Pellet for treating ankylosing spondylitis and preparation method thereof

Abstract

The invention discloses a pellet for treating ankylosing spondylitis and a preparation method, and relates to the technical field of pellet preparations, the pellet comprises a pellet core and a coating, and the coating comprises a sustained-release coating and an enteric coating; wherein the pellet core comprises a main drug and microcrystalline cellulose; the microcrystalline cellulose accounts for 3% of the total mass of the pellet core; the sustained-release coating comprises a sustained-release layer and mannitol; the enteric coating is prepared by spraying an enteric solution; the sustained-release coating is prepared by mixing a modified polylactic acid solution and an ethyl cellulose aqueous dispersion, has a sustained-release effect, controls the release speed of the medicine, enables the medicine to be slowly released in vivo, prolongs the action time of the medicine, reduces the medicine taking frequency, and improves the compliance of a patient.

Description

Technical Field

[0001] The invention relates to the technical field of micropill preparations, and in particular to a micropill for treating ankylosing spondylitis and a preparation method thereof. Background Art

[0002] Ankylosing spondylitis (AS) is a common chronic inflammatory disease that belongs to the category of rheumatic autoimmune diseases. The main lesions are the sacroiliac joints, spine and peripheral joints. Some patients with severe disease may develop spinal deformity and spinal ankylosis. AS has an insidious onset. Early symptoms are usually dull pain and morning stiffness in the lumbar sacral region, which may be relieved after activity. During the progression of the disease, lesions of varying degrees may occur in multiple organs such as the eyes, heart, lungs, and kidneys. It is not contagious. The treatment of AS is mainly symptomatic treatment, including drug therapy and surgical treatment when necessary. Traditional Chinese medicine has the effects of dispelling wind and dampness, dispelling cold and unblocking meridians, promoting blood circulation and removing blood stasis, unblocking meridians and relieving pain. It can quickly relieve patients' pain, stiffness and other symptoms and improve their quality of life. However, since ankylosing spondylitis is difficult to cure completely, long-term medication is required, and patient compliance is poor. Direct use of traditional Chinese medicine decoction is troublesome and the dosage is difficult to balance, resulting in fluctuations in blood drug concentrations. Summary of the invention

[0003] The embodiments of the present application provide a solution to the problem in the prior art that ankylosing spondylitis requires long-term medication and has poor patient compliance, thereby achieving a simpler and more convenient therapeutic preparation.

[0004] The embodiment of the present application provides a micro-pellet for treating ankylosing spondylitis, comprising a pellet core and a coating, wherein the coating comprises a sustained-release coating and an enteric coating; The pellet core includes the main drug and microcrystalline cellulose; the microcrystalline cellulose accounts for 3% of the total mass of the pellet core; the sustained-release coating includes a sustained-release layer and mannitol; and the enteric coating is made by spraying an enteric solution.

[0005] Further, the main drugs include, by weight: 30-50 parts of epimedium, 15-30 parts of tripterygium wilfordii, 60-80 parts of atractylodes macrocephala, 30-45 parts of aconite root, 50-70 parts of codonopsis pilosula, 20-40 parts of cornus officinalis, 70-90 parts of eucommia bark, 30-50 parts of rehmannia root, 30-50 parts of poria, 30-50 parts of cyathula, 30-50 parts of licorice, 30-50 parts of roasted ginger, 20-30 parts of cinnamon bark, 20-30 parts of pilose antler, 50-70 parts of dog spine, 70-90 parts of wolfberry, 40-60 parts of salvia miltiorrhiza, 30-50 parts of chuanxiong, 50-70 parts of dipsaci, 50-70 parts of yam, 50-70 parts of angelica and 30-50 parts of astragalus.

[0006] Furthermore, the sustained-release coating is prepared by spraying a sustained-release solution and a mannitol solution, wherein the sustained-release solution is prepared by mixing a modified polylactic acid solution and an ethyl cellulose aqueous dispersion in a mass ratio of 5:1 and stirring at 30° C. for 60 minutes.

