A traditional Chinese medicine composition for improving cancer-related fatigue, a tincture and a preparation method thereof

Abstract

This application relates to the field of traditional Chinese medicine composition technology, and particularly to a traditional Chinese medicine composition, tincture, and preparation method for improving cancer-related fatigue. The tincture preparation method includes: S1, weighing raw materials according to weight parts: prepared aconite root, dried ginger, ephedra, cinnamon twig, platycodon root, red peony root, cinnamon bark, asarum, luffa fruit, angelica root, raw astragalus root, safflower, sandalwood, clove, and borneol; S2, pulverizing the raw materials obtained in step S1, sieving, and obtaining a pulverized traditional Chinese medicine composition; S3, placing the pulverized traditional Chinese medicine composition in a container, then adding a solvent, sealing the container, and placing it in a light-proof, dry environment for soaking; S4, filtering the soaking liquid to obtain a preliminary extract; S5, adding a diluent to the preliminary extract obtained in step S4 for dilution, stirring, and obtaining the tincture. The tincture for improving cancer-related fatigue of this invention, through transdermal administration, allows the active pharmaceutical ingredients to be absorbed directly into the systemic circulation through the skin, avoiding gastrointestinal degradation and the first-pass effect of the liver.

Description

Technical Field

[0001] This application relates to the field of traditional Chinese medicine technology, and in particular to a traditional Chinese medicine composition, tincture and preparation method for improving cancer-related fatigue. Background Technology

[0002] Cancer-related fatigue (CRF) is a subjective, persistent, and distressing physical, emotional, or cognitive fatigue or exhaustion commonly experienced by patients with malignant tumors during treatment or disease progression. It is disproportionate to recent activity levels and severely interferes with normal functioning. This symptom differs from ordinary fatigue, is difficult to relieve with regular rest, and is one of the core issues significantly impacting the quality of life of cancer patients. Currently, the pathophysiological mechanisms of CRF are not fully understood in modern medicine. It is generally considered a complex process involving multiple factors and systems, encompassing widespread dysregulation of the neuroendocrine-immune network. Specifically, the tumor itself and its treatments (such as chemotherapy and radiotherapy) trigger a persistent inflammatory response, leading to elevated levels of pro-inflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α). These cytokines act on the central nervous system, potentially affecting the function of the hypothalamus-pituitary-adrenal axis and interfering with the metabolism of neurotransmitters (such as serotonin and dopamine), ultimately resulting in energy metabolism disorders, muscle dysfunction, and persistent fatigue and lack of energy. In addition, anemia, pain, malnutrition, sleep disorders, and psychological and emotional problems (such as anxiety and depression) are also intertwined, all of which exacerbate the severity of fatigue.

[0003] In terms of current clinical treatment, Western medicine lacks specific targeted drugs for the management of CRF, and currently mainly adopts a comprehensive intervention and supportive treatment strategy. This includes non-pharmacological interventions, such as moderate aerobic exercise, cognitive behavioral therapy, sleep hygiene education, and nutritional support. At the pharmacological level, medications are often used based on accompanying symptoms. For example, stimulants (such as methylphenidate) are used to temporarily boost energy and attention; antidepressants (such as selective serotonin reuptake inhibitors) are used to improve mood and sleep; or erythropoietin is used to correct anemia. However, these methods have significant limitations. Stimulants may cause side effects such as insomnia, anxiety, palpitations, and addiction, and their long-term efficacy and safety are poorly documented in cancer patients. Antidepressants have a slow onset of action and are not effective for all patients, also accompanied by adverse reactions such as gastrointestinal reactions and sexual dysfunction. Although exercise therapy has been proven effective, it is difficult to implement and has low adherence for patients with severe fatigue, extremely poor physical condition, or complications such as bone metastases. Overall, existing Western medicine treatments are mostly symptomatic, lacking fundamental treatments that regulate the body's overall imbalance. Their efficacy is unstable, and patient satisfaction needs to be improved. There is an urgent need to explore safer, more effective, and more acceptable complementary or alternative therapies.

[0004] In the field of traditional medicine, Traditional Chinese Medicine (TCM) has a long history of understanding and rich experience in treating conditions similar to CRF, such as "debility," "spiritual fatigue," and "weariness." TCM theory holds that the depletion of the body's vital energy (Qi) by cancerous toxins is the root cause of tumor development and progression. While aggressive therapies like surgery, radiotherapy, and chemotherapy eliminate pathogens, they also further damage the body's Qi, blood, Yin, and Yang, leading to dysfunction of the internal organs, with spleen and kidney Yang deficiency and insufficient Qi as the core pathogenesis. The spleen is the foundation of acquired constitution, the source of Qi and blood production, and governs muscles and limbs; the kidney is the foundation of innate constitution, containing primordial Yin and Yang, and is the driving force of life activities. When spleen and kidney Yang Qi are deficient, the production of Qi and blood lacks a source, clear Yang fails to ascend, and muscles lack warmth and nourishment, resulting in symptoms such as fatigue, weakness, shortness of breath, reluctance to speak, aversion to cold, cold limbs, poor appetite, and loose stools. Therefore, "tonifying Qi and warming Yang" has become an important TCM treatment method for this type of debilitating fatigue.

[0005] Currently, the main methods of TCM intervention for chronic renal failure (CRF) are oral herbal decoctions or prepared Chinese medicines, and acupuncture. While oral administration allows for holistic treatment based on syndrome differentiation, it suffers from drawbacks such as poor taste, inconvenience in preparation, gastrointestinal irritation, hepatic first-pass effect, and poor patient compliance, especially for cancer patients experiencing nausea, vomiting, or difficulty swallowing. Acupuncture, though effective, requires professional physician operation, involves frequent treatments, and some patients have a fear of needles; its application is also limited in certain situations (such as thrombocytopenia or high infection risk). Transdermal drug delivery systems, as a non-invasive method, allow active drug components to be absorbed directly into the systemic circulation through the skin, avoiding gastrointestinal degradation and hepatic first-pass effect, improving bioavailability, providing a stable and continuous blood drug concentration, reducing the frequency of administration, and enhancing patient convenience and comfort. Therefore, developing a new external TCM treatment approach that avoids the drawbacks of oral administration, is easy to operate, readily accepted by patients, and can continuously exert its "tonifying and warming yang" effects is of significant clinical need and practical importance. Summary of the Invention

[0006] The purpose of this application is to provide a traditional Chinese medicine composition, tincture, and preparation method thereof to improve chronic renal failure (CRF), addressing the following technical problems: CRF lacks safe, effective, and easily acceptable fundamental treatments. CRF is a severe and persistent subjective fatigue caused by malignant tumors and their treatments, with a complex pathophysiological mechanism involving widespread dysregulation of the neuroendocrine and immune networks, leading to energy metabolism disorders, muscle dysfunction, and lack of energy. Existing Western medicine management strategies are mostly symptomatic and supportive treatments, such as using stimulants, antidepressants, or erythropoietin. However, these drugs have significant side effects, insufficient evidence of efficacy, slow onset of action, or are not universally effective. Non-pharmacological interventions such as exercise therapy are difficult to implement for patients with severe fatigue. Therefore, there is an urgent clinical need for a new therapy that can holistically regulate the body's imbalance, has stable efficacy, and few side effects. The tincture of this invention avoids the disadvantages of oral administration, is easy to administer, and is readily accepted by patients.

[0007] The first aspect of this application provides a traditional Chinese medicine composition for improving cancer-related fatigue, the composition comprising the following raw materials in parts by weight: 15-30 parts of processed aconite root, 20-30 parts of dried ginger, 20-30 parts of ephedra, 15-30 parts of cinnamon twig, 5-10 parts of platycodon root, 15-30 parts of red peony root, 5-15 parts of cinnamon bark, 3-10 parts of asarum, 15-30 parts of luffa fruit, 15-30 parts of angelica root, 30-60 parts of raw astragalus root, 15-45 parts of safflower, 3-5 parts of sandalwood, 3-5 parts of clove, and 1-3 parts of borneol.

[0008] Optionally, the traditional Chinese medicine composition includes the following raw materials in parts by weight: 30 parts of prepared aconite root, 30 parts of dried ginger, 30 parts of ephedra, 30 parts of cinnamon twig, 10 parts of platycodon root, 30 parts of red peony root, 15 parts of cinnamon bark, 10 parts of asarum, 30 parts of luffa fruit, 30 parts of angelica root, 60 parts of raw astragalus root, 45 parts of safflower, 5 parts of sandalwood, 5 parts of clove, and 3 parts of borneol.

[0009] The formula is based on herbs that warm the kidneys and invigorate yang, combined with herbs that warm the middle jiao, dispel cold, restore yang and unblock the meridians to enhance the warming effect. At the same time, herbs that dispel wind and cold, warm the meridians and relieve pain are added to dredge the meridians. In addition, herbs that nourish blood, promote blood circulation, remove blood stasis and unblock the meridians are added to harmonize the ying and wei and promote blood circulation. Furthermore, herbs that carry the medicine upward are used to regulate the rise and fall of qi. All the herbs work together to invigorate qi, warm yang, and tonify the spleen and kidneys.

[0010] A second aspect of the present invention provides a traditional Chinese medicine tincture for improving CRF, the traditional Chinese medicine tincture comprising the following raw materials: the traditional Chinese medicine composition as described in the first aspect, a solvent and a diluent.

