Traditional Chinese medicine compound composition as well as preparation method and application thereof

Abstract

The invention provides a traditional Chinese medicine compound which is prepared from the following raw material medicines: rhizoma smilacis glabrae, rhizoma dioscoreae septemlobae, semen coicis, rhizoma curcumae longae, herba taxilli, radix salviae miltiorrhizae, cortex phellodendri, rhizoma acori graminei, plantain herb, rhizoma atractylodis macrocephalae, wine-treated rhubarb, radix angelicae pubescentis, bran-fried rhizoma atractylodis and vinegar-treated rhizoma corydalis, and also provides application of the traditional Chinese medicine compound composition in medicines for treating gout and gouty nephropathy. In addition, the invention also provides a preparation method of the sustained-release granule of the compound composition, which comprises the following steps: firstly, preparing the raw medicinal materials into a traditional Chinese medicine fluid extract, then adding the filler into the traditional Chinese medicine fluid extract, stirring to form a soft material, passing the soft material through a swinging granulator, and drying to obtain a medicine-containing pill core; and putting the pill cores into a fluidized bed, laterally spraying the slow-release coating solution, drying, and sieving to prepare the slow-release granules. The prepared traditional Chinese medicine formula sustained-release granules can release 90% or above within 8-10 hours, have a good constant-speed sustained-release characteristic, can meet the clinical requirement of 1-2 times of administration every day, and have good clinical application prospects and market value.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, specifically to a traditional Chinese medicine compound composition with sustained-release properties for treating gout and gouty nephropathy, its preparation method, and its application. Background Technology

[0002] Gout and hyperuricemia are common metabolic diseases caused by purine metabolism disorders and / or reduced uric acid excretion. With the improvement of people's living standards and changes in dietary structure, their incidence is showing an increasing trend year by year.

[0003] Gout falls under the categories of "Bi syndrome," "Li Jie," "Bai Hu Li Jie," and "Gout" in Traditional Chinese Medicine, characterized by redness, swelling, heat, pain, and limited range of motion in the joints. Records of this disease are ancient, such as in the *Suwen* (Plain Questions) chapter on Bi syndrome, which states, "When wind, cold, and dampness combine, they cause Bi syndrome." The *Jinkui Yaolue* (Essential Prescriptions of the Golden Chamber) includes a chapter on "Stroke and Li Jie Diseases: Pulse, Symptoms, and Treatment," describing symptoms such as "pain in all joints, emaciation, and swelling of the feet as if they were about to fall off," which are quite similar to acute gout attacks. The Yuan Dynasty physician Zhu Danxi first proposed the name "gout," stating in his *Danxi Xinfa* (Danxi's Heart Method): "Gout is characterized by pain that moves through all the joints of the limbs; medical texts refer to it as Bai Hu Li Jie syndrome."

[0004] Regarding the etiology and pathogenesis of gout, ancient physicians generally believed that it was mainly caused by external pathogenic factors such as wind, cold, dampness, and heat, while internal causes were closely related to spleen and kidney deficiency, internal accumulation of phlegm and dampness, and blood stasis. Improper diet (such as excessive consumption of rich and fatty foods and alcoholism) is often a significant contributing factor, leading to dysfunction of the spleen and stomach, the generation of internal damp-heat and turbid toxins, which flow into the meridians and joints, causing pain due to obstruction. Prolonged illness can lead to the accumulation of dampness, turbidity, and blood stasis, which can damage tendons and bones, and even attack internal organs, causing complications such as "guan ge" (e.g., gouty nephropathy).

[0005] Although traditional Chinese medicine has not formed a completely unified system of syndrome differentiation for gout, a review of historical literature shows that its syndrome differentiation mainly revolves around core pathological factors such as "dampness, heat, phlegm, blood stasis, and deficiency." In terms of treatment, it focuses on treating the spleen, kidney, and liver, and the common methods are clearing heat and dampness, resolving phlegm and eliminating turbidity, promoting blood circulation and unblocking collaterals, and strengthening the spleen and tonifying the kidney.

[0006] Currently, commonly used chemical drugs in clinical practice, such as allopurinol, febuxostat (to lower uric acid), and colchicine (anti-inflammatory and analgesic), have certain therapeutic effects, but they also have significant side effects such as liver and kidney damage, gastrointestinal reactions, and allergies. Furthermore, long-term use can easily lead to drug resistance.

[0007] Traditional Chinese medicine (TCM) has unique advantages in treating gout, including multi-target therapy, holistic regulation, and fewer side effects. While some existing TCM compound formulas are used for gout treatment, limitations remain. For example, patent CN101590168B discloses a TCM prescription composition for treating gout, but the components are relatively potent and prone to toxic side effects. Furthermore, the addition of honey or lactose during the preparation of pills and capsules may affect blood glucose levels in gout patients, impacting efficacy. In addition, common TCM preparations (such as decoctions and granules) are administered multiple times daily, leading to large fluctuations in blood drug concentrations and a "peak-trough phenomenon," which is detrimental to the sustained and stable control of uric acid levels. Different components have different onset times and metabolic rates; using common dosage forms results in premature metabolism of some components, hindering the formation of sustained synergistic effects. Volatile components in the preparation (such as turmeric volatile oil and acorus tatarinowii volatile oil) are easily lost during preparation and storage, affecting efficacy.

[0008] Preparing traditional Chinese medicine compositions into sustained-release granules can maintain stable blood drug concentrations, achieving sustained uric acid reduction, anti-inflammation, and long-term conditioning effects. This aligns better with the treatment logic of gout as a chronic disease requiring long-term management and addressing both the symptoms and root cause, thereby improving patient compliance and medication safety.