[0007] Furthermore, the modified polylactic acid solution is prepared by adding a dichloromethane / ethanol mixture to gluconic acid and polylactic acid, high-speed shearing, adding silicon dioxide and mixing, ultrasonicating, adding tocopherol, and reacting in a water bath to obtain the modified polylactic acid solution; the mass ratio of the gluconic acid, polylactic acid, dichloromethane / ethanol mixture, silicon dioxide and tocopherol is 2:6:30:5:0.1; and the particle size of the silicon dioxide is 50-100 nm.

[0008] Furthermore, the enteric solution comprises hydroxypropyl methylcellulose and talc in a mass ratio of 1:1 dissolved in purified water and stirred for 30 minutes.

[0009] Furthermore, the mass ratio of the main drug: sustained-release coating: enteric coating is 4:10:1, and the mass ratio of the modified polylactic acid solution, ethyl cellulose aqueous dispersion, mannitol, the main drug, dimethicone, hydroxypropyl methylcellulose and talc is 45-48:9-12:20-28:30-38:8-10:4-6:4-8.

[0010] The preparation method of the above-mentioned micro-pills for treating ankylosing spondylitis is specifically as follows: S1, the main drug component is formulated according to the formula and then ground into powder, and then extracted by continuous reflux to obtain a water extract, and then the water extract is placed in a centrifuge for centrifugation at a speed of 4000 revolutions per minute, and a supernatant is obtained after centrifugation for 15 minutes; the supernatant is placed in a rotary evaporator, evaporated to remove water, and the water content of the extract is 60%, the dry extract is dried to obtain a dry extract, and then microcrystalline cellulose is added, squeezed into particles with a 15-mesh sieve, and then spread out and placed in an oven for drying to make its water content 5%, to obtain a pill core; S2. Spray the sustained-release liquid and the mannitol solution onto the pellet cores by alternating spraying. One alternating cycle is to first spray 2% of the total amount of the sustained-release liquid and then spray 4% of the weight of the mannitol solution. The volume ratio of the sustained-release liquid to the mannitol solution is 1:2. After spraying, the pellet cores are dried at 50° C. for 60 minutes to obtain the sustained-release coated pellet cores. S3. Spray the pellet core containing the sustained-release coating with an enteric solution, and then dry it at 50° C. for 30 minutes to obtain micropellets for treating ankylosing spondylitis.

[0011] Furthermore, the sustained-release coating also includes an inner sustained-release coating and an outer sustained-release coating, wherein the mannitol solution in the outer sustained-release coating also includes silicon dioxide particles, accounting for 1% of the mass of the mannitol solution in the outer sustained-release coating.

[0012] Furthermore, the mannitol solution in the inner sustained-release coating also includes silicon dioxide particles, which account for 1% of the mass of the mannitol solution in the outer sustained-release coating; The particle size of the silicon dioxide particles in the mannitol solution in the inner sustained-release coating is 300-500 nm; The particle size of silicon dioxide particles in the mannitol solution in the outer sustained-release coating is 10-50 nm.

[0013] Furthermore, the silicon dioxide contained in the mannitol solution of the inner sustained-release coating is a combination of silicon dioxide particles having large particle sizes and small particle sizes, wherein the mass ratio of large particle size to small particle size silicon dioxide is 5:1.