[0011] A third aspect of this invention provides a method for preparing a traditional Chinese medicine tincture for improving CRF as described in the second aspect, characterized by comprising the following preparation steps: S1. Weigh the raw materials according to their weight parts: prepared aconite, dried ginger, ephedra, cinnamon twig, platycodon root, red peony root, cinnamon bark, asarum, luffa fruit, angelica root, raw astragalus root, safflower, sandalwood, clove, and borneol. S2. The raw materials obtained from the crushing step S1 are weighed, sieved, and mixed evenly to obtain a crushed Chinese herbal medicine composition. S3. Place the pulverized Chinese herbal medicine composition from step S2 into a container, then add solvent, seal the container, and place it in a dark, dry environment for soaking. S4. Filter the impregnation solution to obtain the initial extract; S5. Add a diluent to the initial extract obtained in step S4 and stir to ensure that the initial extract and water are fully mixed to obtain a tincture.

[0012] Optionally, in step S2, the sieving is performed using an 80-mesh sieve.

[0013] Optionally, in step S3, the temperature of the immersion environment is 20-25°C.

[0014] Optionally, in step S3, the soaking time is 14-17 days.

[0015] Optionally, in step S3, during the impregnation process, the pulverized Chinese medicine composition and solvent in the container are stirred 1-3 times daily.

[0016] Optionally, the weight-volume ratio (g / mL) of the pulverized traditional Chinese medicine composition to the solvent is (4-5.5):(9-11).

[0017] Optionally, the solvent is an ethanol solution; the diluent is distilled water or water for injection.

[0018] The fourth aspect of the present invention provides a method for using the tincture prepared in the second aspect or the tincture prepared in the third aspect, wherein the tincture is applied wet to acupoints and meridian pathways that have the functions of invigorating qi and warming yang, warming and tonifying the spleen and kidneys, and strengthening the body's resistance.

[0019] Optionally, the acupoints and meridian pathways that have the functions of invigorating qi and warming yang, warming and tonifying the spleen and kidneys, and strengthening the body's resistance are as follows: On the abdomen, select the Huangshu acupoint of the Foot Shaoyin Kidney Meridian (0.5 cun lateral to the umbilicus), the Tianshu acupoint of the Foot Taiyin Spleen Meridian (2 cun lateral to the anterior midline, level with the umbilicus), the Daheng acupoint of the Foot Yangming Stomach Meridian (4 cun lateral to the umbilicus), and the Shenque acupoint, Qihai acupoint (1.5 cun below the umbilicus), and Guanyuan acupoint (3 cun below the umbilicus) on the Ren Meridian; On the back, select the Shenshu acupoint (1.5 cun lateral to the spinous process of the 2nd lumbar vertebra), Qihaiyu acupoint (1.5 cun lateral to the spinous process of the 3rd lumbar vertebra), and Guanyuanyu acupoint (1.5 cun lateral to the spinous process of the 5th lumbar vertebra) on the Foot Taiyang Bladder Meridian, and the Mingmen acupoint (between the spinous processes of the 2nd and 3rd lumbar vertebrae) on the Du Meridian, with the latter serving as the main acupoint for the lower back.

[0020] The fifth aspect of the present invention provides a treatment method for CRF, which uses the tincture described in the second or third aspect in combination with moxibustion.

[0021] The technical solutions provided in this application have the following advantages compared with the prior art: 1. The traditional Chinese medicine tincture for invigorating qi and warming yang provided by this invention is based on the theory of "invigorating qi and warming yang, and tonifying the spleen and kidneys" in traditional Chinese medicine. It targets the core pathogenesis of CRF and acts directly on the human body through skin administration, avoiding the gastrointestinal irritation and first-pass effect of the liver that may be caused by oral Chinese medicine. It improves the bioavailability of the drug and the convenience and comfort of patients taking the medicine. It is especially suitable for cancer patients with digestive symptoms or difficulty swallowing.

[0022] 2. This invention provides a method for preparing a traditional Chinese medicine tincture for improving CRF with clear process parameters, standardized operation steps, and controllable quality. This method strictly follows the pharmacopoeia specifications, controls the quality of raw materials from the source, maximizes the extraction of effective components through an optimized impregnation process, and finally produces a topical tincture with uniform specifications and relatively clear components, providing a stable and reliable material basis for subsequent transdermal drug delivery treatment.

[0023] 3. The tincture of this invention was confirmed by UHPLC-MS / MS technology to contain multiple active ingredients such as L-proline, osthol, and 6-gingerol, ensuring the stability and controllability of the tincture quality. The transdermal application method is simple to operate, which is conducive to long-term adherence by patients and can provide continuous and stable efficacy, thereby regulating the imbalance of Qi, blood, Yin and Yang in the body as a whole, and improving the patient's fatigue, cold limbs, poor appetite and other accompanying symptoms. Compared with existing Western medicine symptomatic drugs (such as stimulants and antidepressants), it has better safety and fewer side effects. Compared with traditional oral Chinese medicine and acupuncture therapy, it has higher patient acceptance and compliance, providing a safe, effective and easy-to-promote new external treatment approach of traditional Chinese medicine for the clinical management of CRF.

[0024] 4. The tincture of the present invention is used to improve CRF. It is administered through the skin and applied in conjunction with acupressure massage, which significantly improves CRF. Attached Figure Description

[0025] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with this application and, together with the description, serve to explain the principles of this application.

[0026] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 This is the total ion chromatogram in positive ion mode.

[0028] Figure 2 This is the total ion current chromatogram in negative ion mode. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments of this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0030] The range descriptions used in this application, such as numerical ranges and proportional ranges, include all possible sub-ranges and single numerical values ​​within that range. For example, the range descriptions of "1 to 6" or "1~6" cover all sub-ranges (such as 1 to 3, 2 to 5, etc.) and single numbers (such as 1, 2, 3, 4, 5, 6) between 1 and 6. Unless otherwise specified, the terms "comprising" and others used herein mean "including but not limited to"; relational terms such as "first" and "second" are used only to distinguish different entities or operations and do not imply an actual order or relationship; "and / or" indicates that multiple situations can exist individually or simultaneously; expressions such as "at least one," "multiple," and "at least one" refer to any combination of the corresponding objects, including combinations of single or multiple objects. The proportional relationships involved in this document, such as mass ratios and molar ratios, should be understood as the correspondence between the first and second terms of a proportional formula, according to the order of description. The raw materials, reagents, instruments, and equipment used herein can all be obtained by purchasing from the market or by existing methods.

[0031] This application provides a traditional Chinese medicine composition for improving CRF, which includes the following raw materials in parts by weight: 15-30 parts of processed aconite root, 20-30 parts of dried ginger, 20-30 parts of ephedra, 15-30 parts of cinnamon twig, 5-10 parts of platycodon root, 15-30 parts of red peony root, 5-15 parts of cinnamon bark, 3-10 parts of asarum, 15-30 parts of luffa fruit, 15-30 parts of angelica root, 30-60 parts of raw astragalus root, 15-45 parts of safflower, 3-5 parts of sandalwood, 3-5 parts of clove, and 1-3 parts of borneol.

[0032] Optionally, the traditional Chinese medicine composition includes the following raw materials in parts by weight: 30 parts of prepared aconite root, 30 parts of dried ginger, 30 parts of ephedra, 30 parts of cinnamon twig, 10 parts of platycodon root, 30 parts of red peony root, 15 parts of cinnamon bark, 10 parts of asarum, 30 parts of luffa fruit, 30 parts of angelica root, 60 parts of raw astragalus root, 45 parts of safflower, 5 parts of sandalwood, 5 parts of clove, and 3 parts of borneol.

[0033] The herbal composition in this invention strictly follows the TCM theory of "tonifying qi and warming yang, nourishing the spleen and kidneys" in its formulation. The principal herb, Aconitum carmichaelii, is used as the chief herb to warm the kidneys and invigorate yang qi throughout the body. Dried ginger and cinnamon are used as assistant herbs to assist the chief herb in warming the middle jiao, dispelling cold, restoring yang, and unblocking the meridians. Ephedra and cinnamon twig are used as adjuvant herbs to warm the meridians, dispel cold, and unblock the channels. Red peony root is added to nourish blood, promote blood circulation, remove blood stasis, and harmonize the ying and wei. Platycodon grandiflorus is used as the guiding herb, taking advantage of its light and ascending nature to carry the medicinal power upwards and regulate the ascending and descending of qi. The dosage ratio of each herb is key to achieving the best synergistic therapeutic effect.

[0034] This invention also provides a traditional Chinese medicine tincture for improving CRF, the traditional Chinese medicine tincture comprising the following raw materials: The aforementioned traditional Chinese medicine composition, solvent, and diluent.

[0035] Furthermore, the solvent is preferably ethanol, and the diluent is distilled water or water for injection.

