A traditional Chinese medicine granule and an oral and injection solution prepared from its extract for treating primary Sjogren's syndrome

Abstract

The present invention relates to the technical field of traditional Chinese medicine, and particularly to a traditional Chinese medicine granule and an oral and injection preparation extracted therefrom for treating primary Sjögren's syndrome. The present invention creatively discovers new medical uses for the curcuma zedoaria granule and the volatile oil thereof, opening up a new application field. The curcuma zedoaria granule and the volatile oil have the effects of anti-inflammatory and improving salivary gland secretion, can be used for relieving and treating Sjögren's syndrome, and have strong pharmacological effects and safe use. The curcuma zedoaria granule and the volatile oil are rich in sources, inexpensive, safe and non-toxic, have a simple preparation process route and low production cost, can be made into drugs or foods, etc., and are convenient to use, and are a very promising and valuable drug for treating Sjögren's syndrome.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine granule and an oral and injection solution prepared from its extract for treating primary Sjögren's syndrome. Background Art

[0002] Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease mainly characterized by dry mouth and eyes, and can involve multiple organ systems. Its etiology is complex and not yet clear. So far, it is generally considered to be related to genetic factors, environmental factors, immune system abnormalities, pathogen infections and other factors (Mariette X, Criswell LA. Primary Sjögren's Syndrome. N Engl J Med. 2018;378(10):931-939.). pSS is a rheumatic immune disease with an incidence second only to rheumatoid arthritis. In China, it is about 0.33%-0.77%. The onset age is mostly 30-60 years old, and it is more common in women (Negrini S, Emmi G, Greco M, et al. Sjögren's syndrome: a systemic autoimmune disease. Clin Exp Med. 2022;22(1):9-25.). At present, the main goal of western medicine in treating Sjögren's syndrome is to relieve symptoms and control inflammation. Conventional treatment methods include using artificial tears to relieve dry eye symptoms, and topical application of glucocorticoids or immunosuppressants to reduce the inflammatory response. Although these treatment methods can help relieve the symptoms of Sjögren's syndrome, they cannot cure the disease fundamentally (Wang Mengjie, Xu Ziqi, Liu Ying. New progress in the treatment of primary Sjögren's syndrome with traditional Chinese and western medicine [J]. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2021, 30(04): 443-448.). In addition, some drugs may cause side effects such as infection, indigestion and immune system suppression. Therefore, the current western medicine treatment methods are mainly for symptom management, rather than radical treatment. In the face of the above limitations and challenges, it has become an urgent need to develop a safe, effective and long-acting drug for treating Sjögren's syndrome. Such a drug can relieve the discomfort symptoms of patients, improve mucosal moisture, and have a low recurrence rate and side effect risk. This will greatly improve the quality of life of patients and bring significant social benefits to the vast number of patients with Sjögren's syndrome.

[0003] In ancient Chinese literature, there was no record of the disease name related to pSS. Professor Lu Zhizheng, a master of traditional Chinese medicine, first created the disease name of "dry arthralgia" in his book "Collection of Medical Essays · Miscellaneous Talks on Arthralgia Diseases · Treatment of Dry Arthralgia" in the late 1980s (Lu Zhizheng. Collection of Medical Essays [M]. Beijing: People's Medical Publishing House, 2009: 121.), and classified pSS into it. Its common syndrome elements include yin deficiency syndrome, qi deficiency syndrome, blood stasis syndrome, etc. The traditional Chinese medicine treatment of pSS focuses on supplementing qi and nourishing yin, promoting the production of body fluids and moistening dryness. However, clinically, after using drugs for nourishing yin and promoting the production of body fluids, the dry symptoms such as dry mouth and dry eyes in some patients have not been relieved, but instead, gastrointestinal involvement manifestations such as "dryness above and diarrhea below" (that is, dry mouth and eyes accompanied by diarrhea) have occurred, and the curative effect is not exact. There have been records of diseases similar to pSS in ancient books. In the chapter "Epilepsy, Hematemesis, Epistaxis, Lower Blood, Chest Fullness, Blood Stasis Diseases" in "Synopsis of Prescriptions of the Golden Chamber", it is described that patients can be caused by "blood stasis" to "dryness", showing obvious blood stasis signs such as "chest fullness, blue lips", and at the same time having dry symptoms such as "dry mouth, but only wanting to rinse the mouth with water and not wanting to swallow". The Qing Dynasty doctor Tang Rongchuan believed that the pathogenesis of "blood stasis causing dryness" is that the internal retention of blood stasis and the blockage of qi movement lead to the difficulty of body fluid distribution. That is, both internal and external dry pathogens can damage body fluids, resulting in the abnormal distribution and metabolism of body fluids, causing blood stasis, blocked blood vessels, the formation of blood stasis, the accumulation of heat and dryness into toxins, the damage of body fluids, and the addition of exogenous toxic pathogens, ultimately resulting in the transformation of body fluids into dryness, toxins and blood stasis (Zhang Hong, Wang Xuyun, Wang Ying, etc. Discussion on the experience of treating Sjogren's syndrome from blood stasis based on the theory of "mini-abdominal mass" [J]. Western Journal of Traditional Chinese Medicine, 2020, 33(03): 84 - 86.). After the formation of the disease, with the progress of the disease course, the formation of blood stasis will gradually be aggravated. Therefore, in the pathogenesis of primary Sjogren's syndrome, in addition to yin deficiency and dryness-heat, toxins and blood stasis play a very important role in its occurrence, development and prognosis. Summary of the Invention

