides a traditional Chinese medicine composition for treating knee osteoarthritis, comprising, by weight, the following raw materials: Fangji 7-12 parts, Huangqi 17-23 parts, Huangbai 7-12 parts, Baizhu 8-15 parts, Cangzhu 7-12 parts, Yiyiren 16-24 parts, Chuanniuxi 7-12 parts, Shengjiang 4-8 parts, Dazao 4-8 parts, Zhigancao 4-8 parts.

[0012] Preferably, the Atractylodes macrocephala is prepared by honey-roasting and wheat bran-frying, and the Coix seed is prepared by wheat bran-frying.

[0013] The traditional Chinese medicine composition of this invention is derived from Fangji Huangqi Decoction and Simiao Decoction. Fangji (Stephania tetrandra) dispels wind and dampness, promotes diuresis and reduces swelling, and relieves pain; Huangqi (Astragalus membranaceus) tonifies qi and strengthens the exterior, invigorates the spleen and promotes diuresis. The combination of these two ingredients balances tonifying qi and strengthening the body's resistance with dispelling dampness and reducing swelling. Huangbai (Phellodendron chinense) clears heat and dries dampness, addressing the issue of dampness transforming into heat due to prolonged stagnation; Baizhu (Atractylodes macrocephala) and Cangzhu (Atractylodes lancea) invigorate the spleen and dry dampness, reducing internal dampness generation and promoting the dissipation of existing dampness; Yiyiren (Coix lacryma-jobi) invigorates the spleen, eliminates dampness, relieves pain, and unblocks the meridians; Chuanniuxi (Achyranthes bidentata) promotes joint mobility and guides the medicine downwards; Shengjiang (Zingiber officinale), Dazao (Ziziphus jujuba), and Zhigancao (Glycyrrhiza uralensis) tonify qi, harmonize the middle jiao, regulate the nutritive and defensive qi, and harmonize the other herbs. The synergistic effect of these ingredients gives the traditional Chinese medicine composition the functions of tonifying qi and strengthening the body's resistance, nourishing the spleen and kidneys, clearing heat and eliminating dampness, and relieving pain.

[0014] Preferably, the traditional Chinese medicine composition comprises, by weight, the following raw materials: 8-10 parts of Fangji, 18-22 parts of Huangqi, 8-10 parts of Huangbai, 10-14 parts of stir-fried Baizhu, 8-10 parts of Cangzhu, 18-22 parts of stir-fried Yiyiren, 8-10 parts of Chuanniuxi, 5-7 parts of fresh ginger, 5-7 parts of jujube, and 5-7 parts of prepared licorice. And the constituent raw materials meet the following usage ratios: The mass ratio of Astragalus membranaceus to Stephania tetrandra is greater than 1.9; The mass ratio of stir-fried Atractylodes macrocephala to Atractylodes lancea is greater than 1. The weight ratio of stir-fried Job's tears to Achyranthes bidentata should not be less than 2.

[0015] Among these measures, the mass ratio of Astragalus membranaceus to Stephania tetrandra is controlled to be greater than 1.9, so that the effects of invigorating qi and strengthening the body and eliminating dampness and promoting diuresis can complement each other, and the formula can address the root cause of qi deficiency while eliminating dampness; the mass ratio of Atractylodes macrocephala stir-fried with wheat bran to Atractylodes lancea is controlled to be greater than 1, so that the effects of invigorating qi and strengthening the body and clearing heat and eliminating dampness can be coordinated, and the formula can avoid being too biased towards bitter and warm drying dampness; the mass ratio of Coix lacryma-jobi stir-fried with Achyranthes bidentata is controlled to be no less than 2, so that the effects of strengthening the spleen and eliminating dampness, promoting diuresis and relieving numbness can be coordinated with the effects of promoting joint mobility and guiding the medicine downward.

[0016] Preferably, the traditional Chinese medicine composition is made from the following raw materials in parts by weight: The principal herbs are: 9 parts of Fangji (Stephania tetrandra) and 20 parts of Huangqi (Astragalus membranaceus); Assistant herbs: 9 parts Phellodendron bark, 12 parts stir-fried Atractylodes macrocephala, and 9 parts Atractylodes lancea; Adjuvant herbs: 20 parts stir-fried coix seed, 9 parts Sichuan achyranthes root; Used ingredients: 6 parts fresh ginger, 6 parts jujube, and 6 parts roasted licorice root.

[0017] Fangji (Stephania tetrandra) and Huangqi (Astragalus membranaceus) are the principal herbs. Fangji focuses on dispelling wind and dampness, promoting diuresis and reducing swelling, and relieving pain, while Huangqi focuses on tonifying qi and consolidating the exterior, as well as promoting diuresis and reducing swelling. Together, they tonify qi and dispel dampness simultaneously. Huangbai (Phellodendron amurense), stir-fried Baizhu (Atractylodes macrocephala), and Cangzhu (Atractylodes lancea) are the assistant herbs. Huangbai clears heat and dries dampness, stir-fried Baizhu strengthens the spleen and tonifies qi, dries dampness and promotes diuresis, and Cangzhu dries dampness, strengthens the spleen, dispels wind and dampness. Together, they assist the principal herbs in clearing dampness and reducing internal dampness. Stir-fried Yiyiren (Coix lacryma-jobi) and Chuanniuxi (Achyranthes bidentata) are the adjuvant herbs. Stir-fried Yiyiren strengthens the spleen, drains dampness, and relieves numbness, while Chuanniuxi tonifies the kidneys, strengthens bones, and guides the medicine downward. Shengjiang (Zingiber officinale), Dazao (Ziziphus jujuba), and Zhigancao (Glycyrrhiza uralensis) are the guiding herbs, used to tonify qi, harmonize the middle jiao, and regulate the effects of the other herbs. The entire formula achieves the goal of "tonifying qi without stagnation of pathogens and dispelling dampness without harming the body's vital energy," thus addressing both the root cause of qi deficiency and the symptoms of dampness obstruction.

[0018] The traditional Chinese medicine composition can be formulated into any one of granules, tablets, capsules, pills, or oral liquids.

[0019] Preferably, the dosage form of the traditional Chinese medicine composition is granules.

[0020] Secondly, the present invention also provides a method for preparing the aforementioned traditional Chinese medicine composition, comprising the following steps: S1. Extraction: Weigh each raw material according to the proportion, add water and decoct 2-3 times to extract, filter and combine the extracts; S2. Concentration: Concentrate the extract into a thick paste at a temperature below 78℃; S3. Drying: The thick paste is vacuum dried at a temperature below 80°C, pulverized and sieved to obtain a dry paste fine powder of the traditional Chinese medicine composition. The dry paste fine powder is used to form any one of the following preparations: granules, tablets, capsules, pills, or oral liquids.

[0021] Preferably, the relative density of the paste, measured at 70-80°C, is 1.1-1.30 g / cm³. 3More preferably 1.25-1.30 g / cm³ 3 .

[0022] Preferably, before step S1, raw material pretreatment is performed, including: Remove impurities from the raw materials, moisten them, cut them, and dry them; Atractylodes macrocephala was prepared by stir-frying honey-fried wheat bran. The stir-frying method included: adding slices of Atractylodes macrocephala to a hot pan after the honey-fried wheat bran was smoking, stir-frying until it turned yellowish-brown and produced a caramel aroma, and then sifting out the wheat bran. The method involves stir-frying Job's tears with wheat bran. The stir-frying process includes: adding Job's tears to a hot pan after the wheat bran has started to smoke, stir-frying until it turns slightly yellow and releases a caramelized aroma, and then sifting out the wheat bran.

[0023] More preferably, the honey-processing method is used to prepare the licorice. The preparation method includes: taking clean licorice slices and weighing out refined honey at a ratio of about 25 kg of refined honey per 100 kg of licorice slices; adding a small amount of boiling water to dilute the refined honey, pouring the diluted refined honey into the licorice slices and mixing well, and letting it soak until the honey liquid is absorbed by the licorice slices; placing the soaked licorice slices in a frying container, heating over a low heat, and frying until the licorice slices darken in color, turn dark yellow on the surface, have slight charred spots and are no longer sticky, removing them, spreading them out to cool and storing them.

