A traditional Chinese medicine composition for osteoarthral pain, rheumatism, rheumatoid arthritis and sciatica, a preparation method, application and quality control method thereof

Abstract

This invention relates to a traditional Chinese medicine composition for treating bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica, as well as its preparation method, application, and quality control method. It belongs to the field of pharmaceutical technology and aims to solve the problems of adverse reactions such as diarrhea and nausea, and poor processability of the composition. The traditional Chinese medicine composition of this invention consists of senna leaves, colchicine, Terminalia chebula pulp, *Gnaphalium affine*, almond kernel, saffron, scarmona resin, and *Sophora sophora root* or licorice. Method: Senna leaves, Terminalia chebula pulp, and *Gnaphalium affine* are pulverized and mixed with pulverized saffron; colchicine is extracted with ethanol, water, and sodium sulfate, and concentrated into an extract; almond kernel, scarmona resin, *Sophora sophora root*, or licorice are extracted with ethanol and concentrated into an extract; then the extract is mixed with the above mixture, wet granulated, and dried. Quality control method: A test solution is prepared from the product; a reference solution is prepared from caffeic acid; thin-layer chromatography is used for detection. This invention controls the content of colchicine-like components while ensuring the efficacy of the product.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a traditional Chinese medicine composition for bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica, as well as its preparation method, application, and quality control method. Background Technology

[0002] Rheumatic diseases encompass over one hundred conditions recognized by modern medicine. It is reported that rheumatic diseases account for approximately 10% of the more than 110 medically intractable diseases worldwide. The World Health Organization (WHO) designated the first decade of the 21st century (2001-2010) as the Decade of Bone and Joint Health, demonstrating the global attention given to the research and treatment of rheumatic diseases. Rheumatic diseases are characterized by multi-system involvement, affecting vital organs such as the heart, brain, liver, and kidneys. They are characterized by long disease courses and high morbidity and disability rates. Internationally, the prognosis of these diseases is sometimes described as the "five Ds": death, disability, discomfort, dollcost, and drug toxicity. With the development of science and technology, the spectrum of clinical diseases has changed significantly. Many infectious diseases that threaten human health and life have been significantly reduced due to the advent of antibiotics and vaccination. For example, rheumatic fever and rheumatoid arthritis, which were common in the 1950s, have also been significantly reduced due to the widespread use of antibiotics. However, with the deepening understanding of diseases such as rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjögren's syndrome, ankylosing spondylitis, systemic vasculitis, gout, osteoarthritis, and osteoporosis, as well as the establishment of early diagnosis, the number of such patients has increased significantly.

[0003] Tongzhi Surunjiang Capsules are formulated with scammonia resin, almond kernel, colchicine, twig of Terminalia chebula, saffron, and senna leaf. It is a pure traditional Chinese medicine compound preparation. Saffron corrects the liver and stomach damage caused by colchicine, almond kernel corrects the gastrointestinal reactions of senna leaf, and twig of Terminalia chebula astringes the intestines and stops diarrhea. It also has anti-inflammatory, cardiotonic, diuretic, spleen-strengthening, and rheumatic pain-relieving effects. However, it still has significant adverse reactions during use, commonly including abdominal pain, diarrhea, nausea, and vomiting. Although the interactions between the principal, assistant, adjuvant, and guide herbs in the prescription can currently significantly reduce the nausea and vomiting caused by colchicine, market feedback indicates that the adverse reactions after using this product are still unsatisfactory.

[0004] We extracted 72 adverse drug reaction (ADR) reports related to Tongzhi Surunjiang Capsules from January 2009 to March 2018 from the National Adverse Drug Reaction Monitoring System (http: / / www.adrs.org.cn / ) as the background for this study. Of the 72 reports surveyed, 50 were new ADRs (69.44%), and 2 had a history of previous ADRs or a family history of ADRs (2.78%). All were administered orally.

[0005] The gender and age distribution of the patients: Among the 72 ADR cases, 25 were male (34.72%) and 47 were female (65.28%); the youngest was 16 years old and the oldest was 87 years old, with an average age of 54 years old. See Table 1 for details.

[0006] Table 1. General information of 72 patients with ADR (cases)

[0007]

[0008] Adverse drug reactions involving organs / systems and major clinical manifestations: 72 ADR reports involved 6 organs / systems, totaling 93 cases (some ADRs involved multiple organs / systems, resulting in multiple clinical manifestations). The corresponding number of cases and major clinical manifestations are detailed in Table 2.

[0009] Table 2. Organs / systems involved and clinical manifestations in 72 cases of ADR.

[0010]

[0011] Note: When patients have two or more types of lesions, each lesion and its clinical manifestation are calculated separately; therefore, the total number of cases is >72.

[0012] As shown in the table above, adverse drug reactions (ADRs) involving Tongzhi Surunjiang Capsules were distributed across all age groups, but the number of cases occurring in middle-aged and elderly individuals over 40 years old was relatively high (79.17%). This may be related to factors such as decreased liver and kidney function in middle-aged and elderly patients, relatively slower drug metabolism and excretion, and the presence of more underlying diseases and complex concurrent medication use. Furthermore, the prevalence of joint and bone pain, rheumatism, and rheumatoid arthritis is higher in the elderly, and the number of patients using this medication is greater than in other age groups, thus increasing the likelihood of ADRs. The clinical manifestations of ADRs were diverse, involving multiple organs / systems, with 52 cases (55.91%) involving gastrointestinal system damage.