[0004] In view of the deficiencies of the prior art, the present invention provides an oral and injection prepared from a traditional Chinese medicine granule and its extract for the treatment of primary Sjogren's syndrome, which is of great significance for enhancing the treatment effect of pSS patients, facilitating regular medication for patients and improving the quality of life of patients.

[0005] In order to achieve the above-mentioned invention purposes, the present invention provides the following technical solutions.

[0006] The present invention provides the use of traditional Chinese medicine zedoary turmeric as the only raw material drug in the preparation of a drug for the treatment of primary Sjogren's syndrome.

[0007] The present invention also provides the use of an extract of traditional Chinese medicine zedoary turmeric as the only active ingredient in the preparation of a drug for the treatment of primary Sjogren's syndrome.

[0008] Furthermore, the extract of traditional Chinese medicine zedoary turmeric is zedoary oil.

[0009] The present invention also provides a pharmaceutical composition for treating primary Sjogren's syndrome, which is characterized in that the pharmaceutical composition contains the traditional Chinese medicine raw material curcuma zedoary described above or curcuma zedoary oil, an extract of curcuma zedoary described in any one of the above, as an active ingredient.

[0010] Further, the drug also includes pharmaceutically acceptable excipients.

[0011] Further, the application of the pharmaceutical composition in the preparation of a drug for treating primary Sjogren's syndrome.

[0012] Further, the preparation method of the granule of the pharmaceutical composition specifically includes the following steps:

[0013] Step 1: Prepare curcuma zedoary slices: Wash the fresh curcuma zedoary medicinal materials, steam them for 3 hours, dry them in an oven at 55°C for 36 hours, cut them into slices with a thickness of 3 - 5 mm, dry them in an oven at 45°C for 6 hours, and turn them over once per hour during the drying process;

[0014] Step 2: Decoct: Put 100 g of the curcuma zedoary slices obtained in Step 1 into a stainless - steel decocting pot, add 1000 mL of pure water, decoct for 30 minutes, then add 0.5 L of pure water and decoct for 20 minutes;

[0015] Step 3: Filter: Filter the mixture after two - time decoction in Step 2 respectively to remove the medicinal residues and obtain the decocted liquid; Combine the two - time decocted liquids to obtain the required concentrated liquid;

[0016] Step 4: Vacuum concentration: Put the concentrated liquid obtained in Step 3 into a vacuum concentration device, start the vacuum concentration device, evaporate the water under the conditions of 90 - 100°C and 0 - 0.1 Mpa to obtain a concentrated decoction in which every 1 mL is equivalent to 1 g of the raw medicinal materials;

[0017] Step 5: Mix: Cool the concentrated decoction obtained in Step 4 to 55°C, while stirring, add 20 g of starch, 40 g of dextrin, and 20 g of microcrystalline cellulose to the concentrated decoction, and after mixing evenly, add 10 g of erythritol and 10 g of mannitol and stir evenly;

[0018] Step 6: Prepare soft material: Moisten the mixture obtained in Step 5 with ethanol with a volume fraction of 70 - 80% to make a soft material;

[0019] Step 7: Granulate: Pass the soft material obtained in Step 6 through a pressure vessel, extrude and sieve to granulate and obtain the granules; Place the granules in an oven at 60 - 70°C and dry for 1 - 2 hours, controlling the environmental humidity below 50%; Then perform sizing treatment on the dried granules to obtain curcuma zedoary granules.