[0036] This invention also provides a method for preparing a traditional Chinese medicine tincture for improving CRF as described above, characterized by comprising the following preparation steps: S1. Weigh the raw materials according to their weight parts: prepared aconite, dried ginger, ephedra, cinnamon twig, platycodon root, red peony root, cinnamon bark, asarum, luffa fruit, angelica root, raw astragalus root, safflower, sandalwood, clove, and borneol. S2. The raw materials obtained from the crushing step S1 are weighed, sieved, and mixed evenly to obtain a crushed Chinese herbal medicine composition. S3. Place the pulverized Chinese herbal medicine composition from step S2 into a container, then add solvent, seal the container, and place it in a dark, dry environment for soaking. S4. Filter the impregnation solution to obtain the initial extract; S5. Add a diluent to the initial extract obtained in step S4 and stir to ensure that the initial extract and water are fully mixed to obtain a tincture.

[0037] In some alternative implementations, in step S2, the sieving is performed using an 80-mesh sieve.

[0038] In these embodiments, pulverization is performed using GMP-compliant pulverization equipment, such as a universal pulverizer or an ultrafine pulverizer. The pulverization equipment grinds the medicinal materials into a fine powder, requiring all the powder to pass through an 80-mesh sieve and to be uniformly mixed, thereby increasing the contact area between the medicinal materials and the solvent and facilitating the extraction of active ingredients. It should be noted that the pulverization process should be carried out in a clean environment to prevent contamination by foreign matter.

[0039] In some alternative implementations, in step S3, the temperature of the immersion environment is 20-25°C.

[0040] In some optional embodiments, the immersion time in step S3 is 14-17 days. Preferably, the immersion time is 14-15 days, and more preferably, the immersion time is 15 days.

[0041] In some optional embodiments, during step S3, the pulverized herbal medicine composition and solvent in the container are stirred 1-3 times daily during the impregnation process. Preferably, stirring is performed 1-2 times daily, and more preferably, each stirring session lasts 10-15 minutes.

[0042] In these embodiments, the herbal composition and solvent are stirred during the impregnation process to ensure sufficient contact between the solid and liquid phases, thereby promoting the dissolution and diffusion of the active ingredients. It is understood that stirring can be performed using a stirring tool (stirring rod, stirring blade, etc.) to ensure sufficient contact between the solid and liquid, or by thoroughly shaking the container to ensure sufficient contact between the solid and liquid.

[0043] In some optional embodiments, the weight-to-volume ratio (g / mL) of the traditional Chinese medicine composition to the solvent is (4-5.5):(9-11). Preferably, the weight-to-volume ratio of the traditional Chinese medicine composition to the solvent is (5-5.5):(9-10), and more preferably, the weight-to-volume ratio of the traditional Chinese medicine composition to the solvent is 5:10.

[0044] In the method for preparing traditional Chinese medicine tinctures of the present invention, the weight-to-volume ratio (g / mL) of the traditional Chinese medicine composition to the solvent is a key process parameter that affects the extraction efficiency, preparation quality and transdermal efficacy. After system optimization, the preferred weight-to-volume ratio of the traditional Chinese medicine composition to the solvent in this invention is (4-5.5):(9-11), and more preferably 5:10. That is, 500g of the pulverized traditional Chinese medicine composition is added to 1000mL of 75% (v / v) ethanol solution for soaking. The 500g of traditional Chinese medicine composition is made from the following raw materials in the following weight parts: 15-30 parts of processed aconite root, 20-30 parts of dried ginger, 20-30 parts of ephedra, 15-30 parts of cinnamon twig, 5-10 parts of platycodon root, 15-30 parts of red peony root, 5-15 parts of cinnamon bark, 3-10 parts of asarum, 15-30 parts of luffa fruit, 15-30 parts of angelica root, 30-60 parts of raw astragalus root, 15-45 parts of safflower, 3-5 parts of sandalwood, 3-5 parts of clove, and 1-3 parts of borneol.

[0045] The advantages of using this preferred ratio are: (1) Sufficient extraction and optimal efficiency. At this ratio, the solvent volume is sufficient to completely immerse the Chinese herbal powder, forming a good solid-liquid interface. 75% ethanol has moderate polarity and solubility for the active ingredients such as alkaloids, glycosides, volatile oils and gingerols in the prescription. During the immersion period of 14-17 days, the dissolution rate of the target components can reach the plateau period, ensuring sufficient extraction, while avoiding the burden of subsequent concentration caused by excessive solvent. (2) Appropriate formulation concentration, which is conducive to quality control and transdermal absorption. The initial extract obtained according to this ratio has a moderate concentration. After dilution with an equal volume (1000mL) of diluent in step S5, the final ethanol concentration of the tincture is about 37.5% (v / v). This final concentration has a good transdermal permeation-promoting effect, reversibly changes the structure of the stratum corneum, promotes the transdermal absorption of drugs, and has low skin irritation, resulting in high patient comfort. (3) Good process repeatability, suitable for standardized production. The fixed ratio facilitates industrial scale-up, the process parameters are linearly predictable, the batch-to-batch consistency is good, and it is conducive to quality control and registration application. (4) Convenient clinical operation. The tincture prepared under this ratio has moderate fluidity, neither too thin (easy to flow and evaporate too quickly) nor too thick (difficult to apply), which makes it easy to apply and massage acupoints after dipping cotton swabs or gauze, thus improving the convenience of clinical use.

[0046] When the volume of ethanol is greater than 1000 mL (i.e., the weight-to-volume ratio of the traditional Chinese medicine composition to the solvent is less than 5:10, such as 1:3 or higher), the increased solvent volume leads to excessive dilution of the active ingredients, a decrease in the initial extract concentration, and a decrease in the content of active ingredients per unit volume in the final tincture, which may result in insufficient efficacy of transdermal administration. In order to achieve the target final concentration, it is necessary to concentrate or reduce the amount of dilution water, which increases the process steps and energy consumption. At the same time, the increase in solvent usage will increase production costs and reduce equipment utilization efficiency.

[0047] When the volume of ethanol is less than 1000 mL (i.e., the weight-to-volume ratio of the herbal composition to the solvent is greater than 5:10, such as 1:1.5 or lower), the solvent volume is insufficient to completely submerge the herbal powder, resulting in insufficient solid-liquid contact and ineffective extraction of some medicinal materials, leading to waste of raw materials and a decrease in extraction rate. During the soaking process, the solvent is easily absorbed by the powder, causing it to dry out and affecting the continuous dissolution of active ingredients. The initial extract is too viscous, making filtration difficult and easily clogging the filter material, thus prolonging the production cycle. Some components in the high-concentration extract may be supersaturated and precipitate, affecting the clarity and stability of the tincture. After final dilution, the final ethanol concentration may be less than 35%, significantly weakening the transdermal penetration-enhancing effect and reducing the transdermal absorption rate of the drug.

[0048] In summary, the preferred weight-to-volume ratio of the traditional Chinese medicine composition to the solvent in this invention is 5:10 (i.e., 500g of traditional Chinese medicine components added to 1000mL of 75% ethanol). This ratio represents the optimal balance between extraction efficiency, formulation stability, transdermal absorption performance, production cost, and clinical operability.

[0049] In some alternative embodiments, the solvent is an ethanol solution; the diluent is distilled water or water for injection. Preferably, the solvent is a 75% (v / v) ethanol solution.

[0050] In these embodiments, the present invention uses a 75% (v / v) ethanol solution as the impregnation solvent. 75% ethanol can effectively extract various alkaloids, glycosides, volatile oils, and other active ingredients from the prescription, and also has a suitable transdermal penetration-enhancing effect. The present invention uses a diluent to adjust the final ethanol concentration of the tincture to a suitable range for external use, while also contributing to the stability of some components in the tincture.

[0051] It should be noted that in step S4, the filtration operation can specifically be as follows: the impregnation liquid is coarsely filtered using multi-layer filter cloth, plate and frame filter press or vacuum filtration device to separate the drug residue from the drug liquid. In order to further obtain a clear tincture, the coarse filtrate is then finely filtered through filter paper or microporous membrane (0.45μm or 0.22μm) with smaller pore size to remove fine particles and insoluble impurities in the solution, and a clear and transparent initial extract with uniform color is obtained.

[0052] In some optional embodiments, step S6 is also included, in which the tincture solution obtained in step S5 is dispensed under clean conditions. Specifically, an automatic filling machine is used to fill the tincture into cleaned, dried and sterilized brown glass bottles, with each bottle containing 30 ml. The bottle opening must be tightly sealed, usually using an aluminum cap or plastic screw cap with an inner PTFE membrane for sealing, thus obtaining a 30 ml / bottle of traditional Chinese medicine tincture for improving CRF.

[0053] It is understandable that using brown bottles can protect against light and prevent the degradation of certain photosensitive components.

[0054] The present invention also provides a method for using the above-mentioned tincture, wherein the tincture is applied as a wet compress or applied to acupoints and meridian pathways that have the functions of invigorating qi and warming yang, warming and tonifying the spleen and kidneys, and strengthening the body's resistance.

