A preparation of coptis chinensis, its preparation method and application

Abstract

This invention discloses a Coptis chinensis preparation, its preparation method, and its application, relating to the field of pharmaceutical technology. The preparation comprises Coptis chinensis extract, Aucklandia lappa extract, and JAK inhibitors, achieving synergistic effects through rational formulation. The preparation method includes extraction, concentration, formulation, and molding steps, with a stable process and ease of industrialization. Pharmacodynamic results show that the preparation of this invention can significantly improve the disease activity index and histopathological damage in a DSS-induced colitis model, and downregulate the expression of JAK1 and JAK3 proteins, exhibiting good anti-inflammatory and intestinal mucosal protective effects. It can be used for the prevention and treatment of inflammatory bowel diseases such as ulcerative colitis.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a Xianglian preparation, its preparation method, and its application. Background Technology

[0002] Inflammatory bowel disease (IBD), primarily including ulcerative colitis and Crohn's disease, is a chronic, nonspecific intestinal inflammation characterized by a long course and high relapse rate. Its pathogenesis is complex, and clinical treatment is challenging. In traditional Chinese medicine (TCM), Xianglian preparations, derived from the classic formula Xianglian Wan, are mainly composed of Coptis chinensis (Huanglian) and Aucklandia lappa (Muxiang). The main components of Coptis chinensis extract, such as berberine, have the effects of clearing heat and drying dampness, purging fire and detoxifying; while Aucklandia lappa extract can regulate qi and relieve pain. Modern pharmacological studies have shown that Xianglian preparations have certain advantages in regulating intestinal flora and repairing intestinal mucosa. However, existing TCM preparations made solely using Coptis chinensis and Aucklandia lappa extracts tend to have a pharmacological mechanism that leans towards multi-target holistic regulation. This often results in slow onset of action and insufficient anti-inflammatory intensity when treating moderate to severe or acute exacerbations of intestinal inflammation, making it difficult to rapidly control severe inflammatory responses and clinical symptoms within a short period.

[0003] On the other hand, with the development of immunology, the Janus kinase (JAK) signaling pathway has been proven to play a crucial role in the signal transduction of inflammatory factors. JAK inhibitors, as a new class of small-molecule targeted drugs, can significantly inhibit the production of various pro-inflammatory cytokines by blocking intracellular signal transduction, demonstrating definite efficacy in the treatment of autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. However, existing universal or non-selective JAK inhibitors often have significant systemic side effects in clinical applications, such as increased risk of infections like herpes zoster, venous thromboembolism, and hematologic toxicity. Especially when higher doses are administered in pursuit of higher efficacy, the toxic side effects increase significantly, severely limiting long-term patient adherence and safety.

[0004] To overcome the aforementioned shortcomings, while combining traditional Chinese medicine (TCM) with chemical drugs is an improvement approach in this field, not all JAK inhibitors combined with TCM extracts can produce synergistic effects and reduce toxicity. Different structural JAK inhibitors may exhibit physicochemical incompatibility with Coptis chinensis and Aucklandia lappa extracts, or interfere with each other in pharmacokinetics, leading to reduced bioavailability or additive toxicity. Currently, there is a lack of existing technologies that can scientifically combine highly selective JAK inhibitors with specific structures and Coptis chinensis extracts. How to screen specific JAK inhibitors to produce significant synergistic anti-inflammatory effects with Coptis chinensis and Aucklandia lappa extracts, while simultaneously utilizing TCM components to alleviate the side effects of chemical drugs, thereby providing a modified formulation that is rapid-onset, highly effective, and safe, is a pressing technical problem in the current pharmaceutical technology field. Summary of the Invention

[0005] To address the problems of slow onset of action and insufficient anti-inflammatory potency in existing Xianglian preparations for treating inflammatory bowel disease, as well as the significant side effects and low safety associated with long-term use of JAK inhibitors, this invention aims to provide a Xianglian preparation, its preparation method, and its application. This invention, through the scientific formulation of specific JAK inhibitors with Coptis chinensis extract and Aucklandia lappa extract, significantly improves the anti-inflammatory efficacy and onset speed of the preparation, while effectively reducing the toxic side effects of chemical drugs, providing a drug option that combines high efficacy and safety.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A scallion preparation, the raw materials of which include the following components in parts by weight: 20 to 50 parts of Coptis chinensis extract, 10 to 30 parts of Aucklandia lappa extract, 0.1 to 5 parts of JAK inhibitor, 30 to 60 parts of filler, 2 to 10 parts of disintegrant, 1 to 5 parts of binder, and 0.5 to 2 parts of lubricant.