[0013] Tongzhi Surunjiang Capsules contain the toxic Chinese medicinal herb colchicine, with colchicine as its active ingredient. While colchicine itself has relatively low toxicity, it metabolizes in the body into highly toxic colchicine derivatives, which strongly irritate the digestive tract, inhibit hematopoietic cells, and cause agranulocytosis and aplastic anemia. In severe cases, it can lead to severe hemorrhagic gastroenteritis or malabsorption syndrome. Therefore, overcoming the adverse drug reaction (ADR) problem caused by colchicine derivatives in the body, while simultaneously maximizing the efficacy of the compound, is currently a bottleneck challenge in the field of traditional Chinese medicine research. Summary of the Invention

[0014] The purpose of this invention is to address the adverse drug reactions (ADRs) of the composition. Research is conducted on the extraction process of colchicine to control the content of colchicine alkaloids, improve yield and purity, and reduce production costs. Research is also conducted on the absorption of toxic components of colchicine to enhance the gastric mucosa's protective effect. This increases the prostaglandin content in gastric tissue, stimulates mucus secretion, thickens mucus, and increases alkaline secretions, protecting the gastric mucosa from irritation. This significantly reduces the occurrence of adverse reactions such as nausea and vomiting caused by colchicine's decomposition product, colchicine derivative, irritating the gastric mucosa. Furthermore, research is conducted on the extraction process of almond kernels and scammonia lipids to improve extraction rate, shorten extraction time, and address the issue of high oil content in the raw herb powder, thereby resolving the problem of poor processability. Finally, a quality control method is provided, particularly for the quality control of *Coptis chinensis*.

[0015] The present invention provides a traditional Chinese medicine composition for treating bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica. The traditional Chinese medicine composition is composed of senna leaves, colchicine, chebula pulp, senna vine, almond kernel, saffron, scarmona resin, and sophora root.

[0016] Alternatively, the traditional Chinese medicine composition may consist of senna leaves, colchicine, chebula pulp, twig cress, almond kernel, saffron, scarmona resin, and licorice.

[0017] Furthermore, the traditional Chinese medicine composition comprises, by weight, 40-45 parts of senna leaves, 50-70 parts of colchicine, 15-20 parts of chebula pulp, 50-70 parts of cassia vine, 55-60 parts of almond kernel, 1-5 parts of saffron, 5-10 parts of scarmona resin and 40-60 parts of Sophora root;

[0018] Alternatively, the traditional Chinese medicine composition consists of 40-45 parts of senna leaves, 50-70 parts of colchicine, 15-20 parts of Terminalia chebula pulp, 50-70 parts of twig cress, 55-60 parts of almond kernel, 1-5 parts of saffron, 5-10 parts of scarmona resin, and 40-60 parts of licorice.

[0019] Furthermore, the traditional Chinese medicine composition comprises, by weight, 42-45 parts of senna leaves, 60-70 parts of colchicine, 18-20 parts of chebula pulp, 60-70 parts of twig cress, 57-60 parts of almond kernel, 3-5 parts of saffron, 7-10 parts of scarmona resin, and 40-60 parts of Sophora tonkinensis root;

[0020] Alternatively, the traditional Chinese medicine composition consists of 42-45 parts of senna leaves, 60-70 parts of colchicine, 18-20 parts of Terminalia chebula pulp, 60-70 parts of twig cress, 57-60 parts of almond kernel, 3-5 parts of saffron, 7-10 parts of scarmona resin, and 40-60 parts of licorice.

[0021] Furthermore, the traditional Chinese medicine composition consists of 42.5 parts of senna leaves, 60 parts of colchicine, 18 parts of chebula pulp, 60 parts of twig cress, 57.5 parts of almond kernel, 3 parts of saffron, 7 parts of scarmona resin and 50 parts of Sophora root by weight.

[0022] Alternatively, the traditional Chinese medicine composition comprises 42.5 parts senna leaves, 60 parts colchicine, 18 parts chebula pulp, 60 parts twig cress, 57.5 parts almond kernel, 3 parts saffron, 7 parts scarmona resin, and 50 parts licorice. A method for using a traditional Chinese medicine composition for bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica according to the present invention is carried out according to the following steps:

[0023] (1) Weigh out 40-45 parts of senna leaves, 50-70 parts of colchicine, 15-20 parts of Terminalia chebula pulp, 50-70 parts of twig vine, 55-60 parts of almond kernel, 1-5 parts of saffron, 5-10 parts of scarmona resin and 40-60 parts of Sophora tonkinensis root or 40-60 parts of licorice root according to the following weight proportions;

[0024] (2) After crushing senna leaves, Terminalia chebula pulp and saffron vine, it is recorded as fine powder A; after crushing saffron, it is recorded as fine powder B; fine powder A and fine powder B are sieved and then mixed.

[0025] (3) Add 1 to 5 times the weight of ethanol and 2 to 6 times the weight of water to the colchicine, soak it, add sodium sulfate, and perform aqueous two-phase extraction under ultrasonic action. The upper layer solution is concentrated under reduced pressure to form an extract.

[0026] (4) Add almond kernel, scammonyl ester, broad bean root or licorice to 4 to 8 times the total mass of the three in 60% ethanol by volume, extract under ultrasonic action, and concentrate the upper layer solution under reduced pressure to form an extract.

[0027] (5) The fine powder mixed in step (2) and the extract in steps (3) and (4) are granulated using wet granulation technology, dried, sieved, filled, and bubbled to complete the process.