[0055] Specifically, the external application sites of the tincture of this invention mainly select acupoints and meridian pathways that have the functions of invigorating qi and warming yang, warming and tonifying the spleen and kidneys, and strengthening the body's resistance: On the abdomen, select the Huangshu acupoint of the Foot Shaoyin Kidney Meridian (0.5 cun lateral to the umbilicus), the Tianshu acupoint of the Foot Taiyin Spleen Meridian (2 cun lateral to the anterior midline, level with the umbilicus), the Daheng acupoint of the Foot Yangming Stomach Meridian (4 cun lateral to the umbilicus), and the Shenque acupoint (center of the umbilicus), Qihai acupoint (1.5 cun below the umbilicus), and Guanyuan acupoint (3 cun below the umbilicus) on the Ren Meridian; On the back, select the Shenshu acupoint of the Foot Taiyang Bladder Meridian (1.5 cun lateral to the spinous process of the 2nd lumbar vertebra), Qihaiyu acupoint (1.5 cun lateral to the spinous process of the 3rd lumbar vertebra), Guanyuanyu acupoint (1.5 cun lateral to the spinous process of the 5th lumbar vertebra), and the Mingmen acupoint on the Du Meridian (between the spinous processes of the 2nd and 3rd lumbar vertebrae), with the latter serving as the main acupoint for the lower back. When applying the tincture, the operator can use their fingertips (usually the thumb or index finger) to gently massage the acupoints. The massage techniques can be either point pressing (pressing vertically downwards on the acupoint, holding for a few seconds and then releasing) or kneading (making small circular kneading motions around the acupoint). Each acupoint should be massaged for about 1-2 minutes. The purpose is to enhance local blood circulation through physical stimulation, while promoting better transdermal absorption of the medicinal components and ethanol in the tincture. After the massage, let the tincture remain on the skin naturally without wiping it off immediately.

[0056] The tincture of this invention is applied directly to specific areas of the patient's body (such as acupoints or meridian pathways), allowing the active pharmaceutical ingredients to be absorbed through the skin and enter the systemic circulation. This transdermal delivery method avoids the gastrointestinal degradation and first-pass effect of oral administration, improving bioavailability and providing a sustained and stable drug effect, making it ideal for cancer-related fatigue symptoms requiring long-term management. The method is simple to operate and can be performed by the patient themselves or with the assistance of family members, greatly improving treatment accessibility and patient compliance.

[0057] The present invention also provides a treatment method for CRF, which uses the above-described tincture in combination with Lei Huo Moxibustion.

[0058] Optionally, the tincture of the present invention can be used in combination with moxibustion therapy. The above-mentioned method of combining the tincture with moxibustion for the treatment of CRF innovatively practices the sequential treatment mode of "tincture first, moxibustion later, synergistic effect of moxibustion and medicine, and transdermal absorption". The tincture of the present invention combined with moxibustion therapy has a clear synergistic effect, can effectively relieve fatigue symptoms in CRF patients, improve quality of life and functional status, and has good safety.

[0059] It should be understood that Lei Huo Jiu can choose conventional commercially available products and their existing treatment methods; no specific restrictions are imposed here.

[0060] The present application is further illustrated below with reference to specific embodiments. Experimental methods in the following embodiments that do not specify specific conditions are generally determined according to national / industry standards; if there is no corresponding national / industry standard, they are performed according to general international standards, conventional conditions, or conditions recommended by the manufacturer.

[0061] The Chinese medicinal materials used in this invention—processed aconite, dried ginger, ephedra, cinnamon twig, platycodon root, red peony root, cinnamon bark, asarum, luffa fruit, angelica root, raw astragalus root, safflower, sandalwood, clove, and borneol—are all purchased from Foshan Zhongtian Chinese Herbal Pieces Co., Ltd., ensuring the stability of the source and traceability of the quality of the medicinal materials. The variety, specifications, processing methods, and quality grades of all medicinal materials must comply with the regulations for each single herb in Part I of the Pharmacopoeia of the People's Republic of China (2020 Edition). Before feeding the raw materials, each batch of medicinal materials must be identified by its properties, microscopic examination, thin-layer chromatography, etc., and limit checks must be conducted on any possible heavy metals, pesticide residues, and aflatoxin and other harmful substances to ensure the safety and qualification of the raw materials.

[0062] The ethanol used in this invention was purchased from Shandong Lierkang Medical Technology Co., Ltd., product specification: 500ml, product batch number / implementation standard: Q / 1400ALX010. The ethanol used complies with the provisions under the "Ethanol" item in the Pharmacopoeia of the People's Republic of China (2020 edition), and the methanol limit must be strictly controlled within the standard.

[0063] Example 1

[0064] A method for preparing a traditional Chinese medicine tincture for improving cancer-related fatigue includes the following preparation steps: S1. Weigh the raw materials according to the following weight parts: 30 parts prepared aconite root, 30 parts dried ginger, 30 parts ephedra, 30 parts cinnamon twig, 10 parts platycodon root, 30 parts red peony root, 15 parts cinnamon bark, 10 parts asarum, 30 parts luffa fruit, 30 parts angelica root, 60 parts raw astragalus root, 45 parts safflower, 5 parts sandalwood, 5 parts clove, and 3 parts borneol. S2. The raw materials obtained from step S1 are weighed, sieved, and mixed evenly to obtain a pulverized Chinese medicine composition. The pulverization is carried out using pulverization equipment that meets GMP requirements, such as a universal pulverizer or an ultrafine pulverizer. The pulverization equipment is used to pulverize the medicinal materials into fine powder. The degree of pulverization requires that all the powder can pass through an 80-mesh sieve and be mixed evenly to increase the contact area between the medicinal materials and the solvent, which is conducive to the leaching of the active ingredients. It should be noted that the pulverization process should be carried out in a clean environment to prevent contamination by foreign matter. S3. Take 500g of the pulverized Chinese herbal medicine composition from step S2 and transfer it to a clean, dry, and well-sealed glass or stainless steel immersion container. Then add 1000mL of 75% ethanol solution to ensure that the powder is completely submerged. After sealing the container, place it in a light-proof, dry environment at a temperature of 20-25℃ for immersion for 15 days. During the immersion process, stir the pulverized Chinese herbal medicine composition and solvent in the container 1-2 times a day for 10-15 minutes each time. S4. Filter the impregnation solution to obtain the initial extract; specifically, the impregnation solution can be coarsely filtered using multi-layer filter cloth, plate and frame filter press or vacuum filtration device to separate the drug residue from the drug solution. In order to further obtain a clear tincture, the coarse filtrate is then finely filtered through filter paper or microporous membrane (0.45μm or 0.22μm) with smaller pore size to remove fine particles and insoluble impurities in the solution, and obtain an initial extract with uniform color and clear transparency. S5. Transfer all the initial extract obtained in step S4 to another clean preparation container, add 1000 ml of distilled water or water for injection to dilute, stir, and mix the initial extract with water thoroughly to obtain the tincture. S6. The tincture solution obtained in step S5 is dispensed under clean conditions. Specifically, the tincture is filled into clean, dried and sterilized brown glass bottles using an automatic filling machine. Each bottle is filled with 30 ml of tincture. The bottle opening must be tightly sealed. Usually, an aluminum cap or plastic screw cap with a polytetrafluoroethylene film inside is used for sealing. This gives the product specification of 30 ml / bottle of traditional Chinese medicine tincture for improving CRF.

[0065] Example 2

[0066] A method for preparing a traditional Chinese medicine tincture for improving cancer-related fatigue includes the following preparation steps: S1. Weigh the raw materials according to the following weight parts: 15 parts prepared aconite root, 20 parts dried ginger, 20 parts ephedra, 15 parts cinnamon twig, 5 parts platycodon root, 15 parts red peony root, 5 parts cinnamon bark, 3 parts asarum, 15 parts luffa fruit, 15 parts angelica root, 30 parts raw astragalus root, 15 parts safflower, 3 parts sandalwood, 3 parts clove, and 1 part borneol. S2. The raw materials obtained in step S1 are weighed, sieved, and mixed evenly to obtain a pulverized traditional Chinese medicine composition. The pulverization is performed using GMP-compliant equipment, such as a universal pulverizer or an ultrafine pulverizer. The pulverizer is used to pulverize the medicinal materials into fine powder, ensuring that all powder can pass through an 80-mesh sieve. The powder is then mixed evenly to increase the contact area between the medicinal materials and the solvent, facilitating the extraction of active ingredients. It should be noted that the pulverization process should be carried out in a clean environment to prevent contamination by foreign matter. S3. Take 500g of the pulverized Chinese herbal medicine composition from step S2 and transfer it to a clean, dry, and well-sealed glass or stainless steel immersion container. Then add 1000mL of 75% ethanol solution to ensure that the powder is completely submerged. After sealing the container, place it in a light-proof, dry environment at a temperature of 20-25℃ for immersion for 15 days. During the immersion process, stir the pulverized Chinese herbal medicine composition and solvent in the container 1-2 times a day for 10-15 minutes each time. S4. Filter the impregnation solution to obtain the initial extract; specifically, the impregnation solution can be coarsely filtered using multi-layer filter cloth, plate and frame filter press or vacuum filtration device to separate the drug residue from the drug solution. In order to further obtain a clear tincture, the coarse filtrate is then finely filtered through filter paper or microporous membrane (0.45μm or 0.22μm) with smaller pore size to remove fine particles and insoluble impurities in the solution, and obtain an initial extract with uniform color and clear transparency. S5. Transfer all the initial extract obtained in step S4 to another clean preparation container, add 1000 ml of distilled water or water for injection to dilute, stir, and mix the initial extract with water thoroughly to obtain the tincture. S6. The tincture solution obtained in step S5 is dispensed under clean conditions. Specifically, an automatic filling machine is used to fill the tincture into clean, dried and sterilized brown glass bottles, with each bottle containing 30 ml. The bottle opening must be tightly sealed, usually with an aluminum cap or plastic screw cap with a polytetrafluoroethylene film liner, thus obtaining a 30 ml / bottle Chinese herbal tincture for improving CRF.