[0024] Furthermore, the Astragalus membranaceus is preferably raw, which focuses on tonifying Qi and strengthening the exterior, as well as promoting diuresis and reducing swelling; in embodiments where it is necessary to enhance the effect of tonifying the middle and replenishing Qi, the Astragalus membranaceus is processed by honey-processing.

[0025] Furthermore, the Phellodendron bark is preferably prepared as a decoction piece to exert its heat-clearing and dampness-drying effects; in embodiments where it is necessary to make the medicinal properties tend downward while also taking into account the effects of nourishing yin and reducing fire, the Phellodendron bark is salted Phellodendron bark.

[0026] Furthermore, the preferred form of Achyranthes bidentata is salt-processed Achyranthes bidentata, which helps to guide the medicine to the kidneys, promote diuresis and eliminate dampness, and tonify the kidneys.

[0027] Preferably, in step S1, 6-12 times the amount of water is added for extraction for 0.5-1.5 hours each time, and the amount of water added in each subsequent extraction is no greater than the amount added in the previous extraction. In a further preferred embodiment, when extracting by boiling with water twice, the first time water is added in an amount equivalent to 8 times the total mass of the raw materials, and the second time water is added in an amount equivalent to 6 times the total mass, with each extraction lasting 1 hour.

[0028] In a further preferred embodiment, when the extraction is carried out three times by boiling with water, water equivalent to 8 times, 6 times and 6 times the total mass of the raw material is added for the first, second and third extractions, respectively, and each extraction lasts for 1 hour.

[0029] In step S2, the extract is concentrated under reduced pressure at a vacuum of -0.01 to -0.085 MPa, the temperature of the evaporator is below 76°C, and the steam pressure is 0.1 to 0.2 MPa. In step S3, the vacuum degree of vacuum drying is lower than -0.09 MPa.

[0030] Preferably, after step S3, the method further includes: S4. Granulation: The dry extract powder with a particle size of less than 200 μm is mixed with pharmaceutically acceptable excipients and granulated to obtain granule formulation; The excipients include at least one of flavoring agents, lubricants, and diluents; Based on the total mass of the dry paste powder and all excipients before granulation as 100%, the flavoring agent content is ≤0.8%, the lubricant content is ≤0.5%, and the diluent content is 10%-30%.

[0031] Furthermore, the flavoring agent includes steviol glycosides, the lubricant includes magnesium stearate, and the diluent includes maltodextrin. Steviol glycosides are used to improve the taste of the granulated formulation; magnesium stearate is used to improve the lubricity of the material and reduce adhesion between the material and equipment during granulation; and maltodextrin is used to adjust the material volume, flowability, and molding properties. Formulation studies have shown that within the excipient ratio range investigated in this invention, the moisture-proof performance of the resulting granules slightly improves with increasing excipient proportions; however, excessively high excipient proportions will correspondingly reduce the content of the herbal extract per unit mass of granules and may increase the single dose for patients. Therefore, this invention comprehensively considers the moisture-proof performance, molding properties, active ingredient content, and ease of administration of the granules to determine the excipient dosage.

[0032] Optionally, based on the total mass of the dry paste powder and diluent before granulation as 100%, the amount of diluent added is 12%-25%, and maltodextrin is preferred as the diluent; flavoring agents and lubricants used in smaller quantities can be added separately as needed.

[0033] In a further preferred embodiment, based on the total mass of the dry paste powder and all excipients before granulation as 100%, the addition amounts of steviol glycosides and magnesium stearate are 0.5%, and the addition amount of maltodextrin is 14%-17%, with the total amount of granulation feed supplemented according to the amount of dry paste.

[0034] Furthermore, step S4 employs dry granulation or one-step fluidized bed granulation.

[0035] When dry granulation is used, the dry paste powder is mixed evenly with excipients, pressed without the addition of liquid binders, then crushed and granulated to obtain the granular formulation. Dry granulation avoids the material undergoing a second wetting and heating drying process, and is suitable for dry paste powders that are sensitive to moisture or heat.

[0036] When using fluidized bed one-step granulation, the dry powder and excipients are placed in a fluidized bed for fluidized mixing. A binder is sprayed into the fluidized material, causing it to aggregate and form wet granules. These granules are then dried and granulated within the fluidized bed to obtain the granular formulation. The binder includes a hydroxypropyl methylcellulose solution. Fluidized bed one-step granulation allows mixing, granulation, and drying to be completed in the same equipment, which is beneficial for improving granulation efficiency and granule uniformity.

[0037] Furthermore, provided that the content of the flavoring agent does not exceed 0.8%, the type and content of the flavoring agent are adjusted according to the taste requirements of the applicable patients and the requirements for controlling sugar excipients.

[0038] For patients with diabetes and other conditions requiring controlled intake of sugary excipients, the content of steviol glycosides is preferably 0.3%-0.5%, and the granule formulation does not contain sucrose, glucose, or other sugar flavoring agents; maltodextrin may not be used as a diluent depending on the formulation requirements.

[0039] For elderly patients, the content of steviol glycosides can be adjusted within the range of 0.3%-0.8% according to their taste and dosage requirements.

[0040] For patients who are sensitive to bitterness and meet the indications and clinical drug requirements of this invention, the content of steviol glycosides is preferably 0.5%-0.8% to further improve the taste of the granule formulation.

[0041] Preferably, in the granule preparation, the content of astragaloside A is not less than 0.24 mg / g, and the content of total alkaloids of Stephania tetrandra is not less than 0.30 mg / g. It should be noted that the total alkaloids of Stephania tetrandra referred to in this invention are the sum of the contents of fangchinorline and tetrandrine.

[0042] Thirdly, the present invention also provides the application of the traditional Chinese medicine composition prepared by the method in the preparation of a drug for treating knee osteoarthritis.

[0043] Preferably, the knee osteoarthritis includes, but is not limited to, knee osteoarthritis caused by qi deficiency and dampness obstruction. The traditional Chinese medicine composition for treating knee osteoarthritis provided by this invention, its preparation method, and its application have at least the following beneficial effects: (1) This invention addresses the pathogenesis of knee osteoarthritis of the Qi deficiency and dampness obstruction type, characterized by "Qi deficiency as the root cause and damp-heat obstruction as the manifestation." It is derived from Fangji Huangqi Decoction and Simiao Decoction. Fangji and Huangqi are used to invigorate Qi, strengthen the exterior, and promote diuresis, thus addressing the root cause of Qi deficiency. Huangbai, stir-fried Baizhu, Cangzhu, stir-fried Yiyiren, and Chuanniuxi are used to clear heat, dry dampness, strengthen the spleen, promote diuresis, and facilitate joint movement, thus removing the manifestation of dampness obstruction. Fresh ginger, jujube, and prepared licorice are used to invigorate Qi, harmonize the middle Jiao, and regulate the effects of the other herbs. The ingredients work together to achieve both invigorating Qi and removing dampness, and to balance supporting the body's resistance with eliminating pathogenic factors. This conforms to the principle of "invigorating Qi without obstructing pathogenic factors and removing dampness without harming the body's resistance," and helps to avoid the potential depletion of vital energy caused by simply using bitter and cold herbs to dry dampness.

[0044] (2) The ingredients used in this invention, including Fangji, Huangqi, Huangbai, Baizhu, Cangzhu, Yiyiren, Chuanniuxi, Shengjiang, Dazao, and Zhigancao, are all commonly used Chinese medicinal materials listed in the Pharmacopoeia of the People's Republic of China. There are no incompatibilities between these ingredients, such as the "Eighteen Incompatibilities" or "Nineteen Antagonisms". Clinical studies have shown that when Yiqi Xuanbi Decoction and Granules are used for knee osteoarthritis of the Qi deficiency and dampness obstruction type, pain, knee joint circumference, range of motion, and TCM syndrome scores are all improved within the observation window of 2 to 4 weeks after the start of treatment. The overall therapeutic effect is better than that of the conventional Western medicine group.