[0009] Therefore, developing a traditional Chinese medicine compound preparation with sustained-release properties, effective retention of volatile components, uniform coating, and uric acid-lowering effects has significant clinical and market value. Summary of the Invention

[0010] In view of this, the present invention provides a traditional Chinese medicine compound composition for treating gout and gouty nephropathy. This compound composition is a traditional Chinese medicine formula with significant clinical efficacy in treating gout and gouty nephropathy, derived from the inventor's many years of clinical experience. This formula is modified from classic formulas such as Bi Xie Fen Qing Yin, Du Huo Ji Sheng Tang, Sheng Jiang San, and Si Miao San, and is an effective formula for treating gout attacks with damp-heat accumulation. The formula uses Smilax glabra as the chief ingredient to eliminate dampness and detoxify, Smilax glabra to promote diuresis and remove turbidity, and Plantago asiatica to clear heat, promote diuresis, cool the blood, and relieve strangury. The two herbs together clear the kidneys and eliminate dampness. Curcuma longa breaks up blood stasis, promotes qi circulation, unblocks meridians, and relieves pain, while rhubarb clears heat, removes blood stasis, eliminates dampness, and detoxifies. The two herbs together reduce turbid yin. The above four herbs are the assistant herbs. The formula is supplemented with Sangjisheng (Taxillus chinensis) to dispel wind and dampness, and tonify the liver and kidneys; Baizhu (Atractylodes macrocephala) to strengthen the spleen, dry dampness, and promote diuresis; Cangzhu (Atractylodes lancea) to dry dampness and strengthen the spleen; Yiyiren (Coix lacryma-jobi) to strengthen the spleen, drain dampness, detoxify, and relieve numbness; Huangbai (Phellodendron chinense) to clear heat, dry dampness, purge fire, and detoxify; Shichangpu (Acorus tatarinowii) to resolve dampness and improve appetite; Danshen (Salvia miltiorrhiza) to invigorate blood, remove blood stasis, regulate menstruation, and relieve pain; and Yanhusuo (Corydalis yanhusuo) to invigorate blood, promote qi circulation, and relieve pain. The formula embodies the principles of strengthening the spleen, eliminating dampness, invigorating blood, and relieving pain. The combined effects of these herbs are to clear heat, eliminate dampness, reduce turbidity, and detoxify.

[0011] Furthermore, to maintain stable blood drug concentrations during treatment, achieve sustained uric acid-lowering, anti-inflammatory, and long-term conditioning effects, and improve patient compliance, the inventors optimized the formulation process of this traditional Chinese medicine formula, preparing it into granules with sustained-release function. Simultaneously, a specific process was used to retain volatile active ingredients and improve formulation stability. The specific scheme is as follows:

[0012] On one hand, the present invention provides a traditional Chinese medicine compound composition, characterized in that the composition is composed of the following raw materials: Smilax glabra, Dioscorea hypoglauca, Coix lacryma-jobi, Curcuma longa, Taxillus chinensis, Salvia miltiorrhiza, Phellodendron chinense, Acorus tatarinowii, Plantago asiatica, Atractylodes macrocephala, Rheum palmatum (processed with wine), Angelica pubescens, Atractylodes lancea (stir-fried with wheat bran), and Corydalis yanhusuo (processed with vinegar).

[0013] Furthermore, the composition comprises the following raw materials in parts by weight: 4-8 parts of Smilax glabra, 1-2 parts of Dioscorea hypoglauca, 2-4 parts of Coix lacryma-jobi, 0.5-1.5 parts of Curcuma longa, 1-2 parts of Taxillus chinensis, 1-2 parts of Salvia miltiorrhiza, 0.5-1.5 parts of Phellodendron chinense, 0.5-1.5 parts of Acorus tatarinowii, 2-4 parts of Plantago asiatica, 0.5-1.5 parts of Atractylodes macrocephala, 0.5-1 part of Rheum palmatum (processed with wine), 0.5-1.5 parts of Angelica pubescens, 0.5-1.5 parts of Atractylodes lancea (processed with wheat bran), and 0.5-0.5 parts of Corydalis yanhusuo (processed with vinegar).

[0014] Preferably, the composition comprises the following medicinal materials in parts by weight: 5 parts Smilax glabra, 1.5 parts Dioscorea hypoglauca, 2.5 parts Coix lacryma-jobi, 1.2 parts Curcuma longa, 1 part Taxillus chinensis, 1.2 parts Salvia miltiorrhiza, 0.7 parts Phellodendron chinense, 1.2 parts Acorus tatarinowii, 2.5 parts Plantago asiatica, 1 part Atractylodes macrocephala, 0.7 parts Rheum palmatum (processed with wine), 1.2 parts Angelica pubescens, 0.8 parts Atractylodes lancea (processed with wheat bran), and 1 part Corydalis yanhusuo (processed with vinegar).

[0015] On the other hand, the present invention also provides a method for preparing the above-mentioned traditional Chinese medicine compound composition, characterized by comprising the following steps:

[0016] S1: Prepare the above-mentioned raw medicinal materials into a traditional Chinese medicine fluid extract for later use;

[0017] S2: Add filler to the fluid extract of traditional Chinese medicine obtained in step S1 and stir until a soft material is formed. Pass the soft material through a 35-40 mesh sieve in a gyratory granulator and dry it at 50-60°C to obtain a drug-containing pill core.

[0018] S3: Prepare a sustained-release coating solution, spray the prepared sustained-release coating solution onto the surface of the drug-containing pellet core obtained in step S2, perform side spray coating in a fluidized bed, dry, sieve, and prepare sustained-release granules.