[0028] Further, the ultrasonic frequency for extraction under ultrasonic action in step (3) is 120~180kHz; the ultrasonic frequency for extraction under ultrasonic action in step (4) is 110~140kHz.

[0029] The traditional Chinese medicine composition described in this invention can treat bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica while reducing adverse drug reactions.

[0030] The present invention provides a quality control method for a traditional Chinese medicine composition used for bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica, which is carried out in the following manner:

[0031] (1) Preparation of test solution: Take the Chinese medicine composition for bone and joint pain, rheumatism, rheumatoid arthritis and sciatica, add 70% methanol solution by volume, sonicate, filter, measure all the filtrate, recover the solvent to dryness, dissolve the residue with methanol solution to obtain the test solution.

[0032] (2) Preparation of reference solution: Weigh caffeic acid reference standard and add methanol to prepare a caffeic acid reference solution containing 0.150 mg per 1 mL;

[0033] (3) Thin-layer chromatography: Chloromethane:methanol:glacial acetic acid was used as the developing solvent and saturated for 30 min. 10 μL of the test solution and 5 μL of the reference solution were spotted onto the same silica gel G thin-layer plate. After developing to the leading edge, the plate was removed and dried. The plate was then examined under a 365 nm ultraviolet lamp.

[0034] Furthermore, the mass-to-volume ratio of the *He Guoteng* medicinal material to methanol with a volume percentage of 70% is 1 g: 5~7 mL.

[0035] Furthermore, the volume ratio of chloromethane:methanol:glacial acetic acid is 5:1:1.

[0036] The herbal composition of this invention is based on the formula of Tongzhi Surunjiang Capsules, and the designed ingredients are: scamonia resin, almond kernel, colchicine, *Heterocarpus anthelmintica*, chebula pulp, saffron, senna leaf, and *Sophora flavescens* root or licorice. Scamonia resin in the formula is derived from *Convolvulaceae* plant *Convolvulaceae*. Convovulus scammoniaL The milky exudate from the roots of the almond is dried and processed; it has the effects of generating heat and clearing abnormal mucus and bile, drying dampness and reducing swelling, dispelling cold and relieving pain, expelling parasites and nourishing the stomach. Almond kernels are from the plant *Almond*, belonging to the Rosaceae family. Amygdalus communisL. The dried, mature seeds of autumn crocus. The seeds are harvested in summer and autumn when the fruit is ripe, and then dried. Autumn crocus is a plant belonging to the lily family (Colchicum officinale). Colohicum autumnaleL. The dried bulbs. Harvested in summer and autumn, impurities removed, and dried. *Convolvulus arvensis* is a plant belonging to the Convolvulaceae family. Operculina turpethum(L.)S The dried rhizomes and vines of *Terminalia chebula*. Harvested after summer and autumn, and dried in the sun; it has diuretic, laxative, and muscle-relaxing properties. It is mainly used for edema, constipation, and muscle stiffness and inability to stretch due to chronic injury. *Terminalia chebula* is a plant of the Cynodontiaceae family. Terminalia chebula Retz. Or Terminalia chebula Terminalia chebula The dried, ripe fruit of *Retz. var. tomentella* Kurt. Harvested in autumn and winter when the fruit is ripe, impurities are removed, and it is sun-dried. It is used to astringe the intestines and stop diarrhea, astringe the lungs and stop coughing, reduce internal heat and soothe the throat. It is also used for chronic diarrhea and dysentery, hematochezia and rectal prolapse, lung deficiency with wheezing and coughing, persistent cough, sore throat and hoarseness. Senna leaves angustifolia Vahl Or, Cassia angustifolia is a leguminous plant. Cassia acuti-folia Delilah The dried small leaves of saffron. It clears heat, promotes bowel movement, and facilitates urination; used for heat accumulation, constipation, abdominal pain, and edema. Saffron is the flower of the iris family. Crocus sativusL. The dried stigmas; possessing the functions of promoting blood circulation and removing blood stasis, cooling blood and detoxifying, relieving depression and calming the mind. Used for amenorrhea, abdominal masses, postpartum blood stasis, febrile rashes, melancholy, epigastric fullness, palpitations, and mania. *Sophora japonica* root is a legume belonging to the Fabaceae family. Sophora tonkinensis Gagnep. The dried roots and rhizomes of licorice. Harvested in autumn, impurities are removed, washed, and dried. It has the effects of clearing heat and detoxifying, reducing swelling and relieving sore throat. Licorice is a legume. Glycyrrhiza uralensis Fisch. licorice root Glycyrrhiza inflata Bat. Or licorice root Glycyrrhiza glabra L. The dried roots and rhizomes of licorice. Harvested in spring and autumn, the fibrous roots are removed, and then dried in the sun. It tonifies the spleen and replenishes qi, and has pharmacological effects such as detoxification, expectoration, analgesia, and antispasmodic properties. In Traditional Chinese Medicine, licorice tonifies the spleen and replenishes qi, nourishes the lungs and relieves cough, alleviates spasms and detoxifies, and harmonizes various medicines.