[0008] By adopting the above technical solution, the JAK inhibitor is further described as 1-(4-((5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one.

[0009] By adopting the above technical solution, the structure of the 1-(4-((5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one is further as follows: .

[0010] By adopting the above technical solution, the Coptis chinensis extract is a powder obtained by reflux extraction of Coptis chinensis with ethanol and drying, wherein the content of berberine hydrochloride is not less than 15%.

[0011] By adopting the above technical solution, the costus extract is a powder obtained by reflux extraction of costus with ethanol and drying, wherein the total content of costus lactone and dehydrocostus lactone is not less than 2%.

[0012] Furthermore, by adopting the above technical solution, the filler is selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, and mannitol.

[0013] Furthermore, by adopting the above technical solution, the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and dry starch.

[0014] Furthermore, by adopting the above technical solution, the adhesive is selected from one or more of povidone K30, hydroxypropyl methylcellulose, starch paste, and methylcellulose.

[0015] By adopting the above technical solution, the lubricant is further selected from one or more of magnesium stearate, talc, micronized silica gel, and stearic acid.

[0016] A method for preparing a xianglian preparation includes the following steps:

[0017] The first step is to prepare the dry powder of the Chinese herbal extract. Slices of Coptis chinensis and Aucklandia lappa are mixed, ethanol solution is added and heated under reflux for extraction. The extracts are combined and filtered. The filtrate is concentrated under reduced pressure to obtain an extract. After drying, it is pulverized to obtain the dry powder of the mixed extract.

[0018] The second step is premixing, in which the JAK inhibitor is mixed with an equal amount of the filler in incremental steps to obtain a drug premix.

[0019] The third step is to mix and prepare a soft material by mixing the mixed extract powder obtained in the first step, the drug premix obtained in the second step, the remaining filler, and 1 / 2 part by weight of disintegrant, and adding a binder solution to make a soft material.

[0020] The fourth step is granulation and drying. The soft material is made into wet granules, dried, and then granulated.

[0021] The fifth step is to mix and compress the granules. The sized dry granules are mixed with 1 / 2 part by weight of disintegrant and all the lubricant, and then compressed into tablets.

[0022] By adopting the above technical solution, in the first step, an ethanol solution with a concentration of 70% is added in an amount of 6 to 8 times the total weight of the medicinal materials, and the mixture is heated and refluxed twice, with each extraction lasting 1.5 to 2 hours; the relative density of the extract is 1.10 to 1.15; and the dry powder of the mixed extract passes through an 80-mesh sieve.

[0023] By adopting the above technical solution, the JAK inhibitor is first passed through a 100-mesh sieve and then mixed with the filler.

[0024] By adopting the above technical solution, further, in the third step, the mixture is placed in a wet mixer and mixed for 10 to 15 minutes; the partial disintegrant is half of the total amount of the formulation; and the concentration of the adhesive solution is 5% to 10%.

[0025] By adopting the above technical solution, further, in the fourth step, the soft material is made into wet granules through a 20 to 24 mesh sieve, the drying temperature is 50 to 60 degrees Celsius, and the moisture content is dried to less than 3%; in the fifth step, the mixing time is 15 to 20 minutes.

[0026] Application of a xianglian preparation in the preparation of drugs for treating inflammatory bowel disease.

[0027] A certain Xianglian preparation relates to the field of biopharmaceutical manufacturing technology.

[0028] 1-(4-((5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one is related to the fields of chemical pharmaceutical raw materials and formulation manufacturing technology.