[0019] Furthermore, step S1 specifically includes the following process:

[0020] Add Phellodendron bark, Plantago asiatica, and Salvia miltiorrhiza to 8-10 times their total weight in purified water, soak for 30-60 minutes, bring to a boil over high heat, then simmer over low heat for 20-60 minutes. Filter out the liquid, remove the residue, and repeat the above decoction steps to obtain the filtrate. Combine the two filtrates and concentrate under reduced pressure to a relative density of 1.1-1.2 to obtain the water extract.

[0021] Add Smilax glabra, Dioscorea hypoglauca, Coix lacryma-jobi, Curcuma longa, Taxillus chinensis, Acorus tatarinowii, Atractylodes macrocephala, Rheum palmatum (processed with wine), Angelica pubescens, Atractylodes lancea (stir-fried with wheat bran), and Corydalis yanhusuo (processed with vinegar) to 8-10 times the total weight of the medicinal materials in ethanol, heat and reflux for 2-3 hours, filter to obtain filtrate 1 and residue 1; add 8-10 times the amount of ethanol to residue 1, heat and reflux for 2-3 hours, filter to obtain filtrate 2, mix filtrate 1 and filtrate 2, concentrate under reduced pressure to a relative density of 0.90-1.05 to obtain the alcohol extract.

[0022] The aqueous extract and the alcohol extract were mixed to obtain a fluid extract of traditional Chinese medicine.

[0023] Further, in step S2, the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, soluble starch, and hydroxypropyl β-cyclodextrin.

[0024] Preferably, the filler is hydroxypropyl β-cyclodextrin.

[0025] Furthermore, the weight ratio of the filler to the fluid extract prepared in step S1 is 1:0.5 to 1.2.

[0026] Furthermore, in step S3, the prepared sustained-release coating solution includes the film-forming material cellulose acetate, the plasticizer dibutyl phthalate, the pore-forming agent hydroxypropyl methylcellulose, and the solvent 75% ethanol.

[0027] Preferably, the components in the above-mentioned sustained-release coating solution are in the following proportions by mass: cellulose acetate 5-8%, dibutyl phthalate 1-2%, hydroxypropyl methylcellulose 2-3%, and 75% ethanol 87-92%.

[0028] Furthermore, in step S3, the atomization pressure is 2.4-2.6 bar, and the material temperature is 38-40℃.

[0029] In another aspect, the present invention provides the application of the above-mentioned traditional Chinese medicine compound composition in the preparation of a drug for treating gout or gouty nephropathy.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] This invention provides an innovative traditional Chinese medicine compound composition and its sustained-release granule formulation. Animal experiments and rat kidney pathological sections demonstrate that this traditional Chinese medicine compound composition and its sustained-release granules have good uric acid-lowering and protective effects against gouty nephropathy. Through the optimized spray coating process technology of this invention, a material yield of 93.2% is achieved, effectively ensuring the retention rate of volatile components and improving the stability of the formulation, ensuring the continued efficacy of the active pharmaceutical ingredients during the sustained-release period. Furthermore, the sustained-release coating technology developed in this invention allows for the release of over 90% of the granules within 8-10 hours with a 30% coating weight gain, exhibiting excellent uniform sustained-release characteristics. This meets the clinical needs of 1-2 daily dosing, demonstrating promising clinical application prospects and market value. Attached Figure Description

[0032] Figure 1 The drug concentration release curves for Examples 6 and 7 and Comparative Examples 2 and 3 are shown.

[0033] Figure 2 These are pathological slide comparison images of gouty nephropathy before and after treatment. Detailed Implementation

[0034] The present invention will be further described in detail below with reference to embodiments, so that those skilled in the art can more clearly understand the present invention.

[0035] The following embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. All other embodiments obtained by those skilled in the art based on specific embodiments of the invention without inventive effort are within the protection scope of the invention.

[0036] Example:

[0037] (I) Preparation of fluid extracts of traditional Chinese medicine

[0038] Example 1:

[0039] Weigh out the following medicinal materials according to the preferred ratio: 50g of Smilax glabra, 15g of Dioscorea hypoglauca, 25g of Coix lacryma-jobi, 12g of Curcuma longa, 10g of Taxillus chinensis, 12g of Salvia miltiorrhiza, 7g of Phellodendron chinense, 12g of Acorus tatarinowii, 25g of Plantago asiatica, 10g of Atractylodes macrocephala, 7g of Rheum palmatum (processed with wine), 12g of Angelica pubescens, 8g of Atractylodes lancea (stir-fried with wheat bran), and 10g of Corydalis yanhusuo (processed with vinegar).

[0040] Extraction process:

[0041] Water extraction: Phellodendron bark, plantain, and salvia miltiorrhiza were soaked in 9 times the amount of purified water for 40 minutes, boiled and simmered for 40 minutes, and then filtered. The residue was then boiled in 9 times the amount of water for 40 minutes, filtered, and the two filtrates were combined and concentrated under reduced pressure at 60°C to a relative density of 1.15.

[0042] Alcohol extraction: Add 9 times the amount of 70% ethanol to the remaining medicinal materials, heat and reflux for 2.5 hours, and filter; add 9 times the amount of 70% ethanol to the residue and reflux for 2.5 hours, filter, combine the two filtrates, and concentrate under reduced pressure at 60℃ to a relative density of 0.98;

[0043] The aqueous extract and the alcohol extract were mixed at room temperature to obtain a fluid extract of traditional Chinese medicine.