[0037] The present invention has the following beneficial effects:

[0038] The present invention aims to study the original plant and harvesting period of Colchicum autumnale L.药材 to solve the problems of diarrhea and nausea adverse drug reactions (ADRs) of the composition, control the content of colchicine alkaloids, and achieve a colchicine content range of 0.0095 mg / capsule - 0.071 mg / capsule in the composition of the present invention. Compared with the prior art, the colchicine content range is 0.0095 mg / capsule - 0.095 mg / capsule, achieving a technical effect of reducing toxicity by 25%. On the basis of ensuring the efficacy of the product, the symptoms of nausea and vomiting adverse reactions are reduced. To effectively control the product quality and reduce the adverse reaction symptoms of diarrhea and abdominal pain, the original plant and harvesting period of Senna leaf are studied, the total content of sennoside A and sennoside B, the active ingredients of Senna leaf, is controlled, and a reasonable upper and lower limit range of 0.46 mg / capsule - 0.51 mg / capsule is formulated. On the premise of ensuring the efficacy of the product, the technical effect of reducing the adverse reaction rate is achieved. In addition, the dosage of Operculina turpethum (L.) S. Manso in the formula is 60 g, accounting for 24.1% of the formula amount. Its functions are promoting diuresis, relieving constipation, and relaxing muscles and tendons. It is the main Chinese medicinal material in the composition. Now, qualitative detection indexes of Operculina turpethum (L.) S. Manso are added to improve the means of controlling the efficacy of the composition. By analyzing and selecting caffeic acid as the index component and combining with the TLC method, a thin-layer chromatography qualitative identification method for Operculina turpethum (L.) S. Manso medicinal materials is established, better controlling the quality and clinical effect of the composition.

[0039] The purpose of the present invention is to provide a quality control method for a traditional Chinese medicine composition for osteoarthralgia, rheumatism, rheumatoid arthritis, and sciatica. The therapeutic window of colchicine is very narrow, and its therapeutic dose is very close to the toxic dose. Mild poisoning reactions may include diarrhea, nausea, vomiting, etc., and severe cases may occur with bone marrow suppression, aplastic anemia, peripheral neuropathy, etc. Existing studies have shown that there is no difference in the effectiveness of treating gout between low-dose and high-dose colchicine. Therefore, current domestic and foreign guidelines all propose using low-dose colchicine to treat gout, which can significantly reduce the occurrence of adverse drug reactions (ADRs). "Chinese Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout (2019)" recommends that when acute gout attacks, the initial dose of colchicine is 1 mg, an additional 0.5 mg is added 1 hour later, and it is changed to 0.5 mg qd or bid 12 hours later. It should be used as early as possible within 12 hours after the onset, and the efficacy is significantly reduced after more than 36 hours. Colchicine can cause pain and inflammation to subside in more than 90% of patients within 12 hours and disappear within 24 - 48 hours. To prevent gout attacks, it is recommended to首选 low-dose (0.5 - 1.0 mg / d) colchicine, which should be maintained for at least 3 - 6 months.

[0040] This invention, through research on the origin and harvesting period of colchicine medicinal material, controls the content of colchicine-like components, achieving a colchicine content range of 0.0095 mg / capsule to 0.071 mg / capsule in the composition of this invention. Compared with the existing technology, which has a colchicine content range of 0.0095 mg / capsule to 0.095 mg / capsule, this invention achieves a 25% reduction in the content of the toxic colchicine component while ensuring the efficacy of the product. Attached Figure Description

[0041] Figure 1 This is a diagram illustrating the pharmacological effects of the traditional Chinese medicine composition of the present invention. Detailed Implementation

[0042] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the spirit of the contents disclosed in the present invention will be described in detail below. After understanding the embodiments of the present invention, any person skilled in the art can make changes and modifications based on the technology taught in the present invention without departing from the spirit and scope of the present invention.

[0043] The illustrative embodiments and descriptions of the present invention are used to explain the present invention, but are not intended to limit the present invention.

[0044] Example 1: First, 42.5g of senna leaves, 18g of Terminalia chebula pulp, and 60g of Hedyotis diffusa vine were pulverized and labeled as fine powder A; 3g of saffron was pulverized and labeled as fine powder B. Fine powder A and fine powder B were sieved separately and then mixed to obtain the final product. The order of pulverizing fine powder A and fine powder B was not important. 60g of colchicine was soaked in 3 times its weight of ethanol and 4 times its weight of water, and then sodium sulfate was added. Aqueous two-phase extraction was performed for 45 minutes under ultrasonic treatment at a frequency of 130kHz. The supernatant was concentrated under reduced pressure to form an extract, which was then desalted, purified, and separated using a macroporous adsorption resin column to obtain colchicine. 57.5g of almond kernels, 7.5g of scarmona resin, and 40g of Sophora flavescens root were extracted in 6 times their weight of 60% ethanol under ultrasonic treatment at a frequency of 110kHz. The supernatant was concentrated under reduced pressure to form an extract. The above fine powder and extract are granulated using wet granulation technology, dried at 55℃, sieved through a 16-mesh sieve, filled, and bubble-capped to obtain the final product.

[0045] Example 2: First, 42.5g of senna leaves, 18g of Terminalia chebula pulp, and 60g of Hedyotis diffusa vine were pulverized and labeled as fine powder A; 3g of saffron was pulverized and labeled as fine powder B. Fine powder A and fine powder B were sieved separately and then mixed to obtain the final product. The order of pulverizing fine powder A and fine powder B was not important. 60g of colchicine was soaked in 4 times its weight of ethanol and 5 times its weight of water, and then sodium sulfate was added. The mixture was subjected to ultrasonic extraction at a frequency of 150kHz for 50 minutes. The supernatant was concentrated under reduced pressure to form an extract, which was then purified by desalting and separated by a macroporous adsorption resin column to obtain colchicine. 57.5g of almond kernel, 7.5g of scarmona resin, and 50g of Sophora flavescens root were extracted in 5 times their weight of 60% ethanol under ultrasonic extraction at a frequency of 130kHz. The supernatant was concentrated under reduced pressure to form an extract. The above fine powder and extract are granulated using wet granulation technology, dried at 60℃, sieved through a 20-mesh sieve, filled, and bubble-capped to obtain the final product.