[0029] This invention achieves multiple synergistic mechanisms through specific component selection and compatibility. First, the JAK inhibitor 1-(4-((5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one, selected in this invention, possesses a unique vinyl group in its chemical structure that endows it with a covalent binding mode, enabling it to selectively block the JAK3 and JAK1 signaling pathways and rapidly interrupt intracellular signal transduction of key inflammatory factors such as interleukin-6 and interferon-gamma. This allows for rapid control of acute inflammatory storms in the early stages of treatment, overcoming the slow onset of action of traditional Coptis chinensis preparations. Second, alkaloids such as berberine hydrochloride in Coptis chinensis extract can exert broad-spectrum anti-inflammatory effects by inhibiting the NF-kappaB pathway, regulating intestinal flora structure, and repairing the intestinal mucosal barrier; while costus lactone and dehydrocostus lactone in Aucklandia lappa extract can promote intestinal gas flow and relieve abdominal pain caused by smooth muscle spasms. The core synergistic mechanism between this targeted and rapid-acting chemical drug and the holistic repair function of traditional Chinese medicine (TCM) is as follows: the specific JAK inhibitor addresses the insufficient anti-inflammatory strength of TCM, while the TCM extract, through multi-target regulation, compensates for the drug resistance problem that easily arises with long-term use of single-target drugs. More importantly, in terms of safety, the active ingredients in Coptis chinensis extract have been shown to regulate the activity of liver metabolic enzymes. At this formulation ratio, it can improve the pharmacokinetic behavior of this specific JAK inhibitor in vivo, enabling the maintenance of effective blood drug concentrations at lower chemical drug doses. This significantly reduces the risk of systemic side effects such as herpes zoster and venous thrombosis caused by JAK inhibitors, achieving the clinical value of synergistic efficacy and reduced toxicity. In addition, the premixing process using an equal-incremental method solves the problem of uneven mixing and poor stability of trace amounts of hydrophobic JAK inhibitors with large amounts of hydrophilic TCM extract powder, ensuring the effective release and bioavailability of the drug components in vivo.

[0030] Compared with the prior art, the beneficial effects of the present invention are:

[0031] 1. By scientifically combining a specific JAK inhibitor with extracts of Coptis chinensis and Aucklandia lappa, the shortcomings of traditional Chinese medicine preparations—slow onset of action and relatively insufficient anti-inflammatory potency—are effectively overcome. This also addresses the issues of single chemical drugs having limited targets and developing drug resistance with long-term use. The specific JAK inhibitor can rapidly block inflammatory signal transduction and quickly control acute symptoms, while the extracts of Coptis chinensis and Aucklandia lappa improve the intestinal microenvironment and repair damaged mucosa through multi-target regulation. The combined use of these two drugs demonstrates superior anti-inflammatory effects and tissue repair capabilities compared to using either traditional Chinese medicine or JAK inhibitors alone in the treatment of inflammatory bowel disease.

[0032] 2. By leveraging the synergistic effects of traditional Chinese medicine extracts, the dosage of a specific JAK inhibitor can be effectively reduced while achieving equivalent or better therapeutic effects. Furthermore, the active ingredients in Coptis chinensis extract and Aucklandia lappa extract have a certain protective effect on the body, antagonizing the potential damage from chemical drug components. This significantly reduces the risk of common adverse reactions to JAK inhibitors, such as herpes zoster, venous thrombosis, and liver and kidney toxicity, thereby improving patient tolerance and adherence to long-term medication.

[0033] 3. By employing a premixing process using an equal-incremental method, trace amounts of JAK inhibitors are first fully dispersed with the filler, and then mixed with the dry powder of traditional Chinese medicine extracts. This ensures the uniformity of the highly active ingredient content in the tablets and avoids the risks caused by excessively high local drug concentrations. Simultaneously, the optimized granulation process results in granules with good flowability and compressibility, leading to high dissolution rates in the prepared formulation. Furthermore, the content of each active ingredient remains stable during storage, demonstrating excellent physicochemical stability. Attached Figure Description

[0034] Figure 1 This is a WB diagram showing the relative protein expression of JAK1 and JAK3 in this invention. Detailed Implementation

[0035] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are merely some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0036] Preparation Example 1

[0037] Preparation of JAK inhibitor 1-(4-((5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one:

[0038] ;

[0039] Y1: 4-Chloro-5-vinyl-7H-pyrrolo[2,3-d]pyrimidine;

[0040] Y2: Tert-butyl-4-(methylamino)piperidine-1-carboxylic acid ester;

[0041] Y3: Tert-butyl-4-(methyl(5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylic acid ester;

[0042] Y4: N-Methyl-N-(piperidin-4-yl)-5-vinyl-7H-pyrimidinopyrrolo[2,3-d]-4-amine

[0043] Y5: Acryloyl chloride.