[0067] Experimental Example 1: Characterization Analysis of Tinctures

[0068] The tincture prepared in Example 1 was analyzed, and the experimental steps are as follows: 1.1 Sample Preparation: Randomly select several bottles from the same batch of finished products prepared according to Example 1 of the implementation scheme; after mixing the tincture sample evenly, accurately measure an appropriate amount (e.g., 1.0 mL) and place it in the sample bottle; if the direct injection concentration of the sample is too high or contains insoluble particles, appropriate pretreatment may be required, such as diluting it with methanol or the initial mobile phase by a certain factor, and filtering it through a 0.22 μm microporous membrane. Take the filtrate as the test solution and place it in the sample tray of the autosampler for testing.

[0069] 1.2 Analytical Instruments and Conditions: An ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS / MS) system was used for analysis. The liquid chromatography section employed an UHPLC system equipped with a binary high-pressure gradient pump, autosampler, column oven, and photodiode array detector. The mass spectrometry section used a high-resolution tandem mass spectrometer, such as a quadrupole-time-of-flight mass spectrometer. Specific instrument analytical parameters required system optimization. a) Chromatographic conditions: A reversed-phase C18 column (100 mm length, 2.1 mm inner diameter, 1.7 μm packing particle size) was used. Mobile phase A was 0.1% formic acid aqueous solution, and mobile phase B was acetonitrile (or 0.1% formic acid in acetonitrile solution). A gradient elution program was used, for example: 0-2 min, 5% B; 2-20 min, 5% B linearly changing to 95% B; 20-22 min, maintaining 95% B; 22-22.1 min, 95% B changing to 5% B; 22.1-25 min, equilibrating at 5% B. The flow rate was set to 0.3 mL / min, the column oven temperature was set to 40℃, and the injection volume was typically 2-5 μL.

[0070] b) Mass spectrometry conditions: The ion source is an electrospray ionization (ESI) source. Data acquisition should be performed in both positive ion mode (ESI+) and negative ion mode (ESI-) to comprehensively detect compounds of different polarities. Ion source parameters need to be optimized, for example: capillary voltage (approximately 3.0 kV in positive mode and approximately 2.5 kV in negative mode), ion source temperature 150 °C, desolvation gas temperature 500 °C, desolvation gas flow rate 800 L / h, and cone gas flow rate 50 L / h. The mass spectrometry scan range is typically set to m / z 50-1500. A data-dependent acquisition mode is used, automatically selecting the highest intensity precursor ion for secondary fragmentation (MS / MS) based on a full scan to obtain fragment ion information of the compound.

[0071] 1.3 Data Acquisition and Total Ion Chromatogram Generation: The test solution prepared in step 1.1 was injected into the UHPLC-MS / MS system, and the analysis was performed under the optimized conditions described above. The instrument software acquired and recorded the mass spectrometric signals generated by the compounds eluting from the column at each time point in real time. After the analysis, the system software integrated the intensities of all mass spectrometric peaks acquired in positive and negative ion modes over time to generate two total ion chromatograms.

[0072] 1.4 Compound Identification and Database Matching: The acquired raw mass spectrometry data is imported into professional data processing software (such as UNIFI, Compound Discoverer, etc.). The software first extracts the precise mass number from the primary mass spectrum and calculates its error (Mass Error) compared to the theoretical mass number. This implementation plan sets strict identification standards: the identification level is Level 1 (matching with standards or secondary spectra with high confidence), and the mass error (Mass Error) must be less than 2 ppm (parts per million). The software will automatically compare the data with built-in or self-built databases of traditional Chinese medicine chemical components and public mass spectrometry databases (such as MassBank, HMDB, etc.). During the comparison, not only is the precise molecular weight compared, but more importantly, the secondary mass spectrometry fragment ion map obtained from the experiment is compared with the reference spectrum in the database to see if they match, and a matching score is given (usually 0-1 points, the closer to 1, the higher the matching degree).

[0073] 1.5 Generation of Representative Active Compound List: UHPLC-MS / MS was used to analyze the active ingredients in the tincture. Raw data from the instrument were preprocessed using XCMS software. Peak extraction, quantification, and alignment were performed first. Then, based on the set ppm and adduct ion information, the data was compared with a high-quality secondary chromatographic database for metabolite identification. Using XCMS data processing software, the detected chromatographic peaks in the sample were integrated, where the peak area of ​​each characteristic peak represents the relative quantitative value of a metabolite. The quantitative results were standardized using the total peak area to obtain the final quantitative results for the metabolites. Based on the screening criteria of Level=1 and MassError<2 ppm, the data processing software outputs a list of identified compounds. This implementation scheme selects the top 10 compounds with high matching scores and the highest relative content (usually estimated by chromatographic peak area or peak height) as the "representative active compounds top 10" for this tincture.

[0074] 1.6 Experimental Results: Figure 1 This is the total ion chromatogram in positive ion mode. Figure 2 This is the total ion current chromatogram in negative ion mode. Figure 1 and Figure 2 In the graph, the horizontal axis represents retention time (RT, in minutes), the vertical axis represents ion signal intensity, and the curve is the total ion chromatogram (TIC). Each chromatographic peak represents one or more compounds ionized in positive ion mode, visually reflecting the complexity of the chemical components in the tincture and their separation on the chromatographic column. Figure 1 and Figure 2As can be seen, the positive and negative ion modes are complementary and comprehensively cover chemical components of different polarities in the tincture. POS (positive ion mode) identified 3077 metabolites, while NEG (negative ion mode) identified 2208 metabolites.

[0075] The results of the detection of representative active compounds in the tincture are shown in Table 1 below: Table 1. Detection results of representative active compounds in tinctures

[0076] As shown in Table 1, the tincture of this invention includes L-proline (an amino acid related to energy metabolism and nerve regulation), osthol (a coumarin component with warming and invigorating effects on the kidneys and yang, and anti-inflammatory activity), 6-gingerol (the pungent component of ginger with warming and dispersing effects on the middle jiao and anti-inflammatory effects), etc. This table clarifies some of the main pharmacodynamic material bases of this Qi-tonifying and Yang-warming tincture in the form of data.

[0077] Experimental Example 2: Method of Using Tinctures

[0078] The specific method for applying the tincture of this invention to the external body is as follows: 2.1 Pre-treatment Assessment and Preparation: Before starting treatment, a comprehensive TCM (Traditional Chinese Medicine) assessment should be conducted on CRF patients. The assessment should focus on whether the patient exhibits symptoms of Yang deficiency and Spleen-Kidney insufficiency. Typical manifestations include: persistent and severe fatigue and weakness, aversion to cold and cold limbs, preference for warmth and pressure, soreness and weakness of the lower back and knees, poor appetite, frequent and clear urination, pale and swollen tongue with teeth marks, white and slippery tongue coating, and a deep, thready, or weak pulse. After confirming that the patient meets the indications for this tincture, patients with local skin damage, ulcers, infections, severe dermatitis, or allergies to any of the prescription's ingredients or ethanol should be excluded. The treatment purpose, method, potential sensations (such as local warming sensation), and precautions should be explained in detail to the patient and their family to obtain informed consent. Items to prepare: One bottle (30ml) of the tincture from Example 1, medical cotton swabs or sterile gauze pads, and a clean towel.

[0079] 2.2 Selection and Cleaning of Application Sites: The external application sites for this tincture mainly select acupoints and meridian pathways with warming and tonifying effects, strengthening and health-preserving properties. Commonly used acupoints include: Acupoint location is based on "Meridian and Acupoint Studies". On the abdomen, select the following acupoints: Huangshu (0.5 cun lateral to the umbilicus) of the Kidney Meridian of Foot-Shaoyin, Tianshu (2 cun lateral to the anterior midline, level with the umbilicus) of the Spleen Meridian of Foot-Taiyin, Daheng (4 cun lateral to the umbilicus) of the Stomach Meridian of Foot-Yangming, and Shenque (center of the umbilicus), Qihai (1.5 cun below the umbilicus), and Guanyuan (3 cun below the umbilicus) of the Bladder Meridian of Foot-Taiyang. On the back, select the following acupoints: Shenshu (1.5 cun lateral to the spinous process of the 2nd lumbar vertebra), Qihai (1.5 cun lateral to the spinous process of the 3rd lumbar vertebra), and Guanyuan (1.5 cun lateral to the spinous process of the 5th lumbar vertebra) of the Bladder Meridian of Foot-Taiyang, and Mingmen (between the spinous processes of the 2nd and 3rd lumbar vertebrae) of the Governing Vessel. The latter is the main acupoint for the lower back. The operator should use a clean towel dampened with warm water to gently wipe the skin at the site where the medication will be applied to remove sebum and dirt, and wait for the skin to dry completely (note that the medication should never be applied to damp skin).