[0046] Example 3: First, 42.5g of senna leaves, 18g of Terminalia chebula pulp, and 60g of Hedyotis diffusa vine were pulverized and labeled as fine powder A; 3g of saffron was pulverized and labeled as fine powder B. Fine powder A and fine powder B were sieved separately and then mixed to obtain the final product. The order of pulverizing fine powder A and fine powder B was not important. 60g of colchicine was added to 5 times its weight of ethanol and 6 times its weight of water, soaked, and then sodium sulfate was added. Aqueous two-phase extraction was performed for 55 minutes under ultrasonic treatment at a frequency of 180kHz. The supernatant was concentrated under reduced pressure to form an extract, which was then desalted, purified, and separated using a macroporous adsorption resin column to obtain colchicine. 57.5g of almond kernel, 7.5g of scarmona resin, and 60g of Sophora flavescens root were added to 6 times their weight of 60% ethanol and extracted under ultrasonic treatment at a frequency of 120kHz. The supernatant was concentrated under reduced pressure to form an extract. The above-mentioned fine powder and extract are granulated using wet granulation technology, dried at 65℃, sieved through a 24-mesh sieve, filled, and bubbled to obtain the final product.

[0047] Example 4: First, 42.5g of senna leaves, 18g of Terminalia chebula pulp, and 60g of cassia vine were pulverized and labeled as fine powder A; 3g of saffron was pulverized and labeled as fine powder B. Fine powder A and fine powder B were sieved separately and then mixed to obtain the final product. The pulverization order of fine powder A and fine powder B was not important. 60g of colchicine was soaked in 3 times its weight of ethanol and 4 times its weight of water, and then sodium sulfate was added. The mixture was subjected to ultrasonic extraction at a frequency of 130kHz for 45 minutes. The supernatant was concentrated under reduced pressure to form an extract, which was then purified by desalting and separated by a macroporous adsorption resin column to obtain colchicine. 57.5g of almond kernel, 7.5g of scarmona oil, and 40g of licorice were extracted in 6 times their weight of 60% ethanol under ultrasonic extraction at a frequency of 110kHz. The supernatant was concentrated under reduced pressure to form an extract. The above fine powder and extract were granulated using wet granulation technology, dried at 55℃, sieved through a 16-mesh sieve, and then blister-capped to obtain the final product.

[0048] Example 5: First, 42.5g of senna leaves, 18g of Terminalia chebula pulp, and 60g of tamarisk vine were pulverized and labeled as fine powder A; 3g of saffron was pulverized and labeled as fine powder B. Fine powder A and fine powder B were sieved separately and then mixed to obtain the final product. The order of pulverizing fine powder A and fine powder B was not important. 60g of colchicine was soaked in 4 times its weight of ethanol and 5 times its weight of water, and then sodium sulfate was added. Aqueous two-phase extraction was performed for 50 minutes under ultrasonic treatment at a frequency of 150kHz. The supernatant was concentrated under reduced pressure to form an extract, which was then desalted, purified, and separated using a macroporous adsorption resin column to obtain colchicine. 57.5g of almond kernel, 7.5g of scarmona oil, and 50g of licorice were extracted in 5 times their weight of 60% ethanol under ultrasonic treatment at a frequency of 130kHz. The supernatant was concentrated under reduced pressure to form an extract. The above fine powder and extract are granulated using wet granulation technology, dried at 60℃, sieved through a 20-mesh sieve, filled, and bubble-capped to obtain the final product.

[0049] Example 6: First, 42.5g of senna leaves, 18g of Terminalia chebula pulp, and 60g of tamarisk vine were pulverized and labeled as fine powder A; 3g of saffron was pulverized and labeled as fine powder B. Fine powder A and fine powder B were sieved separately and then mixed to obtain the final product. The order of pulverizing fine powder A and fine powder B was not important. 60g of colchicine was added to 5 times its weight of ethanol and 6 times its weight of water, soaked, and then sodium sulfate was added. Aqueous two-phase extraction was performed for 55 minutes under ultrasonic treatment at a frequency of 180kHz. The supernatant was concentrated under reduced pressure to form an extract, which was then desalted, purified, and separated using a macroporous adsorption resin column to obtain colchicine. 57.5g of almond kernel, 7.5g of scarmona oil, and 60g of licorice were added to 6 times their weight of 60% ethanol and extracted under ultrasonic treatment at a frequency of 120kHz. The supernatant was concentrated under reduced pressure to form an extract. The above-mentioned fine powder and extract are granulated using wet granulation technology, dried at 65℃, sieved through a 24-mesh sieve, filled, and bubbled to obtain the final product.

[0050] The following experiments were conducted using the products from the above embodiments:

[0051] Experiment 1

[0052] 1. Experimental Materials

[0053] 1.1 Experimental Drugs

[0054] Tongzhi Surunjiang Capsules, supplied by Heilongjiang Jiren Pharmaceutical Co., Ltd., are a commercially available product. Each capsule contains 0.3g. The clinical dosage is 5-7 capsules twice daily, with an intermediate dosage of 6 capsules per dose, totaling 12 capsules per person per day (3.6g capsules per person per day). Based on an adult weight of 60kg, this equates to 0.06g / kg. Examples 1-6 are experimental products supplied by Heilongjiang Jiren Pharmaceutical Co., Ltd. Colchicine Tablets, supplied by Guangdong Bidi Pharmaceutical Co., Ltd., are a commercially available product with a dosage of 0.5mg.