[0044] Under a nitrogen atmosphere at room temperature, Y2 (5.00 g), Y1 (4.61 g), and n-butanol (120 mL) were added sequentially to a round-bottom flask. After stirring until uniformly dispersed, DIPEA (10.2 mL) was slowly added dropwise to the reaction system. After the addition was complete, the reaction system was heated to 110°C and refluxed with stirring for 12 hours. After the reaction was completed, the reaction flask was removed from the oil bath and cooled to room temperature. The reaction mixture was concentrated using a rotary evaporator under reduced pressure to obtain a viscous residue. This residue was redissolved in ethyl acetate (150 mL), and the solution was transferred to a 500 mL separatory funnel. The organic phase was washed sequentially with water (100 mL × 2) and saturated brine (100 mL). The separated organic phase was dried over anhydrous sodium sulfate for 30 minutes. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mixed solution of petroleum ether and ethyl acetate (4:1 to 1:1, v / v). The fraction containing the target product was collected, evaporated under reduced pressure, and 7.36 g of Y3 was obtained.

[0045] Under a nitrogen atmosphere at room temperature, Y3 (7.36 g) and anhydrous DCM (95 mL) were added to a round-bottom flask. Stirring was started until the mixture was uniformly dispersed, and TIPS (4.43 mL) were added. The reaction flask was placed in an ethanol dry ice bath to cool for 10 minutes. After the internal temperature dropped to 0°C, TFA (23.7 mL) was slowly added dropwise, with the addition temperature not exceeding 5°C. After the addition was complete, the mixture was stirred at 0°C for 15 minutes. The ice bath was then removed, and the reaction system was allowed to warm naturally to room temperature, with stirring continuing for 3 hours. After the reaction was complete, the reaction solution was concentrated directly on a rotary evaporator under reduced pressure to remove most of the DCM and excess TFA. The resulting oily residue was redissolved in DCM (150 mL). Under ice bath cooling, a saturated sodium bicarbonate aqueous solution was slowly added dropwise to the organic phase to quench the reaction and adjust the pH until the pH of the aqueous phase was approximately 8-9 and no bubbles were generated. The mixture was transferred to a separatory funnel to separate the organic layer. The aqueous layer was back-extracted using DCM (3 × 50 mL). All organic phases were combined and washed successively with water (50 mL) and saturated brine (100 mL). The organic phases were dried over anhydrous sodium sulfate for 30 minutes and filtered to remove the desiccant. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mixed solution of DCM and MeOH (100:0 to 20:1, v / v). The fraction containing the target product was collected, evaporated under reduced pressure, and yielded 3.41 g of Y4.

[0046] Under a nitrogen atmosphere at room temperature, Y4 (3.41 g) and anhydrous dichloromethane (DCM, 40 mL) were added to a round-bottom flask and stirred until evenly dispersed. The reaction flask was placed in an ethanol dry ice bath and cooled to 0°C. DIPEA (4.41 mL) was added, and stirring was continued for 5 minutes. Y5 (1.13 mL) was dissolved in 10 mL of anhydrous DCM. Acryloyl chloride solution was slowly added dropwise to the reaction system at 0°C, controlling the dropping rate to maintain the internal temperature not exceeding 5°C. After the addition was complete, the ice bath was removed, and the reaction system was allowed to naturally rise to room temperature. The reaction was stirred for 1.5 hours. After the reaction was completed, the reaction mixture was cooled back to 0°C, and a saturated sodium bicarbonate aqueous solution (30 mL) was slowly added to quench the reaction. The mixture was transferred to a separatory funnel and shaken. The lower organic phase was separated. The aqueous phase was extracted a second time using DCM (2 × 20 mL). All organic phases were combined and washed successively with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate for 30 minutes. The desiccant was removed by filtration, and the solvent was removed by rotary evaporation under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a gradient elution with a mixed solution of DCM and MeOH (100:0 to 95:5, v / v). The fraction containing the target product was collected, evaporated under reduced pressure, and 2.46 g of JAK inhibitor was obtained.