[0014] One or more technical solutions provided in the embodiments of the present application have at least the following technical effects or advantages: First, the combination of epimedium and tripterygium wilfordii can warm and nourish the kidney yang, dispel wind and dampness, and relieve inflammation and pain. It can not only relieve the patient's symptoms, but also regulate the body's immune function to achieve the effect of treating both the symptoms and the root causes. Epimedium and tripterygium wilfordii have a certain synergistic effect in terms of efficacy, which can enhance each other's therapeutic effects and improve the overall therapeutic effect. Since tripterygium wilfordii and some ingredients will produce gastrointestinal reactions, the use of enteric-coated microcapsules can reduce adverse reactions. The sustained-release coating is made by mixing modified polylactic acid solution and ethyl cellulose aqueous dispersion, and has a sustained-release effect. This sustained-release coating controls the release rate of the drug, allowing the drug to be slowly released in the body, prolonging the drug's action time, reducing the number of medications, and improving patient compliance; Second, both the inner and outer sustained-release coatings are sprayed with a solution containing mannitol, but the outer mannitol solution contains silicon dioxide particles to achieve dual control of the drug release rate. Mannitol is a commonly used osmotic pressure regulator, which plays a role in regulating the drug release rate in the sustained-release coating. When the drug dissolves in the body, mannitol absorbs water to form a high osmotic pressure environment, thereby controlling the dissolution rate of the drug. Silicon dioxide particles are porous and adsorbent, adsorbing mannitol molecules and slowing down the dissolution rate of mannitol. Therefore, adding silicon dioxide particles to the outer mannitol solution can further prolong the release time of the drug and achieve a more lasting sustained-release effect. Third, the particle size of silicon dioxide will significantly affect its adsorption performance and release rate. Silicon dioxide with a small particle size has a larger specific surface area and can more tightly adsorb mannitol molecules, thereby slowing down the dissolution rate of mannitol and prolonging the release time of the outer sustained-release coating. In contrast, silicon dioxide with a large particle size has a smaller specific surface area and a weaker adsorption capacity for mannitol molecules, so the release rate of the inner sustained-release coating will be relatively fast. Through this design of the difference in particle size between the inner and outer sustained-release coatings, dual control of the drug release rate is achieved. The inner sustained-release coating provides initial drug release, and the outer sustained-release coating further prolongs the drug release time through the silicon dioxide with a small particle size, achieving a more lasting and stable sustained-release effect. Fourthly, the combined silica particles containing large and small particles can form a multi-layer structure in the inner sustained-release coating. The large-sized silica particles provide skeleton support, while the small-sized silica particles fill the gaps between the skeletons, increasing the density and adsorption performance of the coating layer. In addition, in the inner sustained-release film, the presence of large particles will cause gaps to appear around the large particles, thereby increasing the release of the drug and preventing the low release rate caused by the double-layer sustained-release layer. When the outer sustained-release coating completely fails, the adsorption of the small-sized particles in the inner sustained-release coating maintains a certain sustained-release capacity, and the generation of gaps can also allow the outer sustained-release coating material to pass through the gaps, thereby increasing the stability and interface bonding ability between the two layers. DETAILED DESCRIPTION

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by technicians in the technical field to which the present invention belongs; the terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention; the term "and / or" used herein includes any and all combinations of one or more related listed items.

[0016] Embodiment 1: The present application provides a pellet for treating ankylosing spondylitis, comprising a pellet core and a coating, wherein the coating comprises a sustained-release coating and an enteric coating; The pellet core includes the main drug and microcrystalline cellulose; the microcrystalline cellulose accounts for 3% of the total mass of the pellet core; The main drugs include, by weight: 30-50 parts of epimedium, 15-30 parts of tripterygium wilfordii, 60-80 parts of atractylodes macrocephala, 30-45 parts of aconite root, 50-70 parts of codonopsis pilosula, 20-40 parts of cornus officinalis, 70-90 parts of eucommia bark, 30-50 parts of rehmannia root, 30-50 parts of tuckahoe, 30-50 parts of cyathulae, 30-50 parts of liquorice, 30-50 parts of roasted ginger, 20-30 parts of cinnamon bark, 20-30 parts of pilose antler, 50-70 parts of dog spine, 70-90 parts of wolfberry, 40-60 parts of salvia miltiorrhiza, 30-50 parts of chuanxiong, 50-70 parts of dipsaci, 50-70 parts of yam, 50-70 parts of angelica and 30-50 parts of astragalus; The sustained-release coating comprises a sustained-release layer and mannitol; the sustained-release coating is prepared by spraying a sustained-release solution and a mannitol solution, wherein the sustained-release solution is prepared by mixing a modified polylactic acid solution and an ethyl cellulose aqueous dispersion in a mass ratio of 5:1, and stirring at 30°C for 60 minutes; the modified polylactic acid solution is prepared by adding a dichloromethane / ethanol mixed solution to gluconic acid and polylactic acid, shearing at high speed, adding silicon dioxide to mix, ultrasonicating, adding tocopherol, and reacting in a water bath to obtain a modified polylactic acid solution; the mass ratio of the gluconic acid, polylactic acid, dichloromethane / ethanol mixed solution, silicon dioxide and tocopherol is 2:6:30:5:0.1; the particle size of the silicon dioxide is 50-100nm; The enteric coating is prepared by spraying an enteric solution, wherein the enteric solution comprises hydroxypropyl methylcellulose and talc in a mass ratio of 1:1 dissolved in purified water and stirred for 30 minutes; The mass ratio of main drug: sustained-release coating: enteric coating is 4:10:1; The mass ratio of modified polylactic acid solution, ethyl cellulose aqueous dispersion, mannitol, main drug, dimethicone, hydroxypropyl methylcellulose and talc is 45-48:9-12:20-28:30-38:8-10:4-6:4-8.