[0055] 1.2 Laboratory Animals

[0056] Young male rats were acclimatized for one week before the experiment and had free access to food and water.

[0057] 2. Experimental Methods

[0058] Forty-eight young mice were randomly divided into three groups: a colchicine tablet group, a control group, and groups according to Examples 1-6, with 15 mice in each group. After 24 hours of fasting and water restriction, and under the following conditions: room temperature 23±2℃ and relative humidity 65±5%, all rats in each group were administered the drug via gavage according to their body weight, ensuring a consistent dosage of the effective colchicine component, twice daily. The administration continued for one week.

[0059] Among them, the colchicine tablet group was administered colchicine tablets by gavage; the groups of Examples 1-6 were administered the drugs prepared in Examples 1-6 by gavage respectively; and the control group was administered Tongzhi Surunjiang capsules, which were commercially available from Heilongjiang Jiren Pharmaceutical Co., Ltd. and did not contain dung bean root or licorice.

[0060] Observe the nausea and vomiting of rats in each group and compare them with the blank group and control group to see if the incidence of adverse reactions has decreased. If there is a significant decrease, it proves that the prescription and process of this embodiment are feasible.

[0061] Table 3. Statistics of Adverse Reactions (ADRs)

[0062]

[0063] The results of a one-week experimental study, as shown in Table 3, indicate that the colchicine tablet group had a higher incidence of nausea and vomiting in rats. Compared with the control group, the number of adverse reactions to nausea and vomiting in the example groups was reduced, and the incidence of adverse reactions to nausea and vomiting was also lower. The incidence of adverse reactions to nausea and vomiting was comparable between Example 5 and Example 6; Example 5 showed better processability. The added medicinal ingredients in the prescription have a synergistic effect, increasing drug efficacy at a dosage of 50g, with an extremely low incidence of adverse reactions. The new extraction and formulation processes address the issue of high oil content in the raw herb powder. After long-term stability testing, the product quality remained qualified after 36 months. The production process is suitable for large-scale production.

[0064] Experiment 2

[0065] Based on the dosage of the traditional Chinese medicine composition of this invention being 1 mg / day, the following experimental scheme was designed:

[0066] Colchicine, a major active ingredient, was selected from different sources and harvested at different times to investigate its content and the incidence of adverse reactions.

[0067] The experimental data are as follows:

[0068] Table 4. Relationship between colchicine origin, harvest time, colchicine content, and incidence of adverse reactions (ADRs) in colchicine.

[0069]

[0070] Table 5 Results of colchicine content, origin, harvest time, and colchicine content of colchicine.

[0071]

[0072] Based on the above data, this invention considers the colchicine content in the composition of this invention to be between 0.0095 mg / pill and 0.071 mg / pill, originating from Fujian and harvested in March. Compared with existing colchicine content control methods, the scheme of this invention controls the incidence of adverse drug reactions (ADRs) while still allowing the medicinal materials to play their role in the formulation.

[0073] Experiment 3

[0074] Furthermore, through research on the origin and harvesting period of senna leaves, a traditional Chinese medicine composition, sennoside A (C), was formulated. 42 H 38 O 20 ) and sennoside B (C 42 H 38 O 20 The total content is within the upper and lower limits. Based on the prescribed dosage of 42.5g, 1000 capsules are made. According to the 2020 edition of the Chinese Pharmacopoeia, the sennoside content is calculated on a dried basis and contains sennoside A (C...). 42 H 38 O 20 ) and sennoside B (C 42 H 38 O 20 The total amount of sennoside A (C) in the composition of this invention shall not be less than 1.1%. 42 H 38 O 20 ) and sennoside B (C 42 H 38 O 20 The total dosage range is 0.46mg / capsule to 0.51mg / capsule, which reduces the incidence of adverse reactions while ensuring the efficacy of the product.

[0075] Sennoside A and sennoside B are representative components of senna leaves, a plant leaf with laxative properties. It has a sweet and bitter taste, is very cold in nature, and has the effect of purging heat and promoting bowel movement, primarily treating constipation due to heat accumulation and abdominal distension due to stagnation. Senna leaves are particularly suitable for patients with symptoms of heat accumulation in the stomach and intestines, food stagnation, abdominal distension, dry mouth and bad breath, flushed face and fever, scanty dark urine, and dry, difficult bowel movements. Many people believe that senna leaves are a natural medicine, safer and more reliable than chemical drugs, and therefore keep them at home for regular use. This medicine can indeed help people relieve constipation quickly, which is a good thing. However, senna leaves are very cold in nature. Those with weak spleen and stomach, those who prefer warmth and dislike cold, those with chronic illness and qi deficiency, the elderly and weak, as well as pregnant women and women during menstruation, should use senna leaves with caution or avoid them altogether, even if they experience constipation. Furthermore, its laxative effect and irritant properties are quite strong, and during the laxative process, it may cause diarrhea, abdominal pain, pelvic congestion, nausea, and vomiting. To address the above-mentioned adverse reactions, upper and lower limits for the total dosage of sennoside A and sennoside B have been established to control their dosage and reduce the incidence of adverse reactions.