[0020] Further, the preparation method of the injection of the pharmaceutical composition specifically includes the following steps:

[0021] Step 1 Mixing: In an electric stirrer, add 5 L of water for injection, 500 g of glucose, then add 100 g of raw zedoary turmeric oil, 300 g of polyethylene glycol 15-hydroxystearate, 500 g of polysorbate, and 1000 g of propylene glycol; stir for 10 minutes while heating and maintaining the liquid temperature at 40 °C;

[0022] Step 2 Volume Fixing: After the temperature of the mixed solution obtained in Step 1 stabilizes, fix the total volume to 10 L by adding water for injection, and slowly add a 2.0 mol / L hydrochloric acid solution to adjust the pH to 5.0;

[0023] Step 3 Filtration: Filter the mixed solution obtained in Step 2 using an activated carbon filter to remove large particles and impurities therein;

[0024] Step 4 Sealing: Seal the filtered liquid obtained in Step 3 into 5 mL ampoules;

[0025] Step 5 Sterilization: Place the sealed ampoules obtained in Step 4 into a sterilizer and rotate and sterilize at 121 °C for 15 minutes; after completion of sterilization, the zedoary turmeric oil injection of zedoary turmeric oil is obtained and stored in a refrigerated environment at 2 - 8 °C.

[0026] Furthermore, the preparation method of the raw zedoary turmeric oil specifically includes the following steps:

[0027] Step 1 Pretreatment of zedoary turmeric roots: Take complete zedoary turmeric roots, wash them twice to ensure that the surface has no impurities, then drain the washed zedoary turmeric roots to remove excess water; suspend the drained zedoary turmeric roots to dry in the air for 48 hours to reduce the moisture content while keeping the root blocks intact;

[0028] Step 2 Preparation and preservation of zedoary turmeric slices: Cut the zedoary turmeric roots dried in Step 1 into zedoary turmeric slices with a thickness of about 5 mm, and the slicing should be carried out when the zedoary turmeric roots are still fresh;

[0029] Step 3 Drying and pulverization of zedoary turmeric: Dry the zedoary turmeric slices obtained in Step 2 in an oven at 45 °C for 6 h, and turn them over once per hour during the drying process. After drying, use a pulverizer to pulverize the zedoary turmeric slices and pass them through a 60-mesh sieve to collect zedoary turmeric granules;

[0030] Step 4 Extraction and fractionation of zedoary turmeric oil: Place the zedoary turmeric granules prepared in Step 3 into the distillation tank of the extraction device, introduce steam at 120 °C into the distillation tank, start the distillation process, and the duration is 5 - 8 hours; during the distillation process, maintain the temperature in the evaporation tank within the range of 75 - 85 °C through a temperature control program to stably volatilize zedoary turmeric oil; collect the volatile oil in the distillation tank and introduce it into the condenser to condense it into a liquid state. The condensed liquid zedoary turmeric oil enters the fractionation barrel through the condenser for fractionation to separate components with different boiling points; the finally obtained product is zedoary turmeric oil.

[0031] Curcuma zedoaria is the dried rhizome of Curcuma phaeocaulis Valeton, a plant of the Zingiberaceae family Curcuma phaeocaulis Val. , Curcuma kwangsiensis S. G. Lee et C. F. Liang Curcuma kwangsiensis S.G.Lee et C.F.Liang or Curcuma wenyujin Y. H. Chen et C. Ling Curcuma wenyujin Y.H.Chen et C.Ling , which is warm in nature and pungent in taste, and has the effects of promoting qi and activating blood circulation, removing blood stasis, reducing accumulation and relieving pain. Modern pharmacological research shows that Curcuma zedoaria mainly contains two major categories of components, namely volatile oils mainly composed of sesquiterpenoid compounds and curcuminoids mainly composed of diphenylheptane compounds. At the same time, it reveals that Curcuma zedoaria exerts anti-inflammatory, antithrombotic, improves blood circulation, regulates blood lipids, and anti-atherosclerotic effects through multiple targets and multiple mechanisms of action (Wei Wei, Wang Bingyao. Research progress on the pharmacological effects of Curcuma zedoaria and its main components [J]. Drug Evaluation Research, 2022, 45(10): 2154-2160.). It is commonly used to treat amenorrhea due to blood stasis, abdominal distension due to food accumulation, etc., and is a commonly used drug for promoting blood circulation and removing blood stasis in clinical practice. It should be noted that since blood stasis is the core pathogenesis of Sjogren's syndrome (dry arthralgia), which runs through the entire process of its onset and is closely related to its prognosis, blood-activating drugs represented by Curcuma zedoaria should be promoted throughout the treatment of Sjogren's syndrome. Therefore, based on the clinical practice of our team, the present invention develops an oral Curcuma zedoaria granule and an injection of an extract of active ingredients of Curcuma zedoaria that are convenient for clinical application, which is of great significance for enhancing the treatment effect of pSS patients, facilitating regular medication for patients and improving the quality of life of patients.

[0032] Compared with the prior art, the beneficial effects of the present invention are as follows.