[0017] The preparation method of the above-mentioned micropellets for treating ankylosing spondylitis is as follows: S1. The main drug component is prepared according to the formula and then ground into powder, and then subjected to continuous reflux extraction to obtain a water extract, and then the water extract is placed in a centrifuge for centrifugation at a speed of 4000 revolutions per minute, and a supernatant is obtained after centrifugation for 15 minutes; the supernatant is placed in a rotary evaporator to evaporate and remove water to obtain an extract with a water content of 60%, the extract is dried to obtain a dry extract, and then microcrystalline cellulose is added, and the extract is squeezed into granules with a 15-mesh sieve, and then spread out and placed in an oven for drying to make its water content 5%, and a pill core is obtained; S2. Spray the sustained-release liquid and the mannitol solution onto the pellet cores by alternating spraying. One alternating cycle is to first spray 2% of the total amount of the sustained-release liquid and then spray 4% of the weight of the mannitol solution. The volume ratio of the sustained-release liquid to the mannitol solution is 1:2. After spraying, the pellet cores are dried at 50° C. for 60 minutes to obtain the sustained-release coated pellet cores. S3. Spray the pellet core containing the sustained-release coating with an enteric solution, and then dry it at 50° C. for 30 minutes to obtain micropellets for treating ankylosing spondylitis.

[0018] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: Yang-warming drugs such as aconite, cinnamon bark, and roasted ginger can warm and nourish kidney yang, dispel cold and relieve pain, and relieve symptoms such as back pain and stiffness caused by insufficient yang and cold-dampness obstruction in patients with ankylosing spondylitis; drugs such as salvia miltiorrhiza and chuanxiong have the effect of promoting blood circulation and removing blood stasis, can promote blood circulation, improve the nutritional status of local tissues, and relieve inflammation and pain; drugs such as tripterygium wilfordii, notopterygium wilfordii, and angelica dahurica have the effect of dispelling wind and dampness, can remove rheumatic evil qi in the body, and relieve symptoms such as joint swelling and pain, and limited mobility caused by rheumatic obstruction; drugs such as eucommia, rehmannia root, and epimedium can nourish the liver and kidney, strengthen the tendons and bones, and relieve symptoms such as back pain and stiffness caused by insufficient liver and kidney and malnutrition of tendons and bones; white atractylodes, codonopsis, and poria can strengthen the spleen and replenish qi, and enhance the body's immunity; angelica, astragalus, etc. can nourish blood and promote blood circulation, and promote the formation and circulation of qi and blood; wolfberry can nourish the liver and kidney, improve eyesight and strengthen the body, and can comprehensively regulate the patient's physical condition and improve the treatment effect; Epimedium is warm in nature and enters the liver and kidney meridians. It can warm and nourish the kidney yang, benefit the essence and qi, and strengthen the tendons and bones. It has a good effect on relieving symptoms such as back pain and stiffness caused by insufficient kidney yang. Epimedium can increase the level of endogenous hormones, enhance the body's immune function, and help relieve the inflammatory response of patients with ankylosing spondylitis. Tripterygium wilfordii has anti-inflammatory and analgesic effects, can inhibit the release of inflammatory mediators, reduce inflammatory response, relieve pain, and can also inhibit cell-mediated immune response, reduce the damage of autoimmune response to joints, and relieve joint swelling and pain in patients with ankylosing spondylitis. The combination of epimedium and tripterygium wilfordii can warm and nourish the kidney yang, dispel wind and dampness, and relieve inflammation and pain. It can not only relieve the patient's symptoms, but also regulate the body's immune function, achieving the effect of treating both the symptoms and the root causes. Epimedium and tripterygium wilfordii have a certain synergistic effect in efficacy, which can enhance each other's therapeutic effects and improve the overall therapeutic effect.