[0047] Structural identification is shown in Table 1:

[0048] Table 1

[0049] Test sample <![CDATA[ 1 HNMR-CDCl3]]> Y3 δ8.15(s,1H),7.85(d,1H),7.05(d,2H),5.68-5.55(m,2H),4.19-4.02( m,3H),3.32(d,3H),3.03(m,2H),2.25(m,2H),1.90(m,2H),1.45(s,9H). Y4 δ8.14(s,1H),7.87(d,1H),7.14-6.82(m,2H),5.63-5.58(m,2H),4.08(m,1H),3. 32(d,3H),3.13(m,2H),2.77(m,2H),2.12(m,2H),2.00(p,1H),1.84-1.72(m,2H). JAK inhibitors δ8.16(s,1H),7.84(d,1H),7.08(d,1H),6.94-6.82(m,1H),6.59-6.47(m,1H),6.06-5.97(m,2 H),5.69-5.53(m,2H),4.19-4.02(m,3H),3.32(d,3H),3.03(m,2H),2.29(m,2H),1.93(m,2H).

[0050] Example 1

[0051] This example provides a quality part raw material component of a Xianglian preparation and its preparation method:

[0052] 1. Quality part raw material components:

[0053] Coptis chinensis extract, 35 parts;

[0054] Aucklandia lappa extract, 20 parts;

[0055] JAK inhibitor, 1 part, obtained from Preparation Example 1;

[0056] Filler, 40 parts, selected: microcrystalline cellulose (PH102 type);

[0057] Disintegrant, 6 parts, selected: croscarmellose sodium;

[0058] Binder, 3 parts, selected: polyvinylpyrrolidone K30 formulated into an 8wt% aqueous solution for use;

[0059] Lubricant, 1 part, selected: magnesium stearate, passed through an 80-mesh sieve.

[0060] 2. Preparation method:

[0061] The first step is to prepare the dry powder of traditional Chinese medicine extract: Take the corresponding weight parts of sliced Coptis chinensis and sliced Aucklandia lappa, mix them, add an ethanol solution with a mass fraction of 70% and a volume 7 times the total weight of the medicinal materials, and heat under reflux for extraction 2 times, each extraction for 1.8 hours; Combine the two extraction liquids, filter with a 300-mesh filter cloth, and concentrate the filtrate under reduced pressure at a vacuum degree of -0.08 to -0.09 MPa and a temperature of 60 to 65 °C to an extract with a relative density of 1.12 (measured at 60 °C); Place the extract in a vacuum drying oven, dry it to constant weight at 55 °C and a vacuum degree of -0.09 MPa, take out the dried product and crush it with a universal crusher, and pass through an 80-mesh sieve to obtain the dry powder of the Coptis chinensis - Aucklandia lappa mixed extract, and set aside;

[0062] The second step is to prepare the drug premix: Crush the 1 part of JAK inhibitor with an ultrafine crusher, pass through a 100-mesh sieve, take the sieved JAK inhibitor and mix it with an equal weight part of microcrystalline cellulose (PH102 type) by equal increment mixing. Each mixing is carried out with a three-dimensional mixer for 5 minutes until the color of the material is uniform and there are no obvious particles, to obtain the drug premix, and set aside.

[0063] Step 3, Total mixing and preparing soft mass: Put the dry powder of the Coptis chinensis-Floral Syzygium aromaticum mixed extract obtained in Step 1, the drug premix obtained in Step 2, and the remaining 39 parts of microcrystalline cellulose (type PH102), and half of the total formula amount of disintegrant (3 parts of croscarmellose sodium) into a wet mixer, set the rotation speed to 150 r / min, and mix for 12 minutes; Slowly drip the aqueous solution of 8% polyvinylpyrrolidone K30 by mass fraction into the uniformly mixed material, stir while dripping until the material forms a soft mass that can be formed into a ball by hand and dispersed when lightly pressed, stop dripping the binder solution, and continue to stir for 2 minutes to make the soft mass uniform;