[0033] Compared with the current clinical western medicine treatment of Sjogren's syndrome, which is biased towards symptom management and cannot fundamentally eliminate the cause, patients need to take medicine for a long time or even for life to combat dry symptoms. Traditional Chinese medicine commonly uses drugs for nourishing yin and promoting fluid production in the treatment of Sjogren's syndrome, often showing gastrointestinal involvement manifestations of "dryness above and diarrhea below" (that is, dry mouth and eyes accompanied by diarrhea at the same time), and the curative effect is not exact. Blood stasis is the core pathogenesis of Sjogren's syndrome (dry arthralgia), which runs through the entire process of its onset and is closely related to its prognosis, and blood-activating drugs represented by Curcuma zedoaria. Based on long-term clinical practice and experimental verification, our team has developed an oral Curcuma zedoaria granule and an injection of an extract of active ingredients of Curcuma zedoaria that are convenient for clinical application, which is of great significance for enhancing the treatment effect of pSS patients, facilitating regular medication for patients and improving the quality of life of patients.

[0034] Traditional Zedoary Turmeric Rhizome slices have defects such as inconvenient portability and administration, oral administration, and poor taste. Making them into granules can facilitate the use and storage for patients. Compared with traditional herbal decoction pills, granules have better portability and preservability. Granules are usually packaged in small bags or vials, which are easy to carry. Patients can simply dissolve the Zedoary Turmeric Rhizome oil granules in hot water above 80°C and take them conveniently at any time and place. Moreover, the formulated granules can reduce the bitter taste and are more palatable when taken, improving the convenience and compliance of patients' medication. Its extract, Zedoary Turmeric Rhizome oil, can be easily made into an injection dosage form. As a common administration route, injections have the advantage of directly entering the blood circulation system. Zedoary Turmeric Rhizome oil injection is prepared from high-purity Zedoary Turmeric Rhizome oil, which can ensure the purity and stability of the drug. At the same time, the injection dosage form can also achieve precise dose control, facilitating individualized treatment by doctors according to the specific conditions of patients. This convenient dosage form makes the use of Zedoary Turmeric Rhizome oil more flexible and controllable in clinical practice and can be used for regular injection administration of inpatients, greatly facilitating clinical application. In animal experiments for treating Sjogren's syndrome, both Zedoary Turmeric Rhizome granules and Zedoary Turmeric Rhizome oil injection have shown significant curative effects. Their safe and reliable characteristics make Zedoary Turmeric Rhizome oil injection an important drug option for treating Sjogren's syndrome, which can bring better treatment effects and higher quality of life to patients.

[0035] The present invention creatively explores new medical uses for Zedoary Turmeric Rhizome granules and volatile oil, opening up a new application field. The Zedoary Turmeric Rhizome granules and volatile oil have the effects of anti-inflammation and improving salivary gland secretion, can be used to relieve and treat Sjogren's syndrome, and have strong pharmacological effects and safe use.

[0036] Zedoary Turmeric Rhizome granules and volatile oil are rich in sources, inexpensive, safe and non-toxic, have a simple preparation process route and low production cost, can be made into drugs or foods, etc., and are convenient to use. They are a very promising and valuable drug for treating Sjogren's syndrome. Brief Description of the Drawings

[0037] Figure 1 Effect of Zedoary Turmeric Rhizome on salivary flow rate in NOD / Ltj mice.

[0038] Figure 2 Effect of Zedoary Turmeric Rhizome on organ index in NOD / ltj mice.

[0039] Figure 3 Effect of Zedoary Turmeric Rhizome on submandibular gland pathological score in NOD / ltj mice. Detailed Embodiments

[0040] The following is a further detailed description of the present invention with specific embodiments. However, it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following embodiments. All technologies implemented based on the content of the present invention belong to the scope of the present invention. Unless otherwise specified, the reagents and materials used in the present invention are all commercially available.

[0041] Example 1 Preparation of Curcuma zedoaria Granules

[0042] 1. Prepare equipment and materials: First, prepare all necessary equipment and materials, including fresh Curcuma zedoaria, 1.5 L of purified water, a stainless steel decocting pot, a filter, a pulverizer, a vacuum concentration device, an oven, 20 g of starch, 40 g of dextrin, 20 g of microcrystalline cellulose, and 15 g of erythritol.

[0043] 2. Preparation of Curcuma zedoaria slices: Wash the fresh Curcuma zedoaria medicinal materials, steam them for 3 hours, dry them in an oven at 55 °C for 36 hours, cut them into slices 3 - 5 mm thick, dry them in an oven at 45 °C for 6 hours, and turn them over once per hour during the drying process.

[0044] 3. Decocting: Put 100 g of the Curcuma zedoaria slices obtained in step 2 into a stainless steel decocting pot, add 1 L of purified water, decoct for 30 minutes, then add 0.5 L of purified water and decoct for 20 minutes. During the decocting process, stir appropriately to help release the medicinal efficacy.