[0080] 2.3 Application of Tincture: Open the tincture bottle cap and use a medical cotton swab to apply an appropriate amount of tincture, ensuring the liquid does not drip; or directly pour a small amount of tincture (approximately 2-3 ml) onto the center of a sterile gauze pad to moisten it. Apply the tincture-soaked cotton swab or gauze to the cleaned and dried acupoints or skin area using circular or even spreading motions. The application area should be slightly larger than the acupoint, approximately 3-5 cm in diameter. Apply gently and evenly, avoiding vigorous rubbing that could damage the skin.

[0081] 2.4 Massage to Promote Penetration and Retention: At the application site, the practitioner can use their fingertips (usually the thumb or index finger) to gently massage acupoints. Massage techniques can include point pressing (pressing vertically downwards on the acupoint, holding for a few seconds, then releasing) or kneading (making small circular kneading motions around the acupoint). Each acupoint should be massaged for approximately 1-2 minutes to enhance local blood circulation through physical stimulation, while simultaneously promoting better transdermal absorption of the medicinal components and ethanol in the tincture. After the massage, allow the medication to remain on the skin naturally; there is no need to wipe it off immediately. During treatment, patients usually experience a gradual, gentle warming sensation at the application site; this is a normal reaction as the medicine penetrates and warms the meridians.

[0082] 2.5 Treatment Frequency and Course: The total amount of medication used in each treatment should be controlled at 5-10 ml (i.e., the total amount applied to multiple acupoints or areas). Treatment should be performed 1-2 times daily, once in the morning and once in the evening. Treatment should be performed approximately one hour after meals, avoiding treatment immediately on an empty stomach or after a full stomach.

[0083] 2.6 Post-treatment observation and care: After treatment, instruct patients to keep the treated area warm and avoid immediate exposure to wind or cold water. Some patients with sensitive skin may experience mild, temporary redness, which usually subsides on its own and requires no special treatment.

[0084] Experimental Example 3: Clinical Trial Case

[0085] 3.1 Study Population: Based on the estimated sample size, the study participants (CRF patients) were planned to include 255 patients, including 127 males and 123 females. Their ages ranged from 25 to 80 years, with a mean age of 61.67 years. 124 patients were ≥ 65 years old, and 126 patients were < 65 years old. In terms of age distribution, the proportion of patients < 55 years old was 25.2%, while the proportion of patients < 75 years old reached 87.2%, indicating that the 55-75 age group is a high-risk group for cancer. The 255 cases were divided into a control group (Group Con: routine supportive treatment combining traditional Chinese and Western medicine), observation group A (leihuo moxibustion combined with routine supportive treatment), and observation group B (leihuo moxibustion combined with routine supportive treatment using external application of traditional Chinese medicine tincture (yiqi yang tincture)). At the last follow-up, a total of 5 cases dropped out: 1 case in the control group due to medical treatment in another location, and 2 cases each in observation groups A and B (1 case lost to follow-up in observation group A due to medical treatment in another location, and 2 cases lost to follow-up in observation group B). A total of 250 evaluable subjects were actually included (84 cases in the control group, and 83 cases each in observation groups A and B). Pathological diagnosis included 58 cases via superficial lymph node biopsy, 85 cases via percutaneous puncture biopsy, 97 cases via surgical biopsy, and 10 cases via cytological diagnosis. Regarding cancer types, lung cancer, colorectal cancer, and breast cancer ranked as the top three, accounting for a cumulative 75.2% of the total population. Regarding TNM staging, there were 12 cases of stage II, 72 cases of stage III, and 166 cases of stage IV, with 66.4% of patients being late-stage. In the study population, the highest percentage (20%) had a disease duration of 7–12 months, while the lowest percentage (1.2%) had a disease duration of more than 60 months. In terms of past medical history, 64%, 76.8%, and 62% of the population had undergone surgery, chemotherapy, and targeted therapy, respectively. According to Traditional Chinese Medicine (TCM) syndromes, 26.4% had spleen qi deficiency, 31.2% had kidney qi deficiency, and 42.4% had spleen and kidney deficiency.

[0086] Before enrollment, participants were assessed based on gender, age, diagnostic method, cancer type, TNM stage of tumor, disease course, history of previous specialist treatment, and TCM syndrome differentiation. Demographic statistics and baseline clinical characteristics of tumors were compared among the three groups; no statistically significant differences were found (P > 0.05), indicating comparability between the groups. Details of the three groups are shown in Table 2.

[0087] Table 2 Comparison of baseline clinical data among the three groups n (%) / M (IQR)

[0088] Note: Continuous variables that do not conform to a normal distribution are represented by M(IQR), and their frequencies are represented by n(%). P The value indicates a comparison between groups.

[0089] 3.2 Test Methods

[0090] 3.2.1 Control Group (Con)

[0091] The integrated traditional Chinese and Western medicine supportive care included standardized health education and lifestyle recommendations for CRF, as well as basic nutritional and psychological support as needed. Supportive treatment also included the application of traditional Chinese medicine decoctions and prepared Chinese medicines based on syndrome differentiation. It is important to clarify that in the supportive care involving combined medications, the use of traditional Chinese medicine decoctions and prepared Chinese medicines should be excluded, including ginseng-containing herbs, spleen- and kidney-tonifying herbs, and other traditional Chinese medicine preparations that have a known impact on CRF, such as injectable Chinese medicines like Shenqi Fuzheng and Kangai injections, and oral Chinese medicines like Zhenqi Fuzheng granules and Zhengyuan capsules. Furthermore, throughout the study period, participants did not receive the Lei Huo moxibustion and Yi Qi Qi Yang Ding interventions investigated in this study.

[0092] 2.2.2 Observation Groups (A, B)

[0093] Group A: Lei Huo Moxibustion combined with routine supportive therapy; Group B: Lei Huo Moxibustion combined with routine supportive therapy using the external application technique of traditional Chinese medicine tincture (Yi Qi Qi Yang Tincture prepared in Example 1).

[0094] The specific method for preparing the tincture using the combined Lei Huo Moxibustion method in Example 1 is as follows: (1) Lei Huo Jiu can be selected as follows: ① Registered and manufactured enterprise name: Chongqing Yuzhong District Zhao's Lei Huo Jiu Traditional Medicine Research Institute. ② Medical device production license number: Yu Food and Drug Administration Medical Device Production Permit No. 20150065; Registration certificate number / product technical requirements number: Yu Medical Device Registration No. 20172270086. ③ Lei Huo Jiu structure and composition: It consists of plant columns and moxibustion tools. The plant columns are made of Chinese medicinal materials such as mugwort leaves, cypress stems, frankincense, and notopterygium root; the moxibustion tools are made of wood or paper products; Specifications: 25g / piece × 3 pieces / box. ④ Treatment principle: The infrared radiation and heat energy released by the burning of the plant columns are directed to specific areas and acupoints of the human body to achieve the effect of disease prevention and treatment.

[0095] (2) Selection of meridians and acupoints: The location of acupoints is based on the "Meridian and Acupoint Study". On the abdomen, the following acupoints are selected: Huangshu (0.5 cun lateral to the umbilicus) of the Kidney Meridian of Foot-Shaoyin, Tianshu (2 cun lateral to the anterior midline, level with the umbilicus) of the Spleen Meridian of Foot-Taiyin, Daheng (4 cun lateral to the umbilicus) of the Stomach Meridian of Foot-Yangming, Shenque (center of the umbilicus), Qihai (1.5 cun below the umbilicus), and Guanyuan (3 cun below the umbilicus) of the Ren Meridian. On the back, the following acupoints are selected: Shenshu (1.5 cun lateral to the spinous process of the 2nd lumbar vertebra), Qihai (1.5 cun lateral to the spinous process of the 3rd lumbar vertebra), Guanyuan (1.5 cun lateral to the spinous process of the 5th lumbar vertebra) of the Bladder Meridian of Foot-Taiyang, and Mingmen (between the spinous processes of the 2nd and 3rd lumbar vertebrae) of the Du Meridian. The latter is the main acupoint for the lower back.

[0096] (3) Thunder-fire moxibustion operation time: Based on the idea of ​​the flow of Qi and blood in the meridians in Ling Shu and the correspondence between the internal organs and the twelve two-hour periods, the abdominal moxibustion is performed at 9-11 am (when the spleen and stomach meridians are in power) and the back moxibustion is performed at 3-5 pm (when the bladder and kidney meridians are in power), so as to coordinate the circulation rhythm of Qi and blood in the human body with the changes of Yin and Yang in the natural world day and night.

[0097] (4) Application of Traditional Chinese Medicine Tincture: The wet compress technique is selected from the application method. Its specific implementation involves the control of key parameters such as the application area, dosage, duration of each application, and course of treatment. Before the operation, maintain a comfortable position. After exposure, clean the local skin and keep it dry. After drying, disinfect with 75% alcohol. Take 3-5 layers of sterile gauze according to the area of ​​the acupoint distribution. When applying, soak the gauze with about 5ml of the required tincture solution. The area is concentric with the target acupoint, and the range is 10 cm in diameter. On the abdomen, apply the tincture with Shenque acupoint as the center, covering the bilateral Huangshu acupoints, Tianshu acupoint, Daheng acupoint, Qihai acupoint, and Guanyuan acupoint. On the waist and back, apply the tincture with Shenshu acupoint, Qihai acupoint, and Guanyuan acupoint as the center. Apply once a day for 7 consecutive days as one treatment cycle. After a 14-day interval, every 21 days is one course of treatment, for a total of 2 courses of treatment.