[0019] Since Tripterygium wilfordii and some of its ingredients may cause gastrointestinal reactions, the use of enteric-coated micropellets can reduce adverse reactions. The sustained-release coating is made by mixing modified polylactic acid solution and ethyl cellulose aqueous dispersion, which has a sustained-release effect. This sustained-release coating controls the release rate of the drug, allowing the drug to be slowly released in the body, prolonging the drug's duration of action, reducing the number of medications, and improving patient compliance; The sustained-release coating is made of a mixture of modified polylactic acid solution and ethylcellulose aqueous dispersion, which has a sustained-release effect. The addition of mannitol adjusts the permeability of the coating and further controls the release rate of the drug. The enteric coating is made of hydroxypropyl methylcellulose and talc, which has enteric properties, protects the drug from gastric acid destruction, and releases it in the intestine.

[0020] Efficacy test: (1) Construction of AS mouse animal model Female BALB / c mice aged 24 weeks were given intraperitoneal injections of proteoglycan (0th, 3rd, 6th The drug was injected once every week for a total of 3 times, with 100 μg injected each time).

[0021] (2) Grouped medication After the AS mouse animal model was established, it was divided into four groups, including the control group, the tumor necrosis factor inhibitor group, and the main drug group. From the 10th week, they were given normal saline, 0.1 mg / g tumor necrosis factor inhibitor, and 0.2 mg / g main drug extract, respectively; The main components were divided into 5 experimental ratios, among which Tripterygium wilfordii was not added in Experiment 3, Epimedium brevicornum was not added in Experiment 4, and Tripterygium wilfordii and Epimedium brevicornum were not added in Experiment 5; Specifically: Experiment 1: 80 parts of Atractylodes macrocephala, 45 parts of Aconite root, 70 parts of Codonopsis pilosula, 40 parts of Cornus officinalis, 90 parts of Eucommia bark, 50 parts of Rehmannia root, 50 parts of Poria cocos, 50 parts of Cyathula officinalis, 30 parts of Tripterygium wilfordii, 50 parts of Licorice root, 50 parts of Paojiang, 30 parts of Cinnamon bark, 50 parts of Epimedium, 30 parts of Pilose antler, 70 parts of Cibotium barbarum, 90 parts of Lycium barbarum, 60 parts of Salvia miltiorrhiza, 50 parts of Chuanxiong, 70 parts of Dipsacus asper, 70 parts of Dioscorea opposita, 70 parts of Chinese Yam, 70 parts of Angelica sinensis and 50 parts of Astragalus membranaceus; Experiment 2: The main drugs in parts by weight include: 60 parts of Atractylodes macrocephala, 30 parts of Aconite root, 50 parts of Codonopsis pilosula, 20 parts of Cornus officinalis, 70 parts of Eucommia bark, 30 parts of Rehmannia root, 30 parts of Poria cocos, 30 parts of Cyathula officinalis, 15 parts of Tripterygium wilfordii, 30 parts of Licorice root, 30 parts of Preserved Ginger, 20 parts of Cinnamon bark, 30 parts of Epimedium, 20 parts of Pilose antler, 50 parts of Cibotium barbarum, 70 parts of Lycium barbarum, 40 parts of Salvia miltiorrhiza, 30 parts of Chuanxiong, 50 parts of Dipsacus asper, 50 parts of Dioscorea opposita, 50 parts of Chinese Yam, 50 parts of Angelica sinensis and 30 parts of Astragalus