[0045] 4. Filtration: Filter the decocted mixture separately to remove the medicinal residues and obtain the decoction.

[0046] 5. Combine the filtrates: Combine the two decoctions to obtain the required concentrated solution.

[0047] 6. Vacuum concentration: Inject the concentrated solution into the vacuum concentration device, start the vacuum concentration device, and evaporate the water under the conditions of 90 - 100 °C and 0 - 0.1 Mpa to obtain a concentrated decoction in which 1 ml is equivalent to 1 g of the raw medicinal materials.

[0048] 7. Mixing: Cool the concentrated decoction to 55 °C, and while stirring, add 20 g of starch, 40 g of dextrin, and 20 g of microcrystalline cellulose to the concentrated decoction and mix evenly.

[0049] 8. Flavoring: Add 10 g of erythritol and 10 g of mannitol to the mixture described in step 7 and stir evenly.

[0050] 9. Preparation of soft material: Moisten the mixture obtained in step 8 with ethanol having a volume fraction of 70 - 80% to make a soft material.

[0051] 10. Granulation: Pass the soft material through a pressure vessel, extrude and screen it to granulate and obtain the granules.

[0052] 11. Drying: Place the granules in an oven at 60 - 70°C and dry for 2 hours, controlling the environmental humidity below 50%.

[0053] 12. Granule sizing: Finally, size the dried granules to obtain the final zedoary turmeric granules.

[0054] Example 2 Preparation of zedoary turmeric extract zedoary turmeric oil.

[0055] 1. Pretreatment of zedoary turmeric roots: Take the complete zedoary turmeric roots, wash them twice to ensure no impurities on the surface, then drain the washed roots to remove excess water. Hang the drained roots to dry in the air for 48 hours to reduce the moisture content while keeping the root pieces intact.

[0056] 2. Preparation and preservation of zedoary turmeric slices: Cut the sun-dried zedoary turmeric roots into slices about 5 mm thick. Slicing should be carried out when the roots are still fresh. The prepared zedoary turmeric slices can be stored in a cold storage for freshness preservation or sealed and stored for later use by vacuum pumping to prevent oxidation and quality degradation.

[0057] 3. Drying and pulverizing of zedoary turmeric: Dry the zedoary turmeric slices in an oven at 45°C for 6 h, and turn them over once per hour during the drying process. After drying, pulverize the zedoary turmeric slices using a pulverizer and sieve through a 60-mesh sieve to collect the zedoary turmeric granules.

[0058] 4. Extraction and fractionation of zedoary turmeric oil: Place the zedoary turmeric granules in the distillation tank of the extraction device, introduce steam at 120°C into the distillation tank, and start the distillation process for 5 - 8 hours. During the distillation process, maintain the temperature in the evaporation tank within the range of 75 - 85°C through the temperature control program to stably volatilize the zedoary turmeric oil. Collect the volatile oil in the distillation tank and introduce it into the condenser to condense it into a liquid state. The condensed liquid zedoary turmeric oil enters the fractionation barrel through the condenser for fractionation, and the finally obtained product is zedoary turmeric oil.

[0059] Through the above detailed steps, the present invention provides a highly efficient and stable method for preparing zedoary turmeric oil, which can effectively extract valuable components from zedoary turmeric roots and obtain high-quality zedoary turmeric oil products that can be further used in the production of finished drugs. According to the above steps, 15 g - 20 g of zedoary turmeric oil can be extracted from each kilogram of zedoary turmeric slices.

[0060] Example 3 Preparation of zedoary turmeric oil injection.

[0061] 1. Preparation of materials: First, prepare all necessary materials, including injection water, 500 g of glucose, 100 g of raw material zedoary turmeric oil (prepared according to the steps described in Example 2), 300 g of 15-hydroxystearic acid polyethylene glycol ester, 500 g of polysorbate, 1000 g of propylene glycol, and 2.0 mol / L hydrochloric acid solution.

[0062] 2. Mixing: In an electric stirrer, add 5 L of water for injection and 500 g of glucose, then add 100 g of raw curcuma zedoary oil, 300 g of polyethylene glycol 15-hydroxystearate, 500 g of polysorbate, and 1000 g of propylene glycol. Stir for 10 minutes while heating and maintaining the liquid temperature at 40 °C.

[0063] 3. Volume fixing: After the temperature of the mixed solution stabilizes, fix the total volume to 10 L by adding water for injection.

[0064] 4. pH adjustment: Slowly add 2.0 mol / L hydrochloric acid solution to adjust the pH to 5.0.

[0065] 5. Filtration: Filter the mixed solution through an activated carbon filter to remove large particles and impurities therein.