[0044] Example 2:

[0045] Weigh out the following medicinal materials according to the preferred ratio: 40g of Smilax glabra, 10g of Dioscorea hypoglauca, 20g of Coix lacryma-jobi, 5g of Curcuma longa, 10g of Taxillus chinensis, 10g of Salvia miltiorrhiza, 5g of Phellodendron chinense, 5g of Acorus tatarinowii, 20g of Plantago asiatica, 5g of Atractylodes macrocephala, 5g of Rheum palmatum (processed with wine), 5g of Angelica pubescens, 5g of Atractylodes lancea (stir-fried with wheat bran), and 5g of Corydalis yanhusuo (processed with vinegar).

[0046] Extraction process:

[0047] Water extraction: Soak Phellodendron bark, Plantago asiatica, and Salvia miltiorrhiza in 8 times the amount of purified water for 30 minutes, boil and simmer for 20 minutes, then filter; add 8 times the amount of water to the residue and simmer for 20 minutes, then filter, combine the two filtrates, and concentrate under reduced pressure at 60℃ to a relative density of 1.10.

[0048] Alcohol extraction: Add 8 times the amount of 70% ethanol to the remaining medicinal materials, heat and reflux for 2 hours, and filter; add 8 times the amount of 70% ethanol to the residue and reflux for 2 hours, filter, combine the two filtrates, and concentrate under reduced pressure at 60℃ to a relative density of 0.90.

[0049] The aqueous extract and the alcohol extract were mixed at room temperature to obtain a fluid extract of traditional Chinese medicine.

[0050] Example 3:

[0051] Weigh out the following medicinal materials according to the preferred ratio: 80g of Smilax glabra, 20g of Dioscorea hypoglauca, 40g of Coix lacryma-jobi, 15g of Curcuma longa, 20g of Taxillus chinensis, 20g of Salvia miltiorrhiza, 15g of Phellodendron chinense, 15g of Acorus tatarinowii, 40g of Plantago asiatica, 15g of Atractylodes macrocephala, 10g of Rheum palmatum (processed with wine), 15g of Angelica pubescens, 15g of Atractylodes lancea (stir-fried with wheat bran), and 10g of Corydalis yanhusuo (processed with vinegar).

[0052] Extraction process:

[0053] Water extraction: Soak Phellodendron bark, Plantago asiatica, and Salvia miltiorrhiza in 10 times the amount of purified water for 60 minutes, boil and simmer for 60 minutes, then filter; add 10 times the amount of water to the residue and simmer for 60 minutes, then filter again, combine the two filtrates, and concentrate under reduced pressure at 60℃ to a relative density of 1.20.

[0054] Alcohol extraction: Add 10 times the amount of 70% ethanol to the remaining medicinal materials, heat and reflux for 3 hours, and filter; add 10 times the amount of 70% ethanol to the residue and reflux for 3 hours, filter, combine the two filtrates, and concentrate under reduced pressure at 60℃ to a relative density of 1.05.

[0055] The aqueous extract and the alcohol extract were mixed at room temperature to obtain a fluid extract of traditional Chinese medicine.

[0056] (II) Screening of fillers

[0057] Example 4

[0058] To screen fillers that can achieve a good retention rate of volatile components in this compound composition, the following experiment was designed.

[0059] Experimental Methods: Drug-containing pellet cores were prepared according to the method in Example 1, using microcrystalline cellulose, pregelatinized starch, soluble starch, and hydroxypropyl β-cyclodextrin as fillers, respectively. The retention rates of volatile components (represented by curcumin and α-asarone) were determined. The results are shown in Table 1.

[0060] Table 1. Effect of different fillers on the retention rate of volatile components (n=3)

[0061]

[0062] As shown in Table 1, hydroxypropyl β-cyclodextrin as a filler can significantly improve the retention rate of volatile components (P<0.01), which is superior to other commonly used fillers. Hydroxypropyl β-cyclodextrin was used as a filler in the subsequent coating process.

[0063] (III) Preparation of sustained-release granules

[0064] Example 5

[0065] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 1 at a weight ratio of 1:0.8. The mixture was stirred to form a soft mass, granulated by passing it through a 40-mesh sieve, and dried at 55°C to obtain a drug-containing pellet core.

[0066] Preparation of sustained-release coating solution: Dissolve 6% cellulose acetate, 1.5% dibutyl phthalate and 2.5% hydroxypropyl methylcellulose in 90% 75% ethanol. The mass of the sustained-release coating solution is 2.5 times the mass of the drug-containing particles.

[0067] Coating: Weigh the drug-containing pellet cores and transfer them to a coating pan. Coating is performed using fluidized bed side-spray technology. The atomization pressure is 2.5 bar, the material temperature is 39℃, the inlet air temperature is 55℃, the turntable speed is 1000 rpm, and the inlet air volume is 45 m³ / min. 3 The spraying rate was 5 ml / min, and the coating weight gain was measured to be 25% after the spraying of the sustained-release coating solution ended.

[0068] Example 6

[0069] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 2 at a weight ratio of 1:0.5. The mixture was stirred to form a soft mass, granulated by passing it through a 35-mesh sieve, and dried at 50°C to obtain a drug-containing pellet core.

[0070] Preparation of sustained-release coating solution: Dissolve 5% cellulose acetate, 1% dibutyl phthalate and 2% hydroxypropyl methylcellulose in 92% 75% ethanol. The mass of the sustained-release coating solution is 2.5 times the mass of the drug-containing particles.

[0071] Coating: The mass of the drug-containing pellet core was weighed and transferred to a coating pan. Coating was performed using fluidized bed side spraying technology, with other conditions the same as in Example 5, controlling the atomization pressure at 2.4 bar and the material temperature at 38°C. The measured weight gain after coating was 20%.