membranaceus; Experiment 3: The main drugs include by weight: 60 parts of Atractylodes macrocephala, 30 parts of Aconite root, 50 parts of Codonopsis pilosula, 20 parts of Cornus officinalis, 70 parts of Eucommia bark, 30 parts of Rehmannia root, 30 parts of Poria cocos, 30 parts of Cyathula officinalis, 30 parts of Licorice root, 30 parts of Paojiang, 20 parts of Cinnamon bark, 30 parts of Epimedium, 20 parts of Pilose antler, 50 parts of Cibotium barbarum, 70 parts of Lycium barbarum, 40 parts of Salvia miltiorrhiza, 30 parts of Chuanxiong, 50 parts of Dipsacus asper, 50 parts of Dioscorea opposita, 50 parts of Chinese yam, 50 parts of Angelica sinensis and 30 parts of Astragalus membranaceus; Experiment 4: 60 parts of Atractylodes macrocephala, 30 parts of Aconite root, 50 parts of Codonopsis pilosula, 20 parts of Cornus officinalis, 70 parts of Eucommia bark, 30 parts of Rehmannia root, 30 parts of Poria cocos, 30 parts of Cyathula officinalis, 15 parts of Tripterygium wilfordii, 30 parts of Licorice root, 30 parts of Preserved ginger, 20 parts of Cinnamon bark, 20 parts of Pilose antler, 50 parts of Cibotium barbarum, 70 parts of Lycium barbarum, 40 parts of Salvia miltiorrhiza, 30 parts of Chuanxiong, 50 parts of Dipsacus asper, 50 parts of Dioscorea opposita, 50 parts of Chinese yam, 50 parts of Angelica sinensis and 30 parts of Astragalus membranaceus; Experiment 5: 60 parts of Atractylodes macrocephala, 30 parts of Aconite root, 50 parts of Codonopsis pilosula, 20 parts of Cornus officinalis, 70 parts of Eucommia bark, 30 parts of Rehmannia root, 30 parts of Poria cocos, 30 parts of Cyathula officinalis, 30 parts of Licorice root, 30 parts of Paojiang, 20 parts of Cinnamon bark, 20 parts of Pilose antler, 50 parts of Cibotium barbarum, 70 parts of Lycium barbarum, 40 parts of Salvia miltiorrhiza, 30 parts of Chuanxiong, 50 parts of Dipsacus asper, 50 parts of Dioscorea opposita, 50 parts of Chinese yam, 50 parts of Angelica sinensis and 30 parts of Astragalus membranaceus; (3) Detection of inflammation in mice Starting from the 14th week, the mice in the four groups were killed by cervical dislocation, once every 4 weeks, for a total of 6 times until the 34th week. After killing, the peripheral blood serum of the mice was separated, and the CRP and IL-17A levels were detected. The results of each group were averaged, as shown in Table 1; (4) Detection of pathological osteogenesis in mice Previous studies have confirmed that early and effective intervention of inflammation can significantly inhibit the progression of pathological osteogenesis, another core pathological feature of AS. Therefore, in this example, the 3rd to 5th lumbar vertebral segments of the mouse spine were simultaneously taken, fixed, decalcified, paraffin-embedded, and sliced ​​in sequence, and the pathological osteogenesis of the mouse spine was observed by HE staining and Masson staining. The pathological osteogenesis scoring criteria are as follows: 0 points: normal; 1 point: mild hyperplasia at the edge of the vertebral body; 2 points: obvious osteophyte formation at the edge of the vertebral body; 3 points: bone bridge formation at the edge of one vertebral body; 4 points: bone bridge formation at the edge of both vertebral bodies and intervertebral fusion. The average value of the results of each group is shown in Table 2.