[0066] 6. Sealing: Seal the filtered liquid into 5-mL ampoules.

[0067] 7. Sterilization: Place the sealed ampoules into a sterilizer and rotate and sterilize at 121 °C for 15 minutes.

[0068] 8. Storage: After sterilization is completed, curcuma zedoary oil injection with a specification of 5 mL / vial and containing 50 mg of curcuma zedoary oil is obtained. Take out the ampoules and store them in a refrigerated environment at 2 - 8 °C.

[0069] Example 4 Preparation of curcuma zedoary oil soft capsules.

[0070] 1. Material preparation: Prepare all necessary materials including no less than 200 g of raw curcuma zedoary oil, no less than 80 g of gelatin, no less than 40 g of glycerol, and no less than 80 g of water. Sterilize by ultraviolet irradiation.

[0071] 2. Capsule material preparation: Heat gelatin, glycerol, and water in a ratio of 2:1:2 to 75 °C to mix them, and cool and flatten them to 1 mm by a machine.

[0072] 3. Soft capsule pressing: Pass the capsule material prepared in step 2 through the two-side die rollers respectively, and press and form it at the joint of the rollers. At the same time, inject the raw curcuma zedoary oil into the soft capsules through the upper nozzle. The prepared soft capsules weigh 0.3 g each and contain 0.2 g of curcuma zedoary oil.

[0073] 4. Drying: The soft capsules pressed and formed in step 3 enter the drying rotating cage through the conveyor belt and are dried at 25 °C for 30 minutes.

[0074] 5. Storage: Store the prepared curcuma zedoary oil soft capsules in an opaque bottle, with 100 capsules in each bottle.

[0075] Example 5 Therapeutic effects of curcuma zedoary granules, curcuma zedoary oil injection, and curcuma zedoary oil soft capsules.

[0076] 1. Experimental methods: 10 SPF-grade 8-week-old ICR mice and 90 NOD / Ltj mice with pSS model were used. The experiment was divided into 8 groups (the gavage solvent was sterile deionized water): A. Blank group (ICR mice, gavaged with deionized water); B. Model group (NOD / Ltj mice, gavaged with deionized water); C. Western medicine hydroxychloroquine group (NOD / Ltj mice, gavaged with aqueous solution, 60 mg / kg); D. Rehmannia glutinosa (common traditional Chinese medicine 1) group (NOD / Ltj mice, gavaged with aqueous solution of granules, 27 g / kg); E. Ligusticum chuanxiong (common traditional Chinese medicine 2) group (NOD / Ltj mice, gavaged with aqueous solution of granules, 27 g / kg); F. Zengye Decoction (common compound prescription) group (NOD / Ltj mice, gavaged with aqueous solution of granules, 27 g / kg); G. Rhizoma zedoariae (granules) group (NOD / Ltj mice, gavaged with aqueous solution of granules, 27 g / kg) H. Zedoary oil (soft capsule) group (NOD / Ltj mice, gavaged with deionized water dilution, 80 mg / kg) I. Zedoary oil (injection) group (NOD / Ltj mice, intraperitoneally injected with normal saline dilution, 60 mg / kg), with 10 mice in each group. After two weeks of adaptive feeding, when the mice developed the disease at 10 weeks of age, they were given drugs for 6 weeks, and the mice were sacrificed after the drug administration was completed. During the experiment, the general condition of the mice, salivary flow rate, and blood glucose were recorded. After the mice were sacrificed, the HE staining method was used to evaluate and analyze the pathological changes of the submandibular gland tissue of the mice. SPSS 26.0 software was used for data analysis. For measurement data that conformed to the normal distribution, analysis of variance was used for comparison, and for data that did not conform to the normal distribution, non-parametric tests were used; for ranked data, the rank sum test was used, and for count data comparison, X 2 test was used.

[0077] 2. Experimental results.

[0078] 2.1 Observation of the general condition of mice: Compared with the mice in the blank group, the mice in the model group and the drug administration groups had slightly yellowish fur, reduced food intake, no obvious increase in body weight, and occasionally scratched their lips and skin. However, the drug administration groups could improve the above symptoms to varying degrees, and the Rhizoma zedoariae granule group, zedoary oil injection group, and zedoary oil soft capsule group could significantly improve the above symptoms.