[0045] (3) Based on the significant therapeutic effect of traditional decoctions, this invention further develops granules, eliminating the need for patients to prepare the decoctions themselves; patients can directly dissolve the granules in water and take them, which improves the convenience of medication and patient compliance. This invention also improves the standardization of formulation production through multiple water extractions, low-temperature vacuum concentration, low-temperature vacuum drying, and granulation processes. Furthermore, it establishes thin-layer chromatography identification and general quality inspection methods, and conducts research on the finished product content of astragaloside A and total alkaloids of Stephania tetrandra. This allows for a comprehensive evaluation of the authenticity of the raw materials, basic quality, and content of characteristic components, which helps ensure the quality stability and consistency of different batches of granule formulations.

[0046] (4) In view of the current situation that there is a lack of specialized Chinese medicine for knee osteoarthritis of Qi deficiency and dampness obstruction, this invention provides a Chinese medicine composition and its granule preparation with clear syndrome targeting, good clinical efficacy, high safety, convenient administration and controllable quality, which provides a new Chinese medicine treatment option for patients with knee osteoarthritis of Qi deficiency and dampness obstruction and has the application value to make up for the lack of existing clinical medicine. Detailed Implementation

[0047] To better understand the above technical solutions, a detailed description of the specific implementation methods will be provided below. Obviously, the described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0048] The terminology used in the embodiments of this invention is for the purpose of describing particular embodiments only and is not intended to limit the invention. The singular forms “a,” “the,” and “the” as used in the embodiments of this invention and the appended claims are also intended to include the plural forms, and “multiple” generally includes at least two unless the context clearly indicates otherwise.

[0049] It should also be noted that the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that an article or device that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such an article or device. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the article or device that includes said element.

[0050] This invention provides a traditional Chinese medicine composition for treating knee osteoarthritis. This composition can be used to prepare a medicine for treating knee osteoarthritis, particularly qi deficiency and dampness obstruction type knee osteoarthritis. Specifically, the traditional Chinese medicine composition includes: (1) Principal drug The principal herbs include 7-12 parts of Stephania tetrandra and 17-23 parts of Astragalus membranaceus.

[0051] Fangji (Stephania tetrandra) dispels wind and dampness, promotes diuresis and reduces swelling, relieves pain and numbness, while Huangqi (Astragalus membranaceus) invigorates qi, strengthens the exterior, and promotes diuresis. When the two are combined, they can simultaneously dispel dampness and promote diuresis while invigorating qi and supporting the body's resistance.

[0052] In one preferred embodiment, the principal herb comprises 8-10 parts of Stephania tetrandra and 18-22 parts of Astragalus membranaceus, and the mass ratio of Astragalus membranaceus to Stephania tetrandra is greater than 1.9, preferably greater than 2.0.

[0053] By controlling the mass ratio of Astragalus membranaceus to Stephania tetrandra, the principal herb can address the root cause of qi deficiency while eliminating dampness, thus avoiding an overemphasis on dampness removal that could damage the body's vital energy.

[0054] In a more preferred embodiment, the principal herb comprises 9 parts of Stephania tetrandra and 20 parts of Astragalus membranaceus. The mass ratio of Astragalus membranaceus to Stephania tetrandra is 20:9, approximately 2.22.

[0055] In some embodiments, the Astragalus membranaceus is either raw or honey-processed. Different processed Astragalus membranaceus products are prepared according to the corresponding Chinese herbal medicine processing standards.

[0056] (2) Ministerial medicine The herbal ingredients include 7-12 parts of Phellodendron bark, 8-15 parts of Atractylodes macrocephala, and 7-12 parts of Atractylodes lancea.

[0057] Phellodendron bark clears heat and dries dampness, and is used to address the issue of dampness stagnation transforming into heat; Atractylodes macrocephala strengthens the spleen and replenishes qi, dries dampness and promotes diuresis, and focuses on reducing the internal generation of dampness; Atractylodes lancea dries dampness, strengthens the spleen, dispels wind and eliminates dampness, and focuses on removing existing dampness.

[0058] In one preferred embodiment, the auxiliary herbs include 8-10 parts of Phellodendron bark, 10-14 parts of stir-fried Atractylodes macrocephala, and 8-10 parts of Atractylodes lancea, with the mass ratio of stir-fried Atractylodes macrocephala to Atractylodes lancea greater than 1.

[0059] By controlling the mass ratio of bran-fried Atractylodes macrocephala to Atractylodes lancea, the spleen-strengthening, qi-tonifying, diuretic, and dampness-resolving effects of bran-fried Atractylodes macrocephala can be coordinated with the bitter, warm, and dampness-drying effects of Atractylodes lancea.

[0060] In a more preferred embodiment, the auxiliary herbs include 9 parts of Phellodendron bark, 12 parts of stir-fried Atractylodes macrocephala, and 9 parts of Atractylodes lancea. The mass ratio of stir-fried Atractylodes macrocephala to Atractylodes lancea is 12:9, approximately 1.33.

[0061] In some embodiments, the Phellodendron bark is Phellodendron bark, salt-processed Phellodendron bark, or wine-processed Phellodendron bark, and different Phellodendron bark products are prepared in accordance with the corresponding Chinese herbal medicine processing specifications.

[0062] (3) Adjuvant medicine The adjuvant herbs include 16-24 parts of coix seed and 7-12 parts of Achyranthes bidentata.

[0063] Coix seed invigorates the spleen, eliminates dampness, relieves numbness, and unblocks the meridians; Achyranthes bidentata promotes joint mobility and guides the medicine downwards.

[0064] In one preferred embodiment, the adjuvant includes 18-22 parts of stir-fried coix seed and 8-10 parts of Achyranthes bidentata, and the mass ratio of stir-fried coix seed to Achyranthes bidentata is not less than 2.

[0065] By controlling the mass ratio of stir-fried coix seed to Achyranthes bidentata, the spleen-strengthening, dampness-removing, diuretic, and pain-relieving effects of stir-fried coix seed are coordinated with the joint-clearing and drug-guiding effects of Achyranthes bidentata.

[0066] In a more preferred embodiment, the adjuvant includes 20 parts of stir-fried coix seed and 9 parts of Achyranthes bidentata. The mass ratio of stir-fried coix seed to Achyranthes bidentata is 20:9, approximately 2.22.

[0067] In some embodiments, the Achyranthes bidentata is either Achyranthes bidentata or Achyranthes bidentata with salt, and different processed Achyranthes bidentata products are prepared in accordance with the corresponding Chinese herbal medicine processing specifications.

[0068] In one preferred embodiment, Achyranthes bidentata is used to guide the medicine to the kidneys, promote diuresis and eliminate dampness, and tonify the kidneys.

[0069] (4) To administer medicine The medicinal ingredients include 4-8 parts of roasted licorice root, 4-8 parts of fresh ginger, and 4-8 parts of jujube.

[0070] Ginger and jujubes benefit the spleen and stomach, and harmonize the body's vital energy; roasted licorice root is used to invigorate qi, harmonize the middle jiao, and harmonize the effects of other herbs.

[0071] In one preferred embodiment, the medicinal ingredients include 5-7 parts ginger, 5-7 parts jujube, and 5-7 parts roasted licorice root.

[0072] In a more preferred embodiment, the medicinal ingredients include 6 parts ginger, 6 parts jujube, and 6 parts roasted licorice root.

[0073] Through the combination of the above-mentioned principal, assistant, adjuvant, and guiding herbs, the traditional Chinese medicine composition of the present invention is derived from Fangji Huangqi Decoction and Simiao Decoction, which takes into account both the root cause of qi deficiency and the symptoms of dampness obstruction.

[0074] In one preferred embodiment, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: The principal herbs are: 9 parts of Fangji (Stephania tetrandra) and 20 parts of Huangqi (Astragalus membranaceus); Assistant herbs: 9 parts Phellodendron bark, 12 parts stir-fried Atractylodes macrocephala, and 9 parts Atractylodes lancea; Adjuvant herbs: 20 parts stir-fried coix seed, 9 parts Sichuan achyranthes root; Used ingredients: 6 parts fresh ginger, 6 parts jujube, and 6 parts roasted licorice root.

[0075] In some embodiments, the dosage form of the traditional Chinese medicine composition is any one of granules, tablets, capsules, pills, or oral liquid.

[0076] In conventional embodiments, the herbal composition is decocted to obtain a soup for oral administration, and this dosage form is more convenient to carry and take. In one preferred embodiment, the herbal composition is made into granules.