[0072] Example 7

[0073] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 3 at a weight ratio of 1:1.2. The mixture was stirred to form a soft mass, granulated by passing it through a 40-mesh sieve, and dried at 60°C to obtain a drug-containing pellet core.

[0074] Preparation of sustained-release coating solution: Dissolve 8% cellulose acetate, 2% dibutyl phthalate and 3% hydroxypropyl methylcellulose in 87% 75% ethanol. The mass of the sustained-release coating solution is 2.3 times the mass of the drug-containing particles.

[0075] Coating: Weigh the drug-containing pellet core and transfer it to a coating pan. Coating is performed using fluidized bed side spraying technology. Other conditions are the same as in Example 5, with the atomization pressure controlled at 2.6 bar, the material temperature at 40°C, and the coating weight gain at 30%.

[0076] Comparative example:

[0077] (I) Preparation of decoction of traditional Chinese medicine compound composition

[0078] Comparative Example 1:

[0079] Weigh out the following medicinal materials according to the preferred ratio: 50g of Smilax glabra, 15g of Dioscorea hypoglauca, 25g of Coix lacryma-jobi, 12g of Curcuma longa, 10g of Taxillus chinensis, 12g of Salvia miltiorrhiza, 7g of Phellodendron chinense, 12g of Acorus tatarinowii, 25g of Plantago asiatica, 10g of Atractylodes macrocephala, 7g of Rheum palmatum (processed with wine), 12g of Angelica pubescens, 8g of Atractylodes lancea (stir-fried with wheat bran), and 10g of Corydalis yanhusuo (processed with vinegar).

[0080] Water decoction: Weigh the above-mentioned medicinal materials and put them into a clay pot. Add water until the liquid level is 2cm above the medicinal materials. Soak for 30 minutes. Bring to a boil over high heat, then simmer over low heat for 30 minutes. Filter while hot. Add 6 times the amount of water to the dregs and heat under reflux for 30 minutes. Combine the two filtrates to obtain the water decoction.

[0081] (II) Investigation of the conditions for weight gain from coating

[0082] Comparative Example 2

[0083] The mass ratio of film-forming material and pore-forming agent was changed, while other conditions and parameters remained the same as in Example 6, as follows:

[0084] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 2 at a weight ratio of 1:0.5. The mixture was stirred to form a soft mass, granulated by passing it through a 35-mesh sieve, and dried at 50°C to obtain a drug-containing pellet core.

[0085] Preparation of sustained-release coating solution: Dissolve 4% cellulose acetate, 1% dibutyl phthalate and 1% hydroxypropyl methylcellulose in 94% 75% ethanol. The mass of the sustained-release coating solution is 1.67 times the mass of the drug-containing particles.

[0086] Coating process: The weight of the drug-containing pellet core was weighed and transferred to a coating pan. Coating was performed using fluidized bed side spraying technology, with other conditions the same as in Example 5, controlling the atomization pressure at 2.4 bar and the material temperature at 38°C. The measured weight gain after coating was 10%.

[0087] Comparative Example 3:

[0088] The mass ratio of film-forming material and pore-forming agent was changed, while other conditions and parameters remained the same as in Example 7, as follows:

[0089] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 3 at a weight ratio of 1:1.2. The mixture was stirred to form a soft mass, which was then granulated by passing it through a 40-mesh sieve and dried at 60°C to obtain a drug-containing pellet core.

[0090] Preparation of sustained-release coating solution: 9% cellulose acetate, 2% dibutyl phthalate and 4% hydroxypropyl methylcellulose by mass were dissolved in 85% 75% ethanol. The mass of the sustained-release coating solution was 2.67 times the mass of the drug-containing particles.

[0091] Coating process: The weight of the drug-containing pill core was weighed and transferred to a coating pan. Coating was carried out using fluidized bed side spraying technology, with the atomization pressure controlled at 2.6 bar and the material temperature at 40°C. Other conditions were the same as in Example 5. The weight gain of the coating was measured to be 40%.

[0092] (III) Investigation of atomization pressure conditions

[0093] Comparative Example 4:

[0094] The atomization pressure parameter was changed, while other conditions and parameters remained the same as in Example 6, as detailed below:

[0095] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 2 at a weight ratio of 1:0.5. The mixture was stirred to form a soft mass, which was then granulated by passing it through a 35-mesh sieve and dried at 50°C to obtain a drug-containing pellet core.

[0096] Preparation of sustained-release coating solution: Dissolve 5% cellulose acetate, 1% dibutyl phthalate and 2% hydroxypropyl methylcellulose in 92% 75% ethanol. The mass of the sustained-release coating solution is 2.5 times the mass of the drug-containing particles.

[0097] Coating process: The weight of the drug-containing pellet core was weighed and transferred to a coating pan. Coating was performed using fluidized bed side-spray technology, with the atomization pressure controlled at 2.2 bar. Other conditions were the same as in Example 6. The measured weight gain after coating was 20%.

[0098] Comparative Example 5:

[0099] The atomization pressure parameter was changed, while other conditions and parameters remained the same as in Example 7, as detailed below:

[0100] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 3 at a weight ratio of 1:1.2. The mixture was stirred to form a soft mass, granulated by passing it through a 40-mesh sieve, and dried at 60°C to obtain a drug-containing pellet core.

[0101] Preparation of sustained-release coating solution: Dissolve 8% cellulose acetate, 2% dibutyl phthalate and 3% hydroxypropyl methylcellulose in 87% 75% ethanol. The mass of the sustained-release coating solution is 2.3 times the mass of the drug-containing particles.