[0064] Step 4, Granulating and drying: Transfer the soft mass obtained in Step 3 to a rocking granulator, and use a 22-mesh sieve to make wet granules; Spread the wet granules evenly on a baking tray, place them in a hot air circulation drying oven, set the drying temperature to 55 °C, and dry until the moisture content of the granules is lower than 3% (detected by the Karl Fischer moisture determination method); Place the dried granules in a rocking granulator and use a 22-mesh sieve to size the granules to obtain dry granules for standby;

[0065] Step 5, Total mixing and tabletting: Put the dry granules obtained in Step 4, the remaining 3 parts of croscarmellose sodium, and 1 part of pre-screened magnesium stearate into a three-dimensional mixer, set the rotation speed to 120 r / min, and mix for 18 minutes until the material is uniform; Place the mixed material in a rotary tabletting machine, set the tablet weight and pressure according to the preparation requirements, and tablet it into plain tablets to obtain the tablets of the Coptis chinensis-Floral Syzygium aromaticum preparation of the present invention. <​​​​​​​​​​​​​​​Referring to the steps of Example 1, replace 35 parts of the Coptis chinensis extract therein with 50 parts, 20 parts of the Aucklandia lappa extract with 30 parts, 1 part of the JAK inhibitor with 3 parts, 40 parts of the filler microcrystalline cellulose (PH102 type) with 30 parts of pregelatinized starch, 3 parts of the binder polyvinylpyrrolidone K30 prepared as an 8 wt% aqueous solution with 2 parts of hydroxypropyl methylcellulose prepared as a 5 wt% aqueous solution, and 1 part of the lubricant magnesium stearate with 1.5 parts of silica micropowder, and the rest is the same as in Example 1.

[0072] Example 4

[0073] This example provides a quality parts raw material component of a Xianglian preparation and its preparation method:

[0074] Referring to the steps of Example 1, replace 35 parts of the Coptis chinensis extract therein with 45 parts, 20 parts of the Aucklandia lappa extract with 25 parts, 1 part of the JAK inhibitor with 5 parts, 40 parts of the filler microcrystalline cellulose (PH102 type) with 35 parts of mannitol, 6 parts of the disintegrant cross-linked carboxymethylcellulose sodium with 8 parts of sodium carboxymethyl starch, 3 parts of the binder polyvinylpyrrolidone K30 prepared as an 8 wt% aqueous solution with 4 parts of starch paste, 1 part of the lubricant magnesium stearate with 0.8 parts of talc powder, and the rest is the same as in Example 1.

[0075] Comparative Example 1

[0076] This comparative example provides a quality parts raw material component of a Xianglian preparation and its preparation method:

[0077] Referring to the steps of Example 1, replace 1 part of the JAK inhibitor therein with 0 parts (i.e., without adding the JAK inhibitor), and the rest is the same as in Example 1.

[0078] Comparative Example 2

[0079] This comparative example provides a quality parts raw material component of a Xianglian preparation and its preparation method:

[0080] Referring to the steps of Example 1, replace the JAK inhibitor therein with (CAS: 1792182-14-9), and the rest is the same as in Example 1.

[0081] Comparative Example 3

[0082] This comparative example provides a quality parts raw material component of a Xianglian preparation and its preparation method:

[0083] Referring to the steps of Example 1, replace the JAK inhibitor therein with tofacitinib citrate, and the rest is the same as in Example 1.

[0084] Comparative Example 4

[0085] This comparative example provides a method for preparing a coptis chinensis preparation by mass fraction of raw material components and its preparation method:

[0086] Following the steps of Example 1, replace 35 parts of Coptis chinensis extract with 0 parts, and keep the rest the same as in Example 1.

[0087] Performance testing:

[0088] 1. In vivo pharmacodynamic evaluation of anti-inflammatory bowel disease:

[0089] 1.1 Animal Model Construction:

[0090] SPF-grade male C57BL / 6 mice, weighing 18-22g, were randomly divided into the example group, the comparative group, and the normal control group.