[0077] The present invention also provides a method for preparing the above-mentioned traditional Chinese medicine composition, specifically including the following steps: S0, Raw material pretreatment Before step S1, each raw material is subjected to impurity removal, moistening, cutting and drying. Atractylodes macrocephala is stir-fried with honey and wheat bran, and Coix seed is stir-fried with wheat bran.

[0078] The above-mentioned pretreatment and processing of raw materials can be completed before the formulation is added. When using pre-processed medicinal slices that meet the corresponding quality standards, the slices should be inspected and weighed before being added.

[0079] Fangji: Remove impurities, soak briefly, wash, moisten thoroughly, cut into thick slices and dry.

[0080] Astragalus: Remove impurities, process according to size, wash, soak thoroughly, cut into thick slices and dry.

[0081] Phellodendron bark: Remove impurities, spray with water to moisten thoroughly, cut into shreds and dry.

[0082] Stir-fried Atractylodes macrocephala with wheat bran: Remove impurities from Atractylodes macrocephala, wash it, moisten it thoroughly, cut it into thick slices and dry it; put honey-roasted wheat bran into a hot pan, and after the honey-roasted wheat bran is heated and smokes, add the Atractylodes macrocephala slices, stir-fry until the Atractylodes macrocephala slices turn yellow-brown and produce a caramel aroma, remove and sift out the honey-roasted wheat bran.

[0083] In one preferred embodiment, 10 kg of honey-fried wheat bran is used to stir-fry every 100 kg of Atractylodes macrocephala slices.

[0084] Atractylodes lancea: Remove impurities, wash, soak thoroughly, cut into thick slices and dry.

[0085] Stir-fry Job's tears: Remove impurities from Job's tears; put bran into a hot pan, and after the bran is heated and smokes, add the cleaned Job's tears and stir-fry until the Job's tears turn slightly yellow and release a caramel aroma. Remove and sift out the bran.

[0086] Achyranthes bidentata: Remove impurities and rootlets, wash, soak thoroughly, slice thinly and dry.

[0087] Ginger: Remove impurities, wash, and cut into thick slices.

[0088] Jujubes: Remove impurities, wash and dry them, and break them open or remove the pits before use.

[0089] Prepared licorice: Take clean licorice slices and weigh out 25 kg of refined honey for every 100 kg of licorice slices. Dilute the refined honey with a small amount of boiling water, pour the diluted refined honey into the licorice slices and mix well. Let it sit until the honey liquid is absorbed by the licorice slices. Place the saty licorice slices in a frying container and heat over a low flame until the licorice slices darken in color, turn a deep yellow on the surface, have slight charred spots and are no longer sticky. Remove them and spread them out to cool.

[0090] S1: Extract Weigh each pretreated raw material according to the corresponding composition ratio, mix the raw materials, add water and decoct to extract 2-3 times, filter and combine the extracts.

[0091] In one preferred embodiment, water equivalent to 6-12 times the total mass of the raw material is added each time, and the extraction time is 0.5-1.5 hours each time, and the amount of water added in each subsequent extraction is no greater than the amount added in the previous extraction.

[0092] When decocting and extracting twice, the amount of water added in the first extraction should be greater than that in the second extraction. For example, it is preferable to add water equivalent to 8 times the total mass of the raw materials in the first extraction and 6 times the total mass in the second extraction, with each extraction lasting 1 hour; alternatively, it is preferable to add 10 times the total mass of water in the first extraction and extract for 1 hour, and then add 8 times the total mass of water in the second extraction and extract for 1 hour.

[0093] When decocting and extracting three times, the amount of water added in each subsequent extraction should not exceed the amount added in the previous extraction. For example, it is preferable to add water equivalent to 8 times, 6 times, and 6 times the total mass of the raw materials for the first, second, and third extractions, respectively, and extract for 1 hour each time; alternatively, it is preferable to add 12 times the amount of water for the first extraction and extract for 1.5 hours, add 9 times the amount of water for the second extraction and extract for 1 hour, and add 6 times the amount of water for the third extraction and extract for 0.5 hours.

[0094] After each extraction, the extract is separated from the residue, and the extract is filtered using a filter cloth. In one specific embodiment, a 300-mesh filter cloth is used for filtration.

[0095] S2: Concentrated The extract obtained in step S1 is concentrated into a thick paste at a temperature below 78°C.

[0096] In one preferred embodiment, a vacuum concentration device is used for concentration, the vacuum degree of the concentration process is -0.01 to -0.085 MPa, the temperature of the evaporator cylinder is not higher than 76°C, and the steam pressure is 0.1-0.2 MPa.

[0097] In one preferred embodiment, the relative density of the paste, measured at 70-80°C, is 1.10-1.30 g / cm³. 3 The preferred concentration is 1.25-1.30 g / cm³. 3 .

[0098] S3: Drying The thick paste obtained in step S2 is vacuum dried at a temperature below 80°C. The dried material is then pulverized and sieved to obtain a fine powder of the traditional Chinese medicine composition.

[0099] In one preferred embodiment, the vacuum degree of vacuum drying is less than -0.09 MPa.

[0100] In one specific embodiment, the dried material is pulverized and passed through an 80-mesh sieve to obtain a fine powder with a particle size of less than 200 μm.

[0101] In one preferred embodiment, the particle size of the resulting dry paste powder is 160-180 μm.

[0102] The resulting dry extract powder can be used to prepare granules, tablets, capsules, pills, or oral liquids.

[0103] S4: Granulation In preparing granule formulations, the dry extract powder obtained in step S3 is mixed with pharmaceutically acceptable excipients and granulated to obtain granule formulations.

[0104] The excipients include at least one of flavoring agents, lubricants, and diluents. Based on the total mass of the dry powder before granulation and all excipients (100%), the content of flavoring agents shall not exceed 0.8%, the content of lubricants shall not exceed 0.5%, and the content of diluents shall be between 10% and 30%.

[0105] In one preferred embodiment, the flavoring agent is steviol glycoside, the lubricant is magnesium stearate, and the diluent is maltodextrin.

[0106] In a preferred embodiment, based on the total mass of the dry paste powder and maltodextrin before granulation as 100%, steviol glycosides and magnesium stearate each account for 0.5% of the total mass of the feed before granulation, and the amount of maltodextrin added is 12%-25%, which can be adjusted according to the amount of dry paste obtained and molding requirements; during pilot-scale granulation, maltodextrin accounts for 14%-17% of the total mass of the dry paste powder and all excipients before granulation.

[0107] When dry granulation is used, the dry paste powder is mixed evenly with the excipients, and then pressed through a dry granulation machine to crush and granulate the pressed material.

[0108] In one-step fluidized bed granulation, the dry paste powder and excipients are added to the fluidized bed and mixed, then a binder is sprayed in for granulation, followed by drying and granulation. In one embodiment, the binder is a hydroxypropyl methylcellulose solution.

[0109] Provided that the flavoring agent content does not exceed 0.8%, the amount of flavoring agent can be adjusted according to the target population. For diabetic patients, the amount of steviol glycosides can account for 0.3%-0.5% of the total mass of the material before granulation, or a pharmaceutically acceptable sugar-free flavoring agent can be used; for middle-aged and elderly patients who meet the indications and clinical drug requirements of this invention and are more sensitive to bitterness, the amount of steviol glycosides can account for 0.5%-0.8% of the total mass of the material before granulation.

[0110] In one preferred embodiment, the obtained granule preparation contains astragaloside A at a concentration of not less than 0.24 mg / g, preferably not less than 0.26 mg / g, and total alkaloids of Stephania tetrandra at a concentration of not less than 0.30 mg / g, preferably not less than 0.33 mg / g, wherein the total alkaloids of Stephania tetrandra are calculated as the sum of the concentrations of tebufenozide and tetrandrine. Astragaloside A is determined by high performance liquid chromatography (HPLC), and total alkaloids of Stephania tetrandra are determined by ultra-high performance liquid chromatography (UHPLC).