[0102] Coating process: Weigh the drug-containing pill core and transfer it to a coating pan. Coating is carried out using fluidized bed side spraying technology. Other conditions are the same as in Example 7. The atomization pressure is controlled at 2.8 bar, and the weight gain of the coating is measured to be 30%.

[0103] (iv) Investigation of material temperature conditions

[0104] Comparative Example 6:

[0105] The material temperature parameter changes, while other conditions and parameters remain the same as in Example 6, as detailed below:

[0106] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 2 at a weight ratio of 1:0.5. The mixture was stirred to form a soft mass, which was then granulated by passing it through a 35-mesh sieve and dried at 50°C to obtain a drug-containing pellet core.

[0107] Preparation of sustained-release coating solution: Dissolve 5% cellulose acetate, 1% dibutyl phthalate and 2% hydroxypropyl methylcellulose in 92% 75% ethanol. The mass of the sustained-release coating solution is 2.5 times the mass of the drug-containing particles.

[0108] Coating process: The weight of the drug-containing pellet core was weighed and transferred to a coating pan. Coating was performed using fluidized bed side-spray technology, with other conditions the same as in Example 6, and the material temperature controlled at 36°C. The measured weight gain after coating was 20%.

[0109] Comparative Example 7:

[0110] The material temperature parameter changes, while other conditions and parameters remain the same as in Example 7, as detailed below:

[0111] Granulation: Hydroxypropyl β-cyclodextrin was added to the fluid extract prepared in Example 3 at a weight ratio of 1:1.2. The mixture was stirred to form a soft mass, granulated by passing it through a 40-mesh sieve, and dried at 60°C to obtain a drug-containing pellet core.

[0112] Preparation of sustained-release coating solution: Dissolve 8% cellulose acetate, 2% dibutyl phthalate and 3% hydroxypropyl methylcellulose in 87% 75% ethanol. The mass of the sustained-release coating solution is 2.3 times the mass of the drug-containing particles.

[0113] Coating: Weigh the drug-containing pill core and transfer it to a coating pan. Coating is performed using fluidized bed side spraying technology. Other conditions are the same as in Example 7, with the material temperature controlled at 42°C. The coating weight gain is 30%.

[0114] Experimental Example 1: Release Rate Comparison Test

[0115] Experimental Methods: Sustained-release coated granules obtained in Examples 6 and 7, and Comparative Examples 2 and 5 were used to investigate the effect of coating weight gain on the sustained-release effect. The release rate was determined according to Method 1 (basket method) of General Chapter 0931, Part IV of the 2020 edition of the Chinese Pharmacopoeia, using 900 ml of pH 6.8 phosphate buffer as the release medium, a rotation speed of 100 r / min, and a temperature of 37 ± 0.5℃. Samples were taken at 0.5, 1, 2, 4, 6, 8, 10, and 12 h for measurement, and the cumulative release rate was calculated. Specific release results are shown in Table 2, and the release rate curves are shown in Figure 2. Figure 1 As shown.

[0116] Table 2 Comparison of weight gain and release rates of different coatings (%, n=6)

[0117]

[0118] As shown in Table 2, under the process conditions of Examples 6 and 7 and Comparative Examples 2 and 5, the coating weight of the prepared sustained-release granules increased by 20%, 30%, 10%, and 40%, respectively. The granules of Comparative Example 2 released over 90% within 4 hours, exhibiting a significant burst release phenomenon and failing to meet the requirements for sustained release. The granules of Comparative Example 3 released too slowly, with less than 85% released after 12 hours, making it difficult to guarantee the full-day efficacy. Granules with a coating weight increase of 20%-30% exhibited ideal sustained-release characteristics. The granules of Example 6 released over 90% within 6 hours, suitable for medium-speed sustained release; the granules of Example 7 released over 90% within 8-10 hours, exhibiting good uniform sustained-release characteristics, matching the clinical needs of 1-2 daily dosing.

[0119] Experimental Example 2: Physical Properties and Yield of Sustained-Release Granules

[0120] Experimental Methods: Examples 6-7 and Comparative Examples 4 and 5 were compared under different atomization pressures (2.2 bar, 2.4 bar, 2.6 bar, and 2.8 bar) to assess the coating effects. The results are shown in Table 3.

[0121] Table 3 Comparison of side-spray coating technologies with different atomization pressures (n=3)

[0122]

[0123] As shown in Table 3, under the conditions of Comparative Example 4, when the atomization pressure is too low (2.2 bar), atomization is insufficient, droplets are large, which easily leads to agglomeration and uneven coating (large particle size distribution D90 / D10 ratio), and the material loss rate is high, resulting in low yield. Under the conditions of Comparative Example 5, when the atomization pressure is too high (2.8 bar), the atomization is too fine, a large amount of fine powder is generated, which also increases material loss and reduces yield, and may affect the continuity of the coating film due to excessively rapid spray drying. The atomization pressure range of 2.4-2.6 bar achieves the best balance: the lowest agglomeration rate (<2.5%), less fine powder generation (<10g), the most concentrated particle size distribution (D90 / D10 <1.75), the lowest material loss rate (<5%), and the highest yield (>92%).

[0124] Experimental Example 3: Stability Study of Sustained-Release Granules

[0125] Experimental methods: The sustained-release granules prepared under the conditions of Examples 6 and 7 and Comparative Examples 6 and 7 were placed under accelerated conditions (40℃±2℃, RH75%±5%) for 0, 1, 2, 3 and 6 months. The retention rate of volatile components (curcumin and α-asarone) was determined according to the stability guidelines for raw material drug pre-preparations in Part IV of the 2025 Pharmacopoeia. The results are shown in Table 4.