[0098] (5) Thunder-fire moxibustion operation method: ① The patient should lie supine or prone to expose the local skin of the corresponding acupoint. ② Open the middle of the moxibustion box and insert the spare pin into the small hole of the moxibustion box to fix the plant column; ③ Light one end of the plant column and aim the flame at the area to be moxibusted, keeping it 2-3cm away from the skin (when operating, pay attention to dusting off the ash and keep the moxibustion flame red and strong) until the local skin is flushed and the deep tissue feels warm but not burning (pay attention to controlling the intensity of moxibustion to prevent burns); ④ When the flame burns to a safe position, open the bottom cover with the pin, push out the moxa cone with your thumb, fix it with the pin, and continue the moxibustion operation. After use, remove the pin and close the box cover (if it cannot be completely sealed, it should not be used) so that it will be extinguished due to lack of oxygen for the next use; or cover the fire with a cup or other items made of non-flammable materials, or immerse it in water (it is necessary to check at any time whether the moxa stick is completely extinguished to prevent fire hazards). ⑤ Each treatment lasts 20 minutes, twice a day, for 7 consecutive days as one treatment cycle. A total of 21 days, with a 14-day interval, constitutes one course of treatment, for a total of 2 courses of treatment.

[0099] The changes in the Piper Fatigue Revision Scale (PFS-R), the Core Quality of Life Scale (EORTC-QLQ-C30), the Karnofsky Performance Status Scale (KPS), and the TCM syndrome scores before and after treatment were compared among the three groups.

[0100] 3.3 Experimental Results

[0101] 3.3.1 Piper Fatigue Scale Assessment

[0102] There were no statistically significant differences in the mean scores of the four fatigue dimensions (behavioral, emotional, physical, and cognitive) and the total score among the three groups before treatment. P > 0.05), indicating comparability between groups. After treatment, the total score and scores of each dimension of the Piper Fatigue Scale in all three groups decreased significantly compared with before treatment, and the differences within each group were statistically significant. P < 0.001). Intergroup comparisons showed significant overall differences among the three groups in total fatigue score and across all four dimensions (H = 42.78, 18.254, 28.179, 7.148, 50.196, ...). P All < 0.05). Further pairwise comparisons revealed that: ① Compared with the control group, the decreases in behavioral, emotional, physical dimensions, and total fatigue scores were more significant in groups A and B ( P < 0.05); In the cognitive dimension, only group B showed a better improvement than the control group (Z = -27.795, P = 0.039). ② Intergroup comparison showed that the improvement in total fatigue score was better in group B than in group A (Z = 27.476, P = 0.043), but the differences between the two in the four subdimensions have not yet reached statistical significance ( P > 0.05).

[0103] The evaluation and differences in Piper fatigue efficacy among the three treatment groups showed statistically significant differences (H = 37.595, 52.42, P < 0.001). Pairwise comparisons among the three groups revealed that groups A and B had significantly better fatigue improvement rates and differences than the control group (83.1% vs. 63.1% and 94.0% vs. 63%) (P < 0.01). Further comparison between groups A and B showed that group B had a significantly better Piper fatigue efficacy evaluation than group A (94.0% vs. 83.1%) (Z = 30.98, P < 0.05).

[0104] The results are shown in Tables 3 and 4.

[0105] Table 3. Piper Fatigue Scale (IQR) scores (M) before and after treatment in the three groups.

[0106] Note: All dimensions of fatigue are continuous variables and, after testing, do not conform to a normal distribution, denoted as M(IQR). The Kruskal-Wallis H test was used to analyze the differences in data between groups;‡ P The value indicates a within-group comparison (compared to baseline);† P The values ​​are derived from inter-group comparisons.

[0107]

[0108] Table 4. Evaluation of Piper Fatigue Scale efficacy after treatment in three groups (n (%) / M (IQR))

[0109] Note: For evaluation dimensions, the frequency of ordinal categorical variables is expressed as n (%), and the Piper difference for continuous variables that do not conform to a normal distribution is expressed as M (IQR). The Kruskal-Wallis H test was used to analyze differences between groups. P The value indicates a comparison between groups.

[0110] 3.3.2 Assessment using the core quality of life scale (EORTC-QLQ-C30)

[0111] Before treatment, there were no significant differences in baseline scores of the three groups of patients in each functional domain, overall health status, and symptom domain of the EORTC-QLQ-C30 scale (P > 0.05), indicating that the groups were comparable.

[0112] After treatment, all three groups showed significant decreases in scores across the physical, role, emotional, social, and overall health dimensions compared to pre-treatment levels (P < 0.001), indicating that the interventions in each group had a certain impact on patients' quality of life. Overall intergroup comparisons showed statistically significant differences in scores across the physical, emotional, social, and overall health dimensions (F / H = 23.886, 29.366, 21.705, 55.648, all P < 0.001). Further pairwise comparisons revealed: ① In physical, emotional, and overall health dimensions, both Group A and Group B showed significantly better improvement than the control group, with Group B showing greater improvement than Group A (P < 0.05); ② In the social function dimension, only Group B showed a better improvement than the control group (Z = 52.031, P < 0.001); ③ In the role and cognitive function dimensions, no statistically significant differences were observed among the three groups after treatment (P > 0.05). After treatment, the scores for fatigue, shortness of breath, sleep, and constipation in all three groups decreased compared to the pre-treatment mean, and the differences within each group before and after treatment were statistically significant (P < 0.001). Furthermore, in groups A and B, the differences in nausea and vomiting, pain, loss of appetite, and diarrhea before and after treatment were also statistically significant (P < 0.001). The results are shown in Table 5.

[0113] Table 5. EORTC-QLQ-C30 scale scores (M(IQR)) before and after treatment in the three groups.

[0114] Note: Functional domain data is based on... Let M(IQR) represent a normally distributed continuous variable, and M(IQR) represent a non-normally distributed continuous variable; P The value indicates a within-group comparison (compared to baseline);† P The value indicates a comparison between groups.

[0115] After treatment, the mean scores of seven symptoms (fatigue, nausea and vomiting, pain, sleep, loss of appetite, constipation, and diarrhea) were compared among the three groups, and the differences between the groups were statistically significant (F / H = 48.064, 24.33, 54.938, 53.146, 86.859, 47.653, 65.744, P < 0.001). In pairwise comparisons of the three symptom domains after treatment, groups A and B showed significantly better reductions in scores for all seven symptoms (fatigue, nausea and vomiting, pain, sleep, loss of appetite, constipation, and diarrhea) than the control group (P < 0.05). Specifically, group B showed better results than group A in fatigue, sleep, and loss of appetite (P < 0.05). No statistically significant differences were observed among the three groups in the areas of shortness of breath and loss of appetite after treatment (P > 0.05). The results are shown in Table 6.

[0116] Table 6. Core Quality of Life Scale Scores (IQR) Before and After Treatment in the Three Groups

[0117] Note: Symptom domain data are based on... Let M(IQR) represent a normally distributed continuous variable, and M(IQR) represent a non-normally distributed continuous variable; P The value indicates a within-group comparison (compared to baseline);† P The value indicates a comparison between groups.

[0118] 3.3.3 KPS Scale Scoring

[0119] There was no statistically significant difference in KPS scores among the three groups before treatment (P > 0.05), but there was a statistically significant difference in KPS scores after treatment (H = 60.31, P < 0.001). Pairwise comparisons of KPS scores after treatment showed that groups A and B were significantly better than the control group (P < 0.05); and group B was significantly better than group A (Z = 35.627, P < 0.05).

[0120] The KPS efficacy evaluation and differences among the three groups after treatment showed statistically significant differences (H = 51.907, 63.521, P < 0.001). Pairwise comparisons among the three groups showed that groups A and B had significantly better KPS differences and efficacy rates than the control group (79.5% vs. 51.2% and 90.4% vs. 51.2%) (P < 0.001 for both). Further comparison between groups A and B showed that group B had better KPS differences and efficacy assessment than group A (90.4% vs. 79.5%) (Z = -3.899, 25.133, P < 0.05 for both).

[0121] The results are shown in Tables 7 and 8.

[0122] Table 7. KPS Scale Scores (IQR) before and after treatment in the three groups.

[0123] Note: KPS data uses the median (interquartile range) [M(IQR)] to represent a non-normally distributed continuous variable; P The value indicates a within-group comparison (compared to baseline);† P The value indicates a comparison between groups.

[0124] Table 8. KPS Scale Efficacy Assessment after Treatment in Three Groups (n(%) / M(IQR))

[0125] Note: For KPS evaluation dimensions, the frequency of ordinal categorical variables is expressed as n (%), and the continuous variables whose KPS differences do not conform to a normal distribution are expressed as M (IQR). The Kruskal-Wallis H test is used to analyze the differences between groups. P The value indicates a comparison between groups.

[0126] 3.3.4 Evaluation of Traditional Chinese Medicine Symptom Scores

[0127] There was no statistically significant difference in TCM syndrome scores among the three groups before treatment (P > 0.05). After treatment, the scores within each of the three groups decreased significantly (P < 0.001). There was a statistically significant difference in TCM syndrome scores among the three groups after treatment (H = 39.404, P < 0.001). In pairwise comparisons of TCM syndrome scores after treatment, both observation groups A and B were significantly better than the control group (P < 0.05); and observation group B was significantly better than observation group A (Z = 35.614, P = 0.004).