[0111] Example 1 The traditional Chinese medicine composition for treating knee osteoarthritis provided in this embodiment has the following raw material composition: Chief herbs: 9 kg of Fangji (Stephania tetrandra) and 20 kg of Huangqi (Astragalus me Assistant herbs: 9kg of Phellodendron bark, 12kg of stir-fried Atractylodes macrocephala, and 9kg of Atractylodes lancea; Adjuvant herbs: 20kg of stir-fried coix seed and 9kg of Achyranthes bidentata; Used ingredients: 6 kg of fresh ginger, 6 kg of jujubes, and 6 kg of roasted licorice root.

[0112] Among them, the mass ratio of Astragalus membranaceus to Stephania tetrandra is 2.22, the mass ratio of stir-fried Atractylodes macrocephala to Atractylodes lancea is 1.33, and the mass ratio of stir-fried Coix lacryma-jobi to Achyranthes bidentata is 2.22.

[0113] This embodiment uses raw Astragalus membranaceus, Phellodendron chinense that has not been processed with salt or wine, and Achyranthes bidentata that has not been processed with wine or salt.

[0114] The preparation method of the above-mentioned traditional Chinese medicine composition is as follows: S0, Raw material pretreatment Each raw material is cleaned to remove impurities, and then washed, moistened, cut, and dried according to its properties.

[0115] The preparation of stir-fried Atractylodes macrocephala is as follows: put honey-fried wheat bran into a hot pan, and after the honey-fried wheat bran is heated and smokes, add Atractylodes macrocephala slices, stir-fry until the Atractylodes macrocephala slices turn yellow-brown and produce a caramel aroma, remove, sift out the honey-fried wheat bran, and let cool before use.

[0116] To prepare roasted Job's tears, put wheat bran into a hot pan. Once the bran is heated and starts to smoke, add the cleaned Job's tears and stir-fry until the Job's tears turn slightly yellow and release a roasted aroma. Remove the meat, sift out the bran, and let it cool before use.

[0117] Prepared licorice root is prepared as follows: Take clean licorice root slices and add refined honey at a ratio of 25 kg of refined honey per 100 kg of clean licorice root slices; dilute the refined honey with a small amount of boiling water, pour the diluted refined honey into the licorice root slices and mix well, let it soak until the honey liquid is absorbed by the licorice root slices; place the soaked licorice root slices in a frying container, heat over low heat, and fry until the licorice root slices darken in color, turn deep yellow on the surface, have slight charred spots and are no longer sticky, remove them, and spread them out to cool. Add the prepared prepared licorice root according to the prescribed amount.

[0118] S1, Extraction Mix the above ten raw materials, add water equivalent to 10 times the total weight of the raw materials for the first time, decoct and extract for 1 hour, then filter. Add water equivalent to 8 times the total weight of the raw materials to the residue for the second time, decoct and extract for 1 hour. After extraction, filter each extract through a 300-mesh filter cloth and combine the two extracts.

[0119] S2, Concentrated The combined extracts were concentrated under reduced pressure at a vacuum level of approximately -0.01 MPa, an evaporator temperature of 76°C, and a vapor pressure of approximately 0.1 MPa, until the relative density was approximately 1.25 g / cm³. 3 A thick paste.

[0120] S3, Drying and Pulverizing The resulting thick paste was vacuum dried at approximately 78°C and a vacuum pressure below -0.09 MPa. The dried material was then pulverized and passed through an 80-mesh sieve (No. 5 sieve) to obtain a fine powder of dry paste with a particle size of approximately 160-180 μm (not exceeding 200 μm).

[0121] S4, Granulation and Packaging Take 8.50 kg of the obtained dry extract powder, add 0.05 kg (0.5%) of steviol glycosides, 0.05 kg (0.5%) of magnesium stearate, and 1.40 kg (14%) of maltodextrin, and mix evenly to make the total weight of the material 10.00 kg. Granulate the mixture using a dry granulation machine, and package it into 13g bags to obtain the traditional Chinese medicine composition granules.

[0122] Example 2 The composition of the active pharmaceutical ingredient, the pretreatment of the active pharmaceutical ingredient, the extraction, concentration, drying and pulverization steps in this embodiment are the same as those in Example 1, the only difference being the granulation step.

[0123] Take 7.45 kg of the dry paste powder prepared according to steps S0-S3 in Example 1, add 2.50 kg (25%) of maltodextrin and 0.05 kg (0.5%) of magnesium stearate, mix evenly, and granulate and shape using a dry granulation machine to obtain granules.

[0124] Example 3 Unlike Example 1, this example uses the following raw materials in the following weight ratios: 9 parts of Fangji, 20 parts of Huangqi, 8 parts of Huangbai, 10 parts of stir-fried Baizhu, 8 parts of Cangzhu, 18 parts of stir-fried Yiyiren, 8 parts of Chuanniuxi, 5 parts of fresh ginger, 5 parts of jujube, and 5 parts of prepared licorice.

[0125] The mass ratio of Astragalus membranaceus to Stephania tetrandra was 2.22, the mass ratio of stir-fried Atractylodes macrocephala to Atractylodes lancea was 1.25, and the mass ratio of stir-fried Coix lacryma-jobi to Achyranthes bidentata was 2.25. The remaining preparation steps were the same as in Example 1.

[0126] Example 4 Unlike Example 1, this example uses the following raw materials in the following weight ratios: 9 parts of Fangji, 20 parts of Huangqi, 10 parts of Huangbai, 14 parts of stir-fried Baizhu, 10 parts of Cangzhu, 22 parts of stir-fried Yiyiren, 10 parts of Chuanniuxi, 7 parts of fresh ginger, 7 parts of jujube, and 7 parts of prepared licorice.

[0127] The mass ratio of Astragalus membranaceus to Stephania tetrandra was 2.22, the mass ratio of stir-fried Atractylodes macrocephala to Atractylodes lancea was 1.40, and the mass ratio of stir-fried Coix lacryma-jobi to Achyranthes bidentata was 2.20. The remaining preparation steps were the same as in Example 1.

[0128] Example 5 Unlike Example 1, this example uses the following raw materials in the following weight ratios: 10 parts of Fangji, 22 parts of Huangqi, 9 parts of Huangbai, 12 parts of stir-fried Baizhu, 9 parts of Cangzhu, 20 parts of stir-fried Yiyiren, 9 parts of Chuanniuxi, 6 parts of fresh ginger, 6 parts of jujube, and 6 parts of prepared licorice.

[0129] The mass ratio of Astragalus membranaceus to Stephania tetrandra was 2.20, the mass ratio of stir-fried Atractylodes macrocephala to Atractylodes lancea was 1.33, and the mass ratio of stir-fried Coix lacryma-jobi to Achyranthes bidentata was 2.22. The remaining preparation steps were the same as in Example 1.

[0130] Example 6 The composition and pretreatment method of the active pharmaceutical ingredient in this embodiment are the same as in Example 1. The difference lies in the extraction conditions of the preparation method. Step S1 includes: Mix the raw materials, add water equivalent to 8 times the total weight of the raw materials for the first time, decoct and extract for 1.0 hour, and then filter. Add water equivalent to 6 times the total weight of the raw materials to the dregs for a second time, and decoct for 1.0 hour. The remaining steps are the same as in Example 1.

[0131] Example 7 The composition and pretreatment method of the active pharmaceutical ingredient in this embodiment are the same as in Example 1. The difference lies in the extraction conditions of the preparation method. Step S1 includes: The raw material was decocted and extracted three times: for the first time, water equivalent to 8 times the total weight of the raw material was added, and the decoction was carried out for 1 hour; for the second time, water equivalent to 6 times the total weight of the raw material was added, and the decoction was carried out for 1 hour; for the third time, water equivalent to 6 times the total weight of the raw material was added, and the decoction was carried out for 1 hour. The remaining preparation steps were the same as in Example 1.

[0132] Example 8 The composition of the active pharmaceutical ingredient and the pretreatment method of Example 8 are the same as those of Example 1. The difference is that the clinical case uses the traditional preparation method, that is, each dose is decocted and extracted in step S1 to obtain 2 bags × 100ml decoction, which is used twice a day, 1 bag each time, after breakfast and dinner.