[0076] Prepare 1000 tablets based on the prescribed dosage of 42.5g. According to the 2020 edition of the Chinese Pharmacopoeia, the sennoside content, calculated on a dried basis, contains sennoside A (C...). 42 H 38 O 20 ) and sennoside B (C 42 H 38 O 20 The total amount of senna should not be less than 1.1%. Senna leaves from different sources and at different harvesting times were selected to investigate the total content of their main active ingredients, sennoside A and sennoside B, and the incidence of adverse reactions.

[0077] The experimental data are as follows:

[0078] Table 6. Relationship between senna leaf origin, harvest time, sennoside content, and incidence of adverse reactions (ADRs).

[0079]

[0080] Table 7 Results of Senna Leaf Origin, Harvesting Time, and Sennoside Content

[0081]

[0082] Analyzing the above data, this invention believes that senna leaves from Yunnan Province and harvested in September meet the requirements of this invention. The total content of sennoside A and sennoside B in the composition of this invention ranges from 0.46 mg / capsule to 0.51 mg / capsule. Compared with existing methods for controlling the total content of sennoside A and sennoside B, the scheme of this invention controls the incidence of adverse drug reactions (ADRs) while still allowing the medicinal materials to play their role in the formulation.

[0083] Example 7

[0084] A quality control method for the traditional Chinese medicine composition described in this embodiment includes the following steps:

[0085] Identification of the fruit vine:

[0086] *Turpethum turpethum*, a perennial twining herb belonging to the genus *Turpethum* in the family Convolvulaceae, is briefly described in dictionaries such as *Zhonghua Bencao* and *Guoquan Zhongcaoyao Huibian* for its medicinal value, original plant, and geographical distribution. *Turpethum turpethum* is mainly distributed in Guangdong, Guangxi, Taiwan, and Yunnan provinces. In Zhuang folk medicine, it is believed to have diuretic and swelling-reducing effects, and to relax muscles and tendons, primarily used to treat edema and constipation; externally, it is used to treat meridian contractures in the later stages of fractures.

[0087] Currently, there is limited research both domestically and internationally on the chemical composition, pharmacodynamic material basis, and quality control of *Heterocarpus indicus*. Quality research on *Heterocarpus indicus* mainly focuses on its identification as a medicinal material. *Heterocarpus indicus* contains a large number of organic acid compounds, including salicylic acid and caffeic acid, all of which possess good pharmacological activities. Studies have found that caffeic acid has various pharmacological activities, including anti-inflammatory, antioxidant, antibacterial, and anticancer effects.

[0088] To effectively control the quality of *Heterocarpus santalinus*, this embodiment selects caffeic acid as an indicator component and establishes a thin-layer chromatography qualitative identification method for *Heterocarpus santalinus* medicinal materials using TLC, providing a basis for quality control of *Heterocarpus santalinus* medicinal materials. *Heterocarpus santalinus* from different producing areas and harvested at different times were selected to examine the repeatability of the identification method.

[0089] Table 8. Data on the source and collection time of the box fruit vines

[0090]

[0091] Preparation of the test solution: Take 5g of each of the Chinese herbal medicine composition powders made from different origins of *He Guoteng* vine, place them in a stoppered conical flask, add 30 mL of 70% methanol solution, sonicate for 30 min, filter, measure all the filtrate, recover the solvent to dryness, dissolve the residue in methanol solution to obtain the test solution.

[0092] Preparation of reference solution: Weigh an appropriate amount of caffeic acid reference standard and add methanol to prepare a caffeic acid reference solution containing 0.150 mg per 1 mL.

[0093] Thin-layer chromatography conditions: Silica gel G thin-layer plate, with chloromethane:methanol:glacial acetic acid (5:1:1) as the developing solvent, saturated for 30 min. TLC experiments were performed according to the thin-layer chromatography method in General Chapter 0502 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. 10 μL of the test solution and 5 μL of the caffeic acid control solution were spotted separately onto the same silica gel G thin-layer plate. After developing to the leading edge, the plate was removed, air-dried, and examined under a UV lamp (365 nm).

[0094] Conclusion: Through observation of thin-layer chromatograms, it was found that the traditional Chinese medicine compositions produced from *He Guo Teng* medicinal materials from various producing areas all had spots of the same color at the same locations as the caffeic acid spot of the reference standard, and the spots were relatively clear.

[0095] Method Filtering

[0096] (1) Screening of test sample solution preparation methods

[0097] This experiment employed single-factor experiments to investigate the preparation methods of the test solution, examining different solvents (50% methanol; 70% methanol; 90% methanol), different extraction methods (ultrasound, reflux), and different extraction times (30, 60, 90 min). By comparing the thin-layer chromatograms of samples extracted using different methods under the same developing solvent conditions, it was found that adding 30 mL of 70% methanol solution to a 5 g sample and sonicating for 30 min resulted in a distinct spot at the same location as the caffeic acid reference solution, with clearer spots and better separation. Therefore, this preparation method was selected as the method for preparing the test solution.

[0098] (2) Screening of developing solvent

[0099] This experiment compared different development systems with ratios such as (dichloromethane:methanol:formic acid; chloroform:methanol:formic acid; chloroform:methanol:glacial acetic acid; petroleum ether:acetone:formic acid). The results showed that the spots observed under UV light were clearer and the separation effect was better when using the chloromethane:methanol:glacial acetic acid (5:1:1) development system.