[0079] 2.2 Salivary flow rate: As shown in Table 1 and Figure 1As shown, compared with the blank group, the salivary flow rate of NOD / Ltj mice in the model group began to significantly decrease after 10 weeks of age (p < 0.01). After 3 weeks of administration, compared with the model group, the hydroxychloroquine group, the Zengye Decoction group, and the Rhizoma Zedoariae treatment group (including the Rhizoma Zedoariae granule group, the Rhizoma Zedoariae oil injection group, and the Rhizoma Zedoariae oil soft capsule group) could significantly increase the salivary flow rate (p < 0.01, p < 0.05). Compared with the model group, the salivary flow rate in the Rehmannia glutinosa group and the Ligusticum chuanxiong group improved, but there was no statistical difference. Moreover, the salivary flow rate in the Rhizoma Zedoariae treatment group was higher than that in other administered groups (p < 0.01, p < 0.05). After 6 weeks of medication, the salivary flow rate in each administered group was significantly increased compared with the model group (p < 0.01, p < 0.05). The salivary flow rate in the Rhizoma Zedoariae treatment group was significantly higher than that in the Rehmannia glutinosa group, the Ligusticum chuanxiong group, the Rhizoma Zedoariae oil group, and the hydroxychloroquine group (p < 0.01), and there was no statistical difference compared with the Zengye Decoction group, indicating that Rhizoma Zedoariae granules, Rhizoma Zedoariae oil injection, and Rhizoma Zedoariae oil soft capsules achieved even better or exceeded the therapeutic effect of the classical famous prescription Zengye Decoction in improving the salivary flow rate of pSS model mice. The above results suggest that Rhizoma Zedoariae granules, Rhizoma Zedoariae oil injection, and oral administration can effectively improve the secretory function of the salivary glands in mice.

[0080] Table 1 Effects of Rhizoma Zedoariae on the salivary flow rate of NOD / Ltj mice (mg) (mean ± sd)

[0081]

[0082] Compared with the blank group, * p < 0.05, ** p < 0.01; compared with the model group, # p < 0.05, ## p < 0.01; compared with the hydroxychloroquine group, △ p < 0.05, △△ p < 0.01; compared with the Rehmannia glutinosa group and the Ligusticum chuanxiong group, ☆ p < 0.05, ☆☆ p < 0.01.

[0083] 2.3 Submandibular gland weight and index: Compared with the blank group of mice, the submandibular gland weight of the model group of mice decreased significantly (P < 0.01). Compared with the model group, the zedoary turmeric treatment groups (including the zedoary turmeric granule group, the zedoary turmeric oil injection group, and the zedoary turmeric oil soft capsule group), the hydroxychloroquine group, the rehmannia glutinosa group, the ligusticum wallichii group, and the zengye decoction group could all significantly increase the submandibular gland index of mice (P < 0.05), improve the submandibular gland weight, and the zedoary turmeric treatment groups and the zengye decoction group had a better effect on improving the submandibular gland index than other drug administration groups (P < 0.01, P < 0.05). Compared with the blank group, the spleen index of the model group increased significantly (P < 0.01). Compared with the model group, the zedoary turmeric granule group, the zedoary turmeric oil injection group, the zedoary turmeric oil soft capsule group, the hydroxychloroquine group, the rehmannia glutinosa group, the ligusticum wallichii group, and the zengye decoction group could all significantly decrease the spleen index of mice (P < 0.01, P < 0.05), and reduce the spleen weight. The above results indicate that zedoary turmeric granules, zedoary turmeric oil injection, and oral administration can improve the general condition of mice, inhibit the atrophy of the submandibular gland, and regulate the immune function of NOD mice, and the effect is better than that of the common traditional Chinese medicines rehmannia glutinosa and ligusticum wallichii. There is no statistical difference compared with the hydroxychloroquine group and the zengye decoction group, indicating that zedoary turmeric granules, zedoary turmeric oil injection, and zedoary turmeric oil soft capsules have an approximate therapeutic effect to that of the commonly used western medicine hydroxychloroquine or the classic famous prescription zengye decoction in improving the submandibular gland index and spleen index of pSS model mice.

[0084] Table 2 Effects of zedoary turmeric on the organ index of NOD / Ltj mice (mg / g) (mean ± sd)

[0085]

[0086] Compared with the blank group, * p < 0.05, ** p < 0.01; compared with the model group, # p < 0.05, ## p < 0.01; compared with the hydroxychloroquine group, △ p < 0.05, △△ p < 0.01; compared with the rehmannia glutinosa group and the ligusticum wallichii group, ☆ p < 0.05, ☆☆ p < 0.01.