[0133] Test methods and results The granule samples from Examples 1-7 were subjected to the following tests and analyses, and the test results are shown in Table 1: (a) Routine inspection of granules 1. Particle size: The particle size shall be checked according to the corresponding method under the Granules section. The total mass of particles and powders that cannot pass through a No. 1 sieve (sieve aperture inner diameter 2000μm±70μm) and can pass through a No. 6 sieve (sieve aperture inner diameter approximately 150 μm) shall not exceed 15% of the mass of the test sample. For a large quantity of granules, it is preferable that they can pass through a No. 5 sieve (sieve aperture inner diameter approximately 180μm).

[0134] 2. Moisture content: The moisture content of granules shall not exceed 8.0% according to the moisture test method for granules.

[0135] 3. Solubility: The solubility of granules was tested according to the method for testing granules. All granules in each example were completely dissolved, and no foreign matter or charred debris was found.

[0136] 4. Dry extract yield: The percentage of the mass of the obtained dry extract relative to the total mass of the raw materials fed; 5. Final product yield: The percentage of packageable granules obtained after necessary rework and granulation out of the total granulation feed weight. Whether rework or recycling occurred should be noted in the original records during testing.

[0137] 6. Microbiological limits: The total aerobic bacteria count of the granule formulation shall not exceed 2000 cfu / g, and the total mold and yeast count shall not exceed 100 cfu / g. Escherichia coli was not detected in any of the examples.

[0138] Table 1

[0139] As shown in Table 1, the moisture content of each granule sample in Examples 1-7 was <8.0%, the particle size non-compliance was <15%, and the microbial limits met the requirements of the Pharmacopoeia standard for granules. Among them, Example 7 used three decoction extractions, resulting in a higher yield of dry extract; Example 2 had a maltodextrin content of 25%, and the high diluent content was beneficial to improving the molding rate.

[0140] (II) Qualitative Identification of Medicinal Flavors The following thin-layer chromatography identification method was used to detect the granules prepared in Examples 1-7 and the decoction in Example 8. For each item, a corresponding sample lacking flavor was set up as a negative control. For each example, samples actually prepared should be taken for testing, and the results should be recorded in Table 3. Existing pilot-scale samples are only used to verify the applicability of the corresponding detection methods, and their test results are not directly used as the actual test results of other examples.

[0141] 1. Identification of Stephania tetrandra: Take 5g of the granular preparation from Examples 1-7 and 25ml of the decoction from Example 8, evaporate to dryness to obtain approximately 5g of dried sample. Dissolve in 40mL of water, adjust to acidity with dilute hydrochloric acid, filter, and adjust to alkalinity with concentrated ammonia solution. Extract three times with 20mL of ether each time. Evaporate the ether solution to dryness, dissolve the residue with 1mL of methanol to obtain the test solution. Take 1g of Stephania tetrandra reference material and prepare the reference material solution in the same way. Take 5μL of each of the two solutions and the negative control solution lacking Stephania tetrandra, spot them on the same silica gel G thin-layer plate, and develop the plate with a mixture of dichloromethane-acetone-methanol-5% concentrated ammonia solution in a volume ratio of 8:1:2:0.1 as the developing solvent. After saturation for 20 minutes, remove and air dry, spray with dilute bismuth potassium iodide solution, and examine under sunlight.

[0142] 2. Identification of Astragalus membranaceus: Take 4g of the granular preparation from Examples 1-7 and 20ml of the decoction from Example 8, evaporate to dryness to obtain approximately 4g of dried sample. Grind finely, add 50mL of methanol, sonicate for 30 minutes, filter, evaporate to dryness, add 20mL of water to dissolve, extract twice with 40mL of water-saturated n-butanol each time; combine the n-butanol solutions, wash four times with ammonia solution, 20mL each time, discard the ammonia solution and evaporate to dryness, dissolve the residue in 3mL of methanol. Take 1g of Astragalus membranaceus reference material and prepare a reference material solution using the same method. Take 4μL each of the test sample, reference material, and negative control solution lacking Astragalus membranaceus, and spot them on the same silica gel G thin-layer plate; use the lower layer solution with a volume ratio of dichloromethane-methanol-water of 20:7:2 as the developing solvent, and let the lower layer solution stand at 10℃ for more than 30 minutes; after saturation for 20 minutes, develop, remove and air dry, spray with 10% sulfuric acid ethanol solution, heat at 105℃ until the spots are clearly visible, and examine under sunlight.

[0143] 3. Identification of Phellodendron bark: Take 1g of the granules from Examples 1-7 and 5ml of the decoction from Example 8, evaporate to dryness to obtain about 1g of dried sample, add 40mL of 1% acetic acid methanol solution, sonicate for 20 minutes and filter, concentrate the filtrate to 2mL; take 0.2g of Phellodendron bark reference material and prepare the reference material solution in the same way; take 5μL each of the test sample and the negative control solution lacking Phellodendron bark, and 2μL of the reference material solution, spot them on the same silica gel G thin layer plate, use a mixture of n-butanol-glacial acetic acid-water in a volume ratio of 6:1:1 as the developing solvent, develop after saturation for 20 minutes, remove and air dry, and examine under sunlight.

[0144] 4. Identification of stir-fried Atractylodes macrocephala and Atractylodes lancea: Take 10g of the granules from Examples 1-7 and 50ml of the decoction from Example 8, evaporate to dryness to obtain about 10g of dried sample, add 30mL of n-hexane and sonicate for 30 minutes, filter, evaporate to dryness, and dissolve in 1mL of methanol; take 1g each of stir-fried Atractylodes macrocephala and Atractylodes lancea reference materials, and prepare reference material solutions in the same way; take 15μL each of the test sample and negative control solutions lacking stir-fried Atractylodes macrocephala and Atractylodes lancea, 10μL of stir-fried Atractylodes macrocephala reference material solution, and 5μL of Atractylodes lancea reference material solution, and spot them on the same silica gel G thin layer plate. Use a mixture of petroleum ether and ethyl acetate with a boiling range of 60-90℃ in a volume ratio of 18:1 as the developing solvent, saturate for 20 minutes, develop, remove and air dry, spray with 2% p-dimethylaminobenzaldehyde in 40% sulfuric acid solution, heat at 105℃, and examine under 365nm ultraviolet light.

[0145] 5. Identification of stir-fried coix seed: Take 10g of the granules from Examples 1-7 and 50ml of the decoction from Example 8, evaporate to dryness to obtain about 10g of dried sample, add 30mL of petroleum ether and sonicate for 30 minutes, filter, evaporate to dryness, and then add 1mL of petroleum ether to dissolve; take 1g of bran-fried coix seed reference material and prepare the reference material solution in the same way; separately take 10μL of the test sample and the negative control solution lacking bran-fried coix seed, and 5μL of the reference material solution, and spot them on the same silica gel G thin layer plate. Use a mixture of petroleum ether, ethyl acetate and glacial acetic acid with a boiling range of 60-90℃ in a volume ratio of 5:1:0.5 as the developing solvent, saturate for 20 minutes, develop, remove and air dry, and examine under 365nm ultraviolet light.

[0146] 6. Identification of processed licorice: Take 2g of the granular preparation from Examples 1-7 and 10ml of the decoction from Example 8, evaporate to dryness to obtain approximately 2g of dried sample. Add 25mL of methanol and sonicate for 30 minutes. Filter, evaporate to dryness, add 20mL of water to dissolve, and extract twice with n-butanol. Combine the n-butanol layers and evaporate to dryness. Dissolve the residue in 2mL of methanol. Take 1g of licorice reference material and prepare a reference material solution using the same method. Take 4μL each of the test sample and the negative control solution lacking licorice, and 2μL of the reference material solution, and spot them on the same silica gel G thin-layer plate. Use the lower layer solution of dichloromethane-methanol-water (volume ratio 17:7:2) as the developing solvent. Develop after 20 minutes of saturation. Remove and air dry, spray with 10% sulfuric acid ethanol solution, heat at 105℃ for color development, and examine under sunlight and 365nm ultraviolet light.

[0147] The above six thin-layer chromatography methods involve Stephania tetrandra, Astragalus membranaceus, Phellodendron chinense, stir-fried Atractylodes macrocephala, Atractylodes lancea, stir-fried Coix lacryma-jobi, and Glycyrrhiza uralensis. For determination, the test sample chromatogram should show a spot of the same color at the corresponding position as the corresponding reference herb chromatogram, and there should be no interference from the corresponding negative control.