[0126] Table 4. Changes in the retention rate of volatile components under accelerated conditions (%, n=3)

[0127]

[0128] As shown in Table 4, the granules prepared in Examples 6 (material temperature 38℃) and 7 (material temperature 40℃) maintained a volatile component retention rate of over 90% after 6 months of accelerated processing, significantly better than the granules prepared in Comparative Examples 6 (material temperature 36℃) and 7 (material temperature 42℃) (P < 0.01). Too low a material temperature may result in incomplete fusion and densification of the coating film, while too high a material temperature may lead to localized defects in the coating film or loss of active ingredients.

[0129] Experimental Example 4: Animal Experimental Study

[0130] 4.1 Experimental Materials: 8-week-old healthy SPF-grade SD male rats were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., with the license number: SCXK (Beijing) 2021-0006. The experimental rats were uniformly raised in the Experimental Animal Center of the Institute of Basic Theory of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences. Since the start of feeding, the wood chip bedding in the cage was changed every other day. The environmental temperature in the experimental animal center was 20°C - 25°C, with lighting: 12 h daytime / 12 h nighttime, and free access to drinking water.

[0131] 4.2 Experimental Methods:

[0132] Sixty healthy SD rats, male, weighing 200±20 g, were randomly divided into 6 groups (n = 10):

[0133] Normal control group: fed with normal feed; Model group: hyperuricemia model (gout); Positive drug group: Model + allopurinol 10 mg / kg / d; Decoction group (Comparative Example 1): Model + decoction 2 ml (administered by gavage 3 times a day); Sustained-release low-dose group (Example 6): Model + sustained-release granules 1.0 g / kg / d (once a day); Sustained-release high-dose group (Example 7): Model + sustained-release granules 1.5 g / kg / d (once a day).

[0134] 4.3 Modeling Method: Potassium oxonate (500 mg / kg) was intraperitoneally injected for 7 consecutive days. Fourteen days after administration, the levels of serum uric acid (SUA), serum creatinine (Scr), and blood urea nitrogen (BUN) were detected, and renal tissues were taken for pathological examination.

[0135] 4.4 Renal Pathological Sections

[0136] Figure 2 are the staining diagrams of renal pathological sections of different experimental groups. According to Figure 2 it can be seen that the surface capsule of the renal tissue of rats in the normal control group was composed of dense connective tissue with uniform thickness; the glomeruli in the cortex were evenly distributed, and the number of cells and matrix in the glomeruli were uniform; a small amount of renal tubule dilation (orange arrow) was visible, the lumen volume increased, the shape was irregular, and the epithelium was flattened; no obvious necrosis or inflammatory cell infiltration and other abnormalities were observed.

[0137] The kidney tissue surface of the model group rats was composed of dense connective tissue of uniform thickness; glomeruli were evenly distributed in the cortex, and the number of cells and matrix in the glomeruli were uniform; many renal tubules and collecting ducts were dilated (orange arrows), with increased lumen volume, irregular shape, and flattened epithelium; a small number of renal tubules were atrophied (yellow arrows), with reduced or absent lumen volume; a large number of renal tubular epithelial cells were edematous (blue arrows), with swollen cells and loose, lightly stained cytoplasm; a small number of lymphocytes were infiltrated in the interstitium (cyan arrows).

[0138] The surface membrane of the rat kidney tissue in the decoction group was composed of dense connective tissue of uniform thickness; the glomeruli were evenly distributed in the cortex, and the number of cells and matrix in the glomeruli were uniform; a small number of renal tubules were dilated (orange arrows), with increased lumen volume, irregular shape, and flattened epithelium; a small number of lymphocytes were infiltrated around the blood vessels (cyan arrows).

[0139] In the sustained-release low-dose group, the surface membrane of the rat kidney tissue was composed of dense connective tissue of uniform thickness; the glomeruli were evenly distributed in the cortex, and the number of cells and matrix in the glomeruli were uniform; a small number of renal tubules were dilated (orange arrows), with increased lumen volume, irregular shape, and flattened epithelium; a small number of renal tubules were atrophied (yellow arrows), with reduced or absent lumen volume; a small number of renal tubular epithelial cells were edematous (blue arrows), with swollen cells and loose, lightly stained cytoplasm; a small number of lymphocytes infiltrated the interstitium (cyan arrows).

[0140] The surface membrane of the kidney tissue of rats in the sustained-release high-dose group was composed of dense connective tissue of uniform thickness; the glomeruli were evenly distributed in the cortex, and the number of cells and matrix in the glomeruli were uniform; a small number of renal tubular dilatations (orange arrows) were observed, with increased lumen volume, irregular shape, and flattened epithelium; no obvious necrosis or inflammatory cell infiltration or other abnormalities were observed.

[0141] 4.5 The effects of different experimental groups on serum parameters in rats are shown in Table 5:

[0142] Table 5 Comparison of serum indices in rats of different groups (x±s, n=10)

[0143]

[0144] As shown in Table 5, the sustained-release granules of this invention have comparable uric acid-lowering effects to the decoction group, but require less frequent administration. The reduction levels of SUA, Scr, and BUN in rat serum were comparable between the decoction group, the sustained-release granules group, and the positive control group, indicating comparable uric acid-lowering effects. Furthermore, the high-dose sustained-release group showed superior uric acid-lowering effects compared to the positive control group and the decoction group (P<0.05). Therefore, the sustained-release granules prepared according to this invention can significantly improve renal function indicators and renal pathological damage, and have a protective effect against gouty nephropathy.