[0128] The differences in TCM syndrome efficacy evaluation and score differences among the three groups after treatment were statistically significant (H=59.632, 59.632, P<0.001). Pairwise comparisons among the three groups showed that the differences in TCM syndrome scores and effective rates in groups A and B were significantly better than those in the control group (90.4% vs. 64.3% and 94.0% vs. 64.3%) (P<0.001). Further comparison between groups A and B revealed that the total TCM syndrome effective rate in group B was significantly higher than that in group A (94.0% vs. 90.4%) (Z=27.627, P<0.05).

[0129] The results are shown in Tables 9 and 10.

[0130] Table 9. Traditional Chinese Medicine Syndrome Scale Scores (IQR) before and after treatment in the three groups.

[0131] Note: TCM syndrome score data are represented by M(IQR) to indicate a non-normally distributed continuous variable; P The value indicates a within-group comparison (compared to baseline);† P The value indicates a comparison between groups.

[0132] Table 10. Evaluation of TCM syndrome efficacy after treatment in three groups (n(%) / M(IQR))

[0133] Note: For TCM syndrome evaluation dimensions, the frequency of ordered categorical variables is represented as n (%), and the continuous variables whose integral differences do not conform to a normal distribution are represented as M (IQR). The Kruskal-Wallis H test was used to analyze the differences in data between groups. P The value indicates a comparison between groups.

[0134] 3.3.5 Safety Evaluation

[0135] During treatment and follow-up, data showed that the tincture of this invention resulted in 5 cases of skin-related adverse events (AEs) during the treatment of CRF (overall incidence rate 3.0%), including 2 cases (2.4%) in observation group A and 3 cases (3.6%) in observation group B, all of which were grade I skin redness and itching. Regarding circulatory system-related adverse reactions, the main manifestation was elevated blood pressure in 7 cases (overall incidence rate 4.2%), including 3 cases (3.6%) of grade I elevated blood pressure in observation group A and 1 case (1.2%) of grade II elevated blood pressure in observation group B. All the skin reactions and blood pressure abnormalities were mild and recovered well after symptomatic treatment, without affecting subsequent treatment. No subjects were dropped or excluded due to related AEs, and there was no statistically significant difference in AEs between the two groups (P values ​​were 0.237 and 0.145 > 0.05, respectively). No treatment-related palpitations, nausea, vomiting, cardiac or hepatic kidney dysfunction, or other treatment-related adverse events occurred in either group during the treatment process and the 4-week follow-up. No grade III or higher adverse events or serious adverse events occurred.

[0136] In summary, the combination of Yiqi Qiyang Tincture and Lei Huo Moxibustion demonstrated superior efficacy across multiple dimensions after treatment: significant relief of fatigue (overall Piper score effective rate 94.0%), marked improvement in quality of life (especially in physical, emotional, social functioning, and overall health), effective improvement in functional status (KPS effective rate 90.4%), and a significant decrease in the spleen and kidney deficiency syndrome score (clinical remission rate 24.1%). All of these indicators were significantly superior to the Lei Huo Moxibustion alone group and the conventional supportive treatment group. Furthermore, this combined regimen exhibited unique advantages in improving accompanying symptoms such as cognitive fatigue, loss of appetite, and sleep disorders, highlighting the holistic regulation, multi-target intervention, and comprehensive approach of traditional Chinese medicine. Only a few mild, transient local reactions occurred throughout the intervention period, with no cases of withdrawal due to adverse reactions, demonstrating good safety. This external treatment regimen has outstanding advantages such as being non-invasive, painless, without systemic toxicity, and highly acceptable to patients, providing a safe, well-compliant, and effective treatment option for CRF patients who are physically weak and intolerant to oral medications or other therapies. This demonstrates that the treatment effect of the tincture in group B was significantly better than that in group A and the control group. Therefore, the tincture combined with moxibustion of this invention can effectively relieve fatigue symptoms, improve quality of life and functional status in CRF patients, and has good safety profile.

[0137] In summary, the traditional Chinese medicine composition, tincture, and preparation method for improving CRF provided in this application combine traditional Chinese medicine acupoint stimulation with modern transdermal drug delivery technology. By administering the medication through the skin surface, it avoids many drawbacks of oral administration, allowing the active ingredients to directly act on meridians, acupoints, and systemic circulation. This exerts a holistic regulatory effect of invigorating Qi and warming Yang, and tonifying the spleen and kidneys, providing CRF patients with a convenient, effective, and easily sustainable home or community-based adjunctive therapy option. This application deeply integrates the core TCM treatment principle of "invigorating Qi and warming Yang" with the unique external treatment technique of "combining moxibustion and medication," innovatively practicing a sequential treatment model of "tincture first, then moxibustion, synergistic effect of moxibustion and medication, and transdermal absorption." Studies have confirmed that this model has a clear synergistic effect, representing a successful and exemplary exploration in modernizing, standardizing, and evidence-based TCM external treatment protocols. It provides a comprehensive TCM external treatment solution for the clinical management of spleen and kidney deficiency-type CRF with definite efficacy, a relatively clear mechanism of action, standardized operation, and high safety. This intervention program aligns with the core concept of the "biopsychosocial" model of modern medicine. It not only focuses on alleviating core symptoms but also emphasizes the reconstruction and recovery of patients' overall functions and the comprehensive improvement of their quality of life. It has good potential for clinical application and socioeconomic benefits.

[0138] The above description is merely a specific embodiment of this application, enabling those skilled in the art to understand or implement this application. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of this application. Therefore, this application is not to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features claimed in this application.

Claims

1. A traditional Chinese medicine composition for improving cancer-related fatigue, characterized in that, The traditional Chinese medicine composition comprises the following raw materials in parts by weight: 15-30 parts of processed aconite root, 20-30 parts of dried ginger, 20-30 parts of ephedra, 15-30 parts of cinnamon twig, 5-10 parts of platycodon root, 15-30 parts of red peony root, 5-15 parts of cinnamon bark, 3-10 parts of asarum, 15-30 parts of luffa fruit, 15-30 parts of angelica root, 30-60 parts of raw astragalus root, 15-45 parts of safflower, 3-5 parts of sandalwood, 3-5 parts of clove, and 1-3 parts of borneol.

2. The traditional Chinese medicine composition for improving cancer-related fatigue according to claim 1, characterized in that, The traditional Chinese medicine composition includes the following raw materials in parts by weight: 30 parts of prepared aconite root, 30 parts of dried ginger, 30 parts of ephedra, 30 parts of cinnamon twig, 10 parts of platycodon root, 30 parts of red peony root, 15 parts of cinnamon bark, 10 parts of asarum, 30 parts of luffa fruit, 30 parts of angelica root, 60 parts of raw astragalus root, 45 parts of safflower, 5 parts of sandalwood, 5 parts of clove, and 3 parts of borneol.

3. A traditional Chinese medicine tincture for improving cancer-related fatigue, characterized in that, The herbal tincture comprises the following ingredients: The traditional Chinese medicine composition, solvent, and diluent as described in claim 1 or 2.

4. The method for preparing a traditional Chinese medicine tincture for improving cancer-related fatigue as described in claim 3, characterized in that, The preparation steps include the following: S1. Weigh the raw materials according to their weight parts: prepared aconite, dried ginger, ephedra, cinnamon twig, platycodon root, red peony root, cinnamon bark, asarum, luffa fruit, angelica root, raw astragalus root, safflower, sandalwood, clove, and borneol. S2. The raw materials obtained from the crushing step S1 are weighed, sieved, and mixed evenly to obtain a crushed Chinese herbal medicine composition. S3. Place the pulverized Chinese herbal medicine composition from step S2 into a container, then add solvent, seal the container, and place it in a dark, dry environment for soaking. S4. Filter the impregnation solution to obtain the initial extract; S5. Add a diluent to the initial extract obtained in step S4 and stir to ensure that the initial extract and water are fully mixed to obtain a tincture.

5. The method for preparing a traditional Chinese medicine tincture for improving cancer-related fatigue according to claim 6, characterized in that, In step S2, the sieving is performed using an 80-mesh sieve.

6. The method for preparing a traditional Chinese medicine tincture for improving cancer-related fatigue according to claim 6, characterized in that, In step S3, the temperature of the immersion environment is 20-25℃; the immersion time is 14-17 days.

7. The method for preparing a traditional Chinese medicine tincture for improving cancer-related fatigue according to claim 6, characterized in that, In step S3, during the impregnation process, the pulverized Chinese medicine composition and solvent in the container are stirred 1-3 times a day.

8. A traditional Chinese medicine tincture for improving cancer-related fatigue according to claim 6, characterized in that, In step S3, the weight-volume ratio (g / mL) of the pulverized traditional Chinese medicine composition to the solvent is (4-5.5):(9-11).

9. A traditional Chinese medicine tincture for improving cancer-related fatigue according to claim 8, characterized in that, The solvent is an ethanol solution; the diluent is distilled water or water for injection.

10. The method of using the tincture prepared by any one of claims 4-9, characterized in that, The tincture is applied as a wet compress to acupoints and meridian pathways that have the functions of invigorating qi and warming yang, tonifying the spleen and kidneys, and strengthening the body's resistance.

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