[0148] The measured results of each embodiment are filled in Table 2. "+" indicates that the chromatogram of the test sample shows the same color / fluorescent spot at the corresponding position as the chromatogram of the reference medicinal material, the negative control has no interference, and the identification result is positive.

[0149] Table 2

[0150] (III) Determination scheme for index components 1. Astragaloside A content: Take approximately 1g of each of the granules from Examples 1-7, add 50mL of 80% methanol solution containing 4% concentrated ammonia (take 4 mL of concentrated ammonia solution, add 80% methanol to 100 mL, and shake well), shake well, sonicate for 45 minutes, filter, and prepare the test solution; determine by high performance liquid chromatography, using an acetonitrile-water mixture with a volume ratio of 32:68 as the mobile phase, using an evaporative light scattering detector, a drift tube temperature of 70℃, and a pressure of 314 kPa, calculate the astragaloside A content according to the logarithmic equation of the external standard two-point method. Five groups of samples were tested in parallel for each example, and the average value was taken. The test results are shown in Table 3. The astragaloside A content in the granules from Examples 1-7 is not less than 0.26 mg / g, and the deviation of each group's test result from the mean is within ±0.015 mg / g.

[0151] Take 5 ml of the decoction from Example 8 and evaporate it to dryness. The dry weight of the five samples was between approximately 1.0 and 1.13 g. The same sample preparation and testing methods as in Examples 1-7 were used. Since the decoction of Example 8 did not contain any excipients, its astragaloside A content was slightly higher. The test results of the five samples were between 0.40 and 0.45 mg / g, and the average value of the five samples was approximately 0.43 mg / g, which is qualified. However, the deviation of each test result from the mean value of Example 8 was within ±0.03 mg / g, which is relatively larger than that of the granules.

[0152] 2. Total alkaloid content of Stephania tetrandra: Approximately 1 g of each of the granules from Examples 1-7 was added to 25 mL of 50% methanol, sonicated for 15 minutes, and then filtered through a 0.22 μm microporous membrane. The content was determined by ultra-high performance liquid chromatography (UHPLC) using an ACQUITY UPLC HSS T3 column with gradient elution of acetonitrile and 0.1% phosphoric acid aqueous solution as the mobile phase. The flow rate was 0.3 mL / min, the column temperature was 35℃, and the detection wavelength was 210 nm. The sum of the contents of tetrandrine and tebufenozide was taken as the total alkaloid content of Stephania tetrandra. Five parallel samples were tested for each example, and the average value was taken. The test results are shown in Table 3. The total alkaloid content of Stephania tetrandra in the granules from Examples 1-7 was not less than 0.33 mg / g, and the deviation of each test result from the mean was within ±0.02 mg / g.

[0153] Five ml of the decoction from Example 8 was evaporated to dryness. The dry weight of the five samples ranged from approximately 1.0 to 1.13 g. The same sample preparation and testing methods as in Examples 1-7 were used. Since the decoction in Example 8 did not contain any excipients, its total alkaloid content was slightly higher. The test results for the five samples ranged from 0.46 to 0.54 mg / g, with an average of approximately 0.51 mg / g, which is acceptable. However, the deviations of the test results from the mean for each group in Example 8 were all within ±0.05 mg / g, showing relatively larger fluctuations compared to the granules.

[0154] The test results of Examples 1-7 are shown in Table 3: Table 3

[0155] As shown in Table 3, all examples 1-7 met the requirements for astragaloside A ≥ 0.24 mg / g, preferably ≥ 0.28 mg / g; and total alkaloids of Stephania tetrandra ≥ 0.30 mg / g, preferably ≥ 0.35 mg / g. Among them, Example 7, with three extractions, showed the highest dissolution of active ingredients and the highest content of both indicators. In Example 2, due to the high proportion of maltodextrin as a diluent, the active ingredients per unit particle were diluted, resulting in lower levels of both indicators within the group, but they still met the minimum requirements.

[0156] (iv) Clinical efficacy observation 1. Research Data 1.1 Study Design and Case Source This study included 367 patients who visited the Department of Orthopedics at a hospital between October 2023 and December 2025. Based on their previous medication use, they were divided into three groups: Group 1 (129 cases, Yiqi Xuanbi Decoction, Example 8), Group 2 (60 cases, Example 7), Group 3 (60 cases, Example 1), and a control group (118 cases, conventional Western medicine). No randomization was performed. This study has been approved ethically.

[0157] 1.2 Diagnostic Criteria The Western medicine diagnostic criteria refer to the "Guidelines for the Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Knee Osteoarthritis"; the TCM syndrome diagnosis criteria are formulated with reference to the "Guidelines for the Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Knee Osteoarthritis (2023 Edition)": The symptoms conform to the Qi deficiency and dampness obstruction syndrome, manifested as joint swelling, muscle and bone pain, limited mobility, or generalized slight swelling, heaviness and weakness, aversion to wind and slight sweating, soreness and weakness of the lower back and knees, and difficulty urinating. The tongue is pale and swollen with teeth marks on the edges, and the coating is white and slippery, or the tongue is pale with a yellow and greasy coating, and the pulse is soft.

[0158] 1.3 Inclusion Criteria (1) Patients with a clear diagnosis of KOA, whose previous inpatient / outpatient medical records clearly state "Qi deficiency and dampness obstruction syndrome" or equivalent syndrome descriptions, and whose clinical medical records are complete.

[0159] (2) Imaging data (X-ray) during the consultation period can determine the Kellgren-Lawrence (KL) stage, and the stage is I to III.

[0160] (3) Record at least one pain visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) or TCM syndrome score before and after treatment as the main efficacy evaluation indicators.

[0161] 1.4 Exclusion Criteria (1) Patients whose medical records show a confirmed diagnosis of rheumatoid arthritis, ankylosing spondylitis, infectious arthritis or other non-degenerative knee joint diseases.

[0162] (2) Patients whose previous imaging or medical records indicate severe structural damage to the knee joint (such as obvious varus or valgus deformity, severe flexion contracture) and who have been identified as having entered the surgical treatment pathway.

[0163] (3) Patients with severe heart, liver, kidney or other vital organ dysfunction during the course of treatment, which may significantly affect treatment options or efficacy assessment.

[0164] (4) Cases where key research variables (such as major efficacy indicators or incomplete treatment records) are missing from medical records, making effective statistical analysis impossible.

[0165] (5) Those who received treatment other than those in the group during the observation period, or whose medication and treatment records were unclear and could not be determined whether there was cross-treatment.

[0166] 2. Treatment methods The control group had previously received routine oral Western medicine, including celecoxib capsules 0.2g, once a day. The first group of patients who previously received the Qi-Boosting and Bi-Calming Formula (Example 8) decoction were prepared by decocting two bags per dose, each bag containing 100mL. The decoction was taken twice daily, one bag each time, after breakfast and dinner.

[0167] The second group of patients who previously received the Qi-Boosting and Bi-Calming Formula granules from Example 7, each bag containing 13g, 2 bags per dose, twice a day, dissolved in warm water; The third group of patients who previously received the Yiqi Xuanbi Formula granules from Example 1, each bag containing 13g, 2 bags per dose, twice a day, dissolved in warm water.

[0168] Effective exposure is defined as continuous treatment for ≥2 weeks, and the actual treatment cycle is mostly 2 to 4 weeks.

[0169] 3. Observation time and indicators Clinical data recorded at the patient's first visit and during relevant treatment were used as the baseline before treatment. Follow-up records from 2–4 weeks after treatment initiation were prioritized; if multiple follow-up visits were available, the closest to 4 weeks was selected as the primary outcome.

[0170] Table 4 Clinical observation indicators and time windows

[0171] The main symptoms of TCM syndrome are joint pain, joint swelling, and difficulty in flexion and extension; the secondary symptoms are slight swelling throughout the body, fatigue, aversion to wind and slight sweating, soreness and weakness of the lower back and knees, and difficulty in urination. All are scored as 0, 2, 4, and 6 points respectively, with the symptoms being none, mild, moderate, and severe. Tongue and pulse are recorded but not scored.