Claims

1. A traditional Chinese medicine compound composition, characterized in that, The traditional Chinese medicine compound composition consists of the following raw materials: Smilax glabra, Dioscorea hypoglauca, Coix lacryma-jobi, Curcuma longa, Taxillus chinensis, Salvia miltiorrhiza, Phellodendron chinense, Acorus tatarinowii, Plantago asiatica, Atractylodes macrocephala, Rheum palmatum (processed with wine), Angelica pubescens, Atractylodes lancea (processed with wheat bran), and Corydalis yanhusuo (processed with vinegar).

2. The traditional Chinese medicine compound composition according to claim 1, characterized in that, The traditional Chinese medicine compound composition consists of the following raw materials in parts by weight: Smilax glabra 4-8 parts, Dioscorea hypoglauca 1-2 parts, Coix lacryma-jobi 2-4 parts, Curcuma longa 0.5-1.5 parts, Taxillus chinensis 1-2 parts, Salvia miltiorrhiza 1-2 parts, Phellodendron chinense 0.5-1.5 parts, Acorus tatarinowii 0.5-1.5 parts, Plantago asiatica 2-4 parts, Atractylodes macrocephala 0.5-1.5 parts, Rheum palmatum (processed with wine) 0.5-1 part, Angelica pubescens 0.5-1.5 parts, Atractylodes lancea (processed with wheat bran) 0.5-1.5 parts, and Corydalis yanhusuo (processed with vinegar) 0.5-1 part.

3. The traditional Chinese medicine compound composition according to claim 2, characterized in that, The traditional Chinese medicine compound composition consists of the following medicinal materials in parts by weight: 5 parts Smilax glabra, 1.5 parts Dioscorea hypoglauca, 2.5 parts Coix lacryma-jobi, 1.2 parts Curcuma longa, 1 part Taxillus chinensis, 1.2 parts Salvia miltiorrhiza, 0.7 parts Phellodendron chinense, 1.2 parts Acorus tatarinowii, 2.5 parts Plantago asiatica, 1 part Atractylodes macrocephala, 0.7 parts Rheum palmatum (processed with wine), 1.2 parts Angelica pubescens, 0.8 parts Atractylodes lancea (processed with wheat bran), and 1 part Corydalis yanhusuo (processed with vinegar).

4. A method for preparing any one of the traditional Chinese medicine compound compositions according to claims 1-3, characterized in that, Includes the following steps: S1: Prepare a traditional Chinese medicine fluid extract from the raw medicinal materials according to any one of claims 1-3; S2: Add filler to the fluid extract of traditional Chinese medicine obtained in step S1 and stir until a soft material is formed. Pass the soft material through a 35-40 mesh sieve and dry it at 50-60°C to obtain a drug-containing pill core. S3: Prepare a sustained-release coating solution, spray the sustained-release coating solution onto the surface of the drug-containing pellet core described in step S2, perform side-spray coating in a fluidized bed, dry, sieve, and prepare sustained-release granules.

5. The method for preparing the traditional Chinese medicine compound composition according to claim 4, characterized in that, Step S1 specifically includes the following process: Add Phellodendron bark, Plantago asiatica, and Salvia miltiorrhiza to 8-10 times their total weight in purified water, soak for 30-60 minutes, bring to a boil over high heat, then simmer over low heat for 20-60 minutes, and filter out the liquid. Filter out the dregs, repeat the above decoction steps to obtain the filtrate, combine the two filtrates and concentrate under reduced pressure to a relative density of 1.1-1.2 to obtain the water extract. Add Smilax glabra, Dioscorea hypoglauca, Coix lacryma-jobi, Curcuma longa, Taxillus chinensis, Acorus tatarinowii, Atractylodes macrocephala, Rheum palmatum (processed with wine), Angelica pubescens, Atractylodes lancea (stir-fried with wheat bran), and Corydalis yanhusuo (processed with vinegar) to 8-10 times their total weight of ethanol, heat and reflux for 2-3 hours, filter to obtain filtrate 1 and residue 1; add 8-10 times their weight of ethanol to residue 1, heat and reflux for 2-3 hours, filter to obtain filtrate 2, mix filtrate 1 and filtrate 2, concentrate under reduced pressure to a relative density of 0.90-1.05 to obtain the alcohol extract; The aqueous extract and the alcohol extract are mixed to obtain a fluid extract of traditional Chinese medicine.

6. The method for preparing the traditional Chinese medicine compound composition according to claim 4, characterized in that, In step S2, the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, soluble starch, and hydroxypropyl β-cyclodextrin, preferably hydroxypropyl β-cyclodextrin.

7. The method for preparing the traditional Chinese medicine compound composition according to claim 6, characterized in that... The weight ratio of the filler to the fluid extract prepared in step 1 is 1:0.5 to 1.

2.

8. The method for preparing the traditional Chinese medicine compound composition according to claim 4, characterized in that, In step S3, the prepared sustained-release coating solution includes: cellulose acetate as a film-forming material, dibutyl phthalate as a plasticizer, hydroxypropyl methylcellulose as a pore-forming agent, and 75% ethanol as a solvent.

9. The method for preparing the traditional Chinese medicine compound composition according to claim 8, characterized in that, The components in the sustained-release coating solution are as follows by mass percentage: cellulose acetate 5-8%, dibutyl phthalate 1-2%, hydroxypropyl methylcellulose 2-3%, and 75% ethanol 87-92%.

10. The method for preparing traditional Chinese medicine compound sustained-release granules according to claim 4, characterized in that, In step S3, the atomization pressure is 2.4 to 2.6 bar, and the material temperature is 38 to 40°C.

11. The use of the traditional Chinese medicine compound composition according to any of the preceding claims in the preparation of a medicament for treating gout or gouty nephropathy.

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