[0100] (3) Screening of stationary phase

[0101] Self-laid plates and commercially available plates were examined separately. Under the same conditions of sample, reference standard and developing agent, it was found that the spots of the self-laid plates were poorly separated, while the spots of the commercially available plates were better separated and the main spots were concentrated. After comparison, the commercially available plates were selected for plate testing.

[0102] The above screening method demonstrates its applicability to the identification of *He Guo Teng* in this product. Therefore, the identification method for *He Guo Teng* in this traditional Chinese medicine composition is determined as follows: Take 5g of powder from different origins of *He Guo Teng* medicinal materials, place them in a stoppered conical flask, add 30 mL of 70% methanol solution, sonicate for 30 min, filter, measure all the filtrate, recover the solvent to dryness, dissolve the residue in methanol solution, and use this as the test solution. Weigh an appropriate amount of caffeic acid reference standard, add methanol to prepare a solution containing 0.150 mg of caffeic acid per mL, and use this as the reference solution. Perform TLC according to the General Chapter 0502 of the 2020 edition of the Chinese Pharmacopoeia. Apply 10 μL of the test solution and 5 μL of the reference solution separately to the same silica gel G thin-layer plate, using chloromethane:methanol:glacial acetic acid (5:1:1) as the developing solvent, saturate for 30 min, develop to the leading edge, remove and air dry, and place under a UV lamp (365°C). Examine the sample at a depth of (nm). The chromatogram of the test sample shows spots of the same color at the corresponding positions as the chromatogram of the reference sample.

Claims

1. A capsule for treating bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica, characterized in that... The capsules described herein are composed of senna leaves, colchicine, chebula pulp, twig, almond kernel, saffron, scarmona resin, and sophora root; Alternatively, the capsule is composed of senna leaves, colchicine, chebula pulp, twig, almond kernel, saffron, scarmona resin, and licorice. Method for preparing the capsules for treating bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica: (1) Weigh out 40-45 parts of senna leaves, 50-70 parts of colchicine, 15-20 parts of Terminalia chebula pulp, 50-70 parts of twig vine, 55-60 parts of almond kernel, 1-5 parts of saffron, 5-10 parts of scarmona resin and 40-60 parts of Sophora tonkinensis root or 40-60 parts of licorice root according to the following weight proportions; (2) After crushing senna leaves, Terminalia chebula pulp and saffron vine, it is recorded as fine powder A; after crushing saffron, it is recorded as fine powder B; after sieving fine powder A and fine powder B respectively, they are mixed together; (3) Add 1 to 5 times the weight of ethanol and 2 to 6 times the weight of water to the colchicine, soak it, add sodium sulfate, and perform aqueous two-phase extraction under ultrasonic action. The upper layer solution is concentrated under reduced pressure to form an extract. (4) Add almond kernel, scammonyl ester, broad bean root or licorice to 4 to 8 times the total mass of the three in 60% ethanol by volume, extract under ultrasonic action, and concentrate the upper layer solution under reduced pressure to form an extract. (5) The fine powder mixed in step (2) and the extract in steps (3) and (4) are granulated using wet granulation technology, dried, sieved, filled, and bubbled to complete the process; The colchicine described is from Fujian Province, harvested in March, and contains colchicine in a range of 0.0095 mg / grain to 0.071 mg / grain. The senna leaves are from Yunnan Province and are harvested in September. The total content of sennoside A and sennoside B in the senna leaves ranges from 0.46 mg / capsule to 0.51 mg / capsule.

2. The capsule for treating bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica according to claim 1, characterized in that... The capsules are composed of 42-45 parts by weight of senna leaves, 60-70 parts of colchicine, 18-20 parts of Terminalia chebula pulp, 60-70 parts of twig clove, 57-60 parts of almond kernel, 3-5 parts of saffron, 7-10 parts of scarmona resin and 40-60 parts of Sophora tonkinensis root. Alternatively, the capsule is composed of 42-45 parts senna leaves, 60-70 parts colchicine, 18-20 parts chebula pulp, 60-70 parts twig cress, 57-60 parts almond kernel, 3-5 parts saffron, 7-10 parts scarmona resin, and 40-60 parts licorice.

3. A capsule for treating osteoarthritis, rheumatism, rheumatoid arthritis, and sciatica according to claim 1 or 2, characterized in that... The capsules are composed of 42.5 parts by weight of senna leaves, 60 parts of colchicine, 18 parts of Terminalia chebula pulp, 60 parts of twig cress, 57.5 parts of almond kernel, 3 parts of saffron, 7 parts of scarmona resin and 50 parts of Sophora tonkinensis root. Alternatively, the capsule is composed of 42.5 parts senna leaves, 60 parts colchicine, 18 parts chebula pulp, 60 parts twig cress, 57.5 parts almond kernel, 3 parts saffron, 7 parts scarmona resin, and 50 parts licorice.

4. The capsule for treating bone and joint pain, rheumatism, rheumatoid arthritis, and sciatica according to claim 1, characterized in that... The ultrasonic frequency for extraction under ultrasonic action in step (3) is 120~180kHz; the ultrasonic frequency for extraction under ultrasonic action in step (4) is 110~140kHz.

5. The application of the capsule for treating osteoarthritis, rheumatism, rheumatoid arthritis, and sciatica as described in claim 1 in the preparation of drugs for osteoarthritis, rheumatism, rheumatoid arthritis, and sciatica, characterized in that... The capsules described herein aim to reduce adverse drug reactions while treating osteoarthritis, rheumatism, rheumatoid arthritis, and sciatica.

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