[0091] An acute colitis model induced by dextran sulfate sodium (DSS) was established: except for the normal control group which drank pure water, the mice in the other groups were allowed to drink 3.5% (w / v) DSS aqueous solution for 7 consecutive days. At the same time, each drug treatment group was given the corresponding drug suspension by gavage at a dose of 10 mL / kg body weight (the test sample was ground and then mixed with 0.5% carboxymethyl cellulose sodium solution to prepare the suspension). The normal control group and the model group were given the same volume of solvent once a day.

[0092] 1.2 Disease Activity Index (DAI) Score: Mouse weight changes, fecal characteristics, and fecal blood loss were observed and recorded daily. The DAI score was calculated according to the following criteria:

[0093] Weight loss: 0 points (no decrease or increase), 1 point (decline of 1-5%), 2 points (decline of 5-10%), 3 points (decline of 10-15%), 4 points (decline of >15%);

[0094] Stool characteristics: 0 points (normal), 2 points (loose), 4 points (diarrhea);

[0095] Blood in stool: 0 points (no bleeding), 2 points (positive for occult blood), 4 points (visible blood in stool).

[0096] DAI = (weight loss score + fecal characteristics score + bloody stool score) / 3, and the data is shown in Table 2.

[0097] 1.3 Colonic histopathological examination: Mice were sacrificed on day 8 of the experiment. The entire colon from the anus to the terminal cecum was harvested. Distal colonic tissue was fixed in 10% neutral formalin solution, embedded in paraffin, sectioned (4 μm thick), and stained with hematoxylin and eosin (HE). Histopathological scoring (0-12 points) was performed based on the depth and extent of the lesions to evaluate the mucosal damage repair. The data are shown in Table 2.

[0098] 1.4 Detection of expression of key proteins in inflammatory signaling pathways: The protein expression levels of JAK1 and JAK3 in colon tissue were detected by Western blotting, and the data are shown in Table 2.

[0099] Table 2

[0100] Group DAI rating Histopathological score JAK1 relative protein expression JAK3 relative protein expression normal control group 0.12±0.05 0.5±0.2 1.00±0.10 1.00±0.08 Model group 3.65±0.21 11.2±0.6 3.85±0.32 4.10±0.25 Example 1 Group 1.15±0.12 2.8±0.4 1.35±0.15 1.28±0.12 Example 2 group 1.68±0.15 4.2±0.5 1.82±0.18 1.75±0.16 Example 3 Group 1.05±0.10 2.4±0.3 1.25±0.14 1.15±0.10 Example 4 group 0.98±0.08 2.2±0.3 1.20±0.12 1.10±0.09 Comparative Example 1 2.55±0.18 7.5±0.5 3.10±0.28 3.35±0.22 Comparative Example 2 1.85±0.16 5.4±0.6 1.95±0.20 2.05±0.18 Comparative Example 3 Groups 1.72±0.14 4.8±0.5 1.78±0.16 1.85±0.15 Comparative Example 4 Groups 2.10±0.15 6.2±0.4 1.90±0.18 2.15±0.16

[0101] The normal control group had a low inflammatory baseline, while the model group showed simultaneous deterioration in three aspects: DAI, histopathology, and JAK1 / JAK3 protein expression. This indicates that DSS-induced colitis not only causes phenotypic damage but also involves the activation of JAK-related inflammatory signals. In contrast, all groups in the example showed unidirectional improvement in these three indicators, and the decrease in JAK1 / JAK3 was synchronous with the decrease in DAI and pathological scores. This suggests that the anti-inflammatory and mucosal protective effects of this Xianglian preparation are likely related to the inhibition of the JAK signaling axis, rather than simply relieving surface symptoms. Further analysis of the comparative examples reinforces this mechanism: removing the JAK inhibitor (Comparative Example 1) significantly reduced the overall efficacy, indicating that the JAK inhibition component in the formula makes a crucial contribution to both pathway inhibition and final efficacy. Replacing the JAK inhibitor with other JAK-related compounds still resulted in improvement, but the overall effect was not as good as the dominant group in the examples, suggesting a potentially superior synergistic effect between the inhibitor used in this invention and the Coptis chinensis / Saussurea costus extract. Removing the Coptis chinensis extract, while still retaining some pathway inhibition and symptom improvement, resulted in a further decrease in efficacy, indicating that the herbal extract may not only provide additional anti-inflammatory, barrier protection, or immunomodulatory effects but may also enhance the overall efficacy brought about by JAK inhibition. Based on all the data in Table 2, the mechanism is a synergistic effect of targeted JAK pathway inhibition combined with the multi-target anti-inflammatory / mucosal repair effects of the herbal components.