[0087] 2.4 Submandibular gland pathology: Severe lymphocyte infiltration was observed in the submandibular glands of the mice in the model group, with increased cell spaces. The infiltrating cells were mostly distributed around the ducts and blood vessels. The acini were of unequal sizes, and the glandular duct structure was disordered. Compared with the model group, the pathological histological scores of the mice in the zedoary turmeric treatment groups (including the zedoary turmeric granule group, the zedoary turmeric oil injection group, and the zedoary turmeric oil soft capsule group), the hydroxychloroquine group, the rehmannia glutinosa group, and the zengye decoction group (see Table 3) were significantly reduced (p < 0.01, p < 0.05). The improvement of the submandibular gland pathological scores in the zedoary turmeric treatment groups was more significant compared with the rehmannia glutinosa group and the ligusticum wallichii group, and there was no statistical difference compared with the hydroxychloroquine group and the zengye decoction group, indicating that zedoary turmeric granules, zedoary turmeric oil injection, and zedoary turmeric oil soft capsules achieved similar therapeutic effects to the commonly used western medicine hydroxychloroquine or the classic famous prescription zengye decoction in improving the submandibular gland pathology of pSS model mice. The above results show that both the injection and oral administration of zedoary turmeric granules and zedoary turmeric oil can inhibit the inflammatory infiltration of the submandibular gland tissue, improve the damage state of the glandular structure, and play a role in increasing the saliva flow rate of the mice by protecting the submandibular gland tissue of NOD mice.

[0088] Table 3 Effects of zedoary turmeric on the pathological morphology of the submandibular glands of NOD / ltj mice (mean±sd)

[0089]

[0090] Compared with the blank group, * p < 0.05, ** p < 0.01; compared with the model group, # p < 0.05, ## p < 0.01; compared with the rehmannia glutinosa group and the ligusticum wallichii group, ☆ p < 0.05, ☆☆ p < 0.01.

[0091] In summary, in this study, guided by traditional Chinese medicine theory, an experimental study was conducted by integrating the pathogenesis characteristics of blood stasis obstruction in traditional Chinese medicine for Sjogren's syndrome and the pharmacological effects of zedoary turmeric. On the basis of determining the effects of zedoary turmeric on NOD / Ltj model mice, the effects of zedoary turmeric oil containing its main active ingredients on model mice were explored, proving that both zedoary turmeric and its main component zedoary turmeric oil are effective in NOD / Ltj model mice, and the therapeutic effects of oral or injection of zedoary turmeric oil are not inferior to those of zedoary turmeric granules and the commonly used classic famous prescription zengye decoction in clinical practice.

[0092] The above are only the preferred embodiments of the present invention and are not used to limit the patent scope of the present invention. For those skilled in the art, the present invention can have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. The application of the traditional Chinese medicine Curcuma zedoaria as the only raw material in the preparation of drugs for the treatment of primary Sjögren's syndrome.

2. The use of a Chinese herbal medicine Curcuma zedoaria extract as the sole active ingredient in the preparation of a drug for treating primary Sjögren's syndrome, wherein the Chinese herbal medicine Curcuma zedoaria extract is Curcuma zedoaria oil.

3. The use according to any one of claims 1 or 2, characterized in that The medicine also includes pharmaceutically acceptable excipients; the dosage form of the medicine is granules and injections.

4. The use according to claim 3, characterized in that: The method for preparing the granules of the drug specifically comprises the following steps: Step 1: Prepare the decoction pieces of Curcuma zedoaria: wash the fresh medicinal materials of Curcuma zedoaria, steam them for 3 hours, dry them in a 55°C oven for 36 hours, cut them into 3-5 mm thick slices, dry them in a 45°C oven for 6 hours, and turn them over once every hour during the drying process; Step 2: decoction: put 100 g of the Curcuma zedoaria slices obtained in step 1 into a stainless steel decoction pot, add 1000 mL of purified water, decoct for 30 minutes, then add 0.5 L of purified water, and decoct for 20 minutes; Step 3: filtering: filtering the mixture after the two decoctions in step 2 respectively to remove the residue and obtain a decoction; combining the two decoctions to obtain the desired concentrated solution; Step 4: vacuum concentration: the concentrated solution obtained in step 3 is placed in a vacuum concentration device, and the vacuum concentration device is started to evaporate water under the conditions of 90-100°C and 0-0.1Mpa to obtain a concentrated decoction with 1 ml equivalent to 1 gram of raw medicinal materials; Step 5: Mixing: Cool the concentrated decoction obtained in step 4 to 55° C., add 20 g of starch, 40 g of dextrin, and 20 g of microcrystalline cellulose to the concentrated decoction while stirring, mix well, then add 10 g of erythritol and 10 g of mannitol, and stir well; Step 6: preparing a soft material: wetting the mixture obtained in step 5 with 70-80% ethanol by volume to prepare a soft material; Step 7: Granulation: The soft material obtained in step 6 is passed through a pressure vessel, extruded and sieved to obtain granules; the granules are placed in an oven at 60 to 70° C. and dried for 1 to 2 hours, and the ambient humidity is controlled below 50%; and the dried granules are then granulated to obtain Curcuma granules.

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