[0172] 4. Statistical methods Continuous variables are expressed as mean ± standard deviation or median (1st quartile, 3rd quartile), while categorical variables are expressed as number of cases and percentage. Chain equation multiple imputation was used to handle missing data, and propensity score was estimated based on gradient boosting machine. Inverse probability weighting was used to control for confounding. Between-group differences in continuous outcomes were assessed using the weighted linear regression results from the paper, and the overall effectiveness was assessed using the weighted logistic regression results.

[0173] Results before and after treatment The unweighted clinical observation results are shown in Table 5, taking the first group of Yiqi Xuanbi Formula (Example 8) as an example. The second and third groups of Yiqi Xuanbi Formula are similar to the first group.

[0174] Table 5 Unweighted Clinical Observation Results

[0175] 6. Weighted inter-group comparisons Table 6 shows the weighted difference between the first group of Yiqi Xuanbi formula (Example 8) and the control group in terms of the change in the "post-treatment - baseline" value. This result provides a reference for the short-term clinical application of the formula. The second and third groups of Yiqi Xuanbi formula are similar to the first group.

[0176] Table 6 Weighted inter-group differences in outcome changes

[0177] Note: β is the regression coefficient of the first group of Yiqi Xuanbi formula relative to the control group on the change in "post-treatment − baseline". The 95% CI is calculated as β ± 1.96 × standard error, which is a normal approximation interval based on the summary data. Negative values ​​for VAS, WOMAC, circumference, and syndrome score indicate greater improvement, while positive values ​​for activity level indicate greater increase.

[0178] 7. Comprehensive therapeutic effect of TCM syndromes The efficacy index EI = (pre-treatment score - post-treatment score) / pre-treatment score × 100%.

[0179] Clinical cure (formerly referred to as clinical control): EI ≥ 95%; Effectiveness: 70% ≤ EI < 95%; Effective: 30% ≤ EI < 70%; Invalid: EI < 30%.

[0180] Overall effective rate = (clinically cured + significantly effective + effective) / total number of cases in this group × 100%.

[0181] Table 7. Therapeutic effects of TCM syndromes 2-4 weeks after treatment

[0182] The unweighted overall effective rate for TCM syndrome improvement was above 90.0%, with the first group using the decoction from Example 8 achieving 91.5% (118 / 129). While the overall effective rates of the second and third groups using the granules of the Yiqi Xuanbi formula fluctuated, the overall effect was still good. The overall effective rate of the conventional Western medicine control group was only 82.2% (97 / 118). The weighted average effective rate (OR) was 2.11, with a 95% CI of 0.94–4.73 and a P=0.070.

[0183] 8. Safety Observation Taking the first group of Yiqi Xuanbi formula as an example, the safety of the Chinese herbal components in this formula was investigated, and the results are shown in Table 8.

[0184] Table 8. Observation of liver and kidney function in the first group of the Qi-tonifying and Bi-dampness-relieving formula.

[0185] Note: The data are medians (Q1, Q3).

[0186] Based on the above tests and analyses, the Qi-invigorating and Bi-regulating formula of the present invention has significant efficacy in the early and middle stages of knee osteoarthritis of Qi deficiency and dampness obstruction type and is safe to use. As granules, the remaining granule examples, such as Examples 1 and 7, have a more uniform distribution of each component compared to the decoction example 8. While basically maintaining the therapeutic effect, the change in dosage form provides patients with a more convenient way to take the medicine and carry it.

[0187] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention. Clearly, those skilled in the art can make various alterations and modifications to the invention without departing from its spirit and scope. Thus, if these modifications and modifications of the invention fall within the scope of the claims and their equivalents, the invention is also intended to include these modifications and modifications.

Claims

1. A traditional Chinese medicine composition for treating knee osteoarthritis, characterized in that, The constituent raw materials, by weight, include: Fangji 7-12 parts, Huangqi 17-23 parts, Huangbai 7-12 parts, Baizhu 8-15 parts, Cangzhu 7-12 parts, Yiyiren 16-24 parts, Chuanniuxi 7-12 parts, Shengjiang 4-8 parts, Dazao 4-8 parts, Zhigancao 4-8 parts.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The constituent raw materials are as follows, by weight: 8-10 parts of Fangji, 18-22 parts of Huangqi, 8-10 parts of Huangbai, 10-14 parts of stir-fried Baizhu, 8-10 parts of Cangzhu, 18-22 parts of stir-fried Yiyiren, 8-10 parts of Chuanniuxi, 5-7 parts of fresh ginger, 5-7 parts of jujube, and 5-7 parts of prepared licorice. And the constituent raw materials meet the following usage ratios: The mass ratio of Astragalus membranaceus to Stephania tetrandra is greater than 1.9; The mass ratio of stir-fried Atractylodes macrocephala to Atractylodes lancea is greater than 1. The weight ratio of stir-fried Job's tears to Achyranthes bidentata should not be less than 2.

3. The traditional Chinese medicine composition according to claim 2, characterized in that, It is made from the following raw materials in parts by weight: The principal herbs are: 9 parts of Fangji (Stephania tetrandra) and 20 parts of Huangqi (Astragalus membranaceus); Assistant herbs: 9 parts Phellodendron bark, 12 parts stir-fried Atractylodes macrocephala, and 9 parts Atractylodes lancea. Adjuvant herbs: 20 parts stir-fried coix seed, 9 parts Sichuan achyranthes root; Used ingredients: 6 parts fresh ginger, 6 parts jujube, and 6 parts roasted licorice root.

4. The traditional Chinese medicine composition according to any one of claims 1-3, characterized in that, The dosage form of the traditional Chinese medicine composition includes any one of granules, tablets, capsules, pills, and oral liquids.

5. A method for preparing a traditional Chinese medicine composition according to any one of claims 1-4, characterized in that, Includes the following steps: S1. Extraction: Weigh each raw material according to the proportion, add water and decoct 2-3 times to extract, filter and combine the extracts; S2. Concentration: Concentrate the extract into a thick paste at a temperature below 78℃; S3. Drying: The thick paste is vacuum dried at a temperature below 80°C, pulverized and sieved to obtain a dry paste fine powder of the traditional Chinese medicine composition. The dry paste fine powder is used to form any one of the following preparations: granules, tablets, capsules, pills, or oral liquids.

6. The preparation method according to claim 5, characterized in that, Before step S1, raw material pretreatment is performed, including: Remove impurities from the raw materials, moisten them, cut them, and dry them; Atractylodes macrocephala is prepared by stir-frying honey-fried wheat bran. The stir-frying method includes: adding slices of Atractylodes macrocephala to a hot pan after the honey-fried wheat bran has started to smoke, stir-frying until it turns yellowish-brown and produces a caramel aroma, and then sifting out the wheat bran. The method involves stir-frying Job's tears with wheat bran. The stir-frying process includes: adding Job's tears to a hot pan after the wheat bran has started to smoke, stir-frying until it turns slightly yellow and releases a caramelized aroma, and then sifting out the wheat bran.

7. The preparation method according to claim 5 or 6, characterized in that, In step S1, add 6-12 times the amount of water each time and extract for 0.5-1.5 hours, and the amount of water added in each subsequent extraction should not be greater than the amount added in the previous extraction. In step S2, the extract is concentrated under reduced pressure at a vacuum of -0.01 to -0.085 MPa, the temperature of the evaporator is below 76°C, and the steam pressure is 0.1 to 0.2 MPa. In step S3, the vacuum degree of vacuum drying is lower than -0.09 MPa.

8. The preparation method according to claim 7, characterized in that, Following step S3, the following is also included: S4. Granulation: The dry extract powder with a particle size of less than 200 μm is mixed with pharmaceutically acceptable excipients and granulated to obtain granule formulation; The excipients include at least one of flavoring agents, lubricants, and diluents; Based on the total mass of the dry paste powder and all excipients before granulation as 100%, the flavoring agent content is ≤0.8%, the lubricant content is ≤0.5%, and the diluent content is 10%-30%.

9. The preparation method according to claim 8, characterized in that, In the granule preparation, the content of astragaloside A is not less than 0.24 mg / g, and the content of total alkaloids of Stephania tetrandra is not less than 0.30 mg / g.

10. The use of a traditional Chinese medicine composition according to any one of claims 1-4, or a traditional Chinese medicine composition prepared by any one of claims 5-9, in the preparation of a medicament for treating knee osteoarthritis.

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