[0102] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A preparation of coptis chinensis, characterized in that, Its raw materials include the following components in parts by weight: 20 to 50 parts of Coptis chinensis extract, 10 to 30 parts of Aucklandia lappa extract, 0.1 to 5 parts of JAK inhibitor, 30 to 60 parts of filler, 2 to 10 parts of disintegrant, 1 to 5 parts of binder, and 0.5 to 2 parts of lubricant; The JAK inhibitor is 1-(4-((5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one; The structure of the 1-(4-((5-vinyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one is as follows: .

2. The Xianglian preparation according to claim 1, characterized in that, The Coptis chinensis extract is a powder obtained by reflux extraction of Coptis chinensis with ethanol and drying, wherein the content of berberine hydrochloride is not less than 15%. The costus extract is a powder obtained by reflux extraction of costus with ethanol and drying, wherein the total content of costus lactone and dehydrocostus lactone is not less than 2%.

3. A xianglian preparation according to claim 1, characterized in that, The filler is selected from one or more of microcrystalline cellulose, lactose, pregelatinized starch, and mannitol; The disintegrant is selected from one or more of croscarmellose sodium cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and dry starch.

4. A xianglian preparation according to claim 1, characterized in that, The adhesive is selected from one or more of polyvinylpyrrolidone K30, hydroxypropyl methylcellulose, starch paste, and methylcellulose. The lubricant is selected from one or more of magnesium stearate, talc, micronized silica gel, and stearic acid.

5. A method for preparing a xianglian preparation as described in any one of claims 1 to 4, characterized in that, Includes the following steps: The first step is to prepare the dry powder of the Chinese herbal extract. Slices of Coptis chinensis and Aucklandia lappa are mixed, ethanol solution is added and heated under reflux for extraction. The extracts are combined and filtered. The filtrate is concentrated under reduced pressure to obtain an extract. After drying, it is pulverized to obtain the dry powder of the mixed extract. The second step is premixing, in which the JAK inhibitor is mixed with an equal amount of the filler in incremental steps to obtain a drug premix. The third step is to mix and prepare a soft material by mixing the mixed extract powder obtained in the first step, the drug premix obtained in the second step, the remaining filler, and 1 / 2 part by weight of disintegrant, and adding a binder solution to make a soft material. The fourth step is granulation and drying. The soft material is made into wet granules, dried, and then granulated. The fifth step is to mix and compress the granules. The sized dry granules are mixed with 1 / 2 part by weight of disintegrant and all the lubricant, and then compressed into tablets.

6. The method for preparing a Xianglian preparation according to claim 5, characterized in that, In the first step, a 70% ethanol solution with a concentration of 6 to 8 times the total weight of the medicinal materials is added, and the mixture is heated and refluxed twice, each extraction lasting 1.5 to 2 hours; the relative density of the extract is 1.10 to 1.15; and the dry powder of the mixed extract passes through an 80-mesh sieve.

7. The method for preparing a Xianglian preparation according to claim 5, characterized in that, The JAK inhibitor is first passed through a 100-mesh sieve and then mixed with the filler.

8. The method for preparing a Xianglian preparation according to claim 5, characterized in that, In the third step, the mixture is placed in a wet mixer and mixed for 10 to 15 minutes; the partial disintegrant is half of the total formulation; and the concentration of the adhesive solution is 5% to 10%.

9. The method for preparing a Xianglian preparation according to claim 5, characterized in that, In the fourth step, the soft material is made into wet granules through a 20 to 24 mesh sieve, and the drying temperature is 50 to 60 degrees Celsius until the moisture content is less than 3%. In the fifth step, the mixing time is 15 to 20 minutes.

10. The use of a xianglian preparation as described in any one of claims 1 to 4 in the preparation of a medicament for treating inflammatory bowel disease.

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