[0022]

[0023] Example 2: The above example improves the medication compliance of ankylosing spondylitis patients by means of a Chinese medicine composition and an enteric-coated sustained-release agent. In order to improve the sustained-release effect, the drug is slowly and evenly released in the body and the action time is prolonged, further improvements are made on the basis of Example 1.

[0024] The sustained-release coating also includes an inner sustained-release coating and an outer sustained-release coating, wherein the mannitol solution in the outer sustained-release coating also includes silicon dioxide particles, which account for 1% of the mass of the mannitol solution in the outer sustained-release coating.

[0025] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: Both the inner and outer sustained-release coatings are sprayed with a solution containing mannitol, but the outer mannitol solution contains silicon dioxide particles to achieve dual control of the drug release rate. Mannitol is a commonly used osmotic pressure regulator, which plays a role in regulating the drug release rate in the sustained-release coating. When the drug dissolves in the body, mannitol absorbs water to form a high osmotic pressure environment, thereby controlling the dissolution rate of the drug. Silicon dioxide particles are porous and adsorbent, adsorbing mannitol molecules and slowing down the dissolution rate of mannitol. Therefore, adding silicon dioxide particles to the outer mannitol solution can further prolong the release time of the drug and achieve a more lasting sustained-release effect. The inner sustained-release coating is mainly formed by spraying a solution containing mannitol. Mannitol absorbs water when the drug dissolves to form a high osmotic pressure environment, thereby controlling the dissolution rate of the drug. Since there are no silica particles in the inner layer, the dissolution rate of mannitol is relatively fast and the drug release rate is also fast; the outer sustained-release coating is formed by spraying a mannitol solution containing silica particles. The silica particles adsorb mannitol molecules and slow down the dissolution rate of mannitol. Therefore, the outer sustained-release coating prolongs the release time of the drug and achieves a more lasting sustained-release effect; the synergistic effect of the inner and outer sustained-release coatings achieves dual control of the drug release rate. The inner sustained-release coating controls the initial release rate of the drug, and the outer sustained-release coating further prolongs the release time of the drug, achieving a more lasting sustained-release effect, reducing the number of medications, improving the sustained-release ability, and also has practical significance for personalized treatment.

[0026] Example 3: Example 2 was further improved on the basis of Example 2 by adding silicon dioxide particles to the mannitol solution of the outer sustained-release coating to further increase the sustained-release capacity in order to optimize the drug release curve.

[0027] The mannitol solution in the inner sustained-release coating also includes silicon dioxide particles, which account for 1% of the mass of the mannitol solution in the outer sustained-release coating; The particle size of the silicon dioxide particles in the mannitol solution in the inner sustained-release coating is 300-500 nm; The particle size of silicon dioxide particles in the mannitol solution in the outer sustained-release coating is 10-50 nm.

[0028] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: The particle size of silicon dioxide will significantly affect its adsorption performance and release rate. Silicon dioxide with a small particle size has a larger specific surface area and can more tightly adsorb mannitol molecules, thereby slowing down the dissolution rate of mannitol and prolonging the release time of the outer sustained-release coating. In contrast, silicon dioxide with a large particle size has a smaller specific surface area and a weaker adsorption capacity for mannitol molecules, so the release rate of the inner sustained-release coating will be relatively fast. Through this design of the difference in particle size between the inner and outer sustained-release coatings, dual control of the drug release rate is achieved. The inner sustained-release coating provides initial drug release, and the outer sustained-release coating further prolongs the drug release time through the small particle size silicon dioxide, achieving a more lasting and stable sustained-release effect. The mannitol solution of the inner sustained-release coating contains silicon dioxide with large particle size, which releases faster and provides initial rapid release of the drug; the mannitol solution of the outer sustained-release coating contains silicon dioxide with small particle size, which releases slower, further extending the release time of the drug and achieving a more lasting sustained-release effect; since the sustained-release ability of the microcapsules is improved, patients can take medicine less frequently and improve compliance; by precisely controlling the release rate of the drug, the peak concentration of the drug in the body is reduced, and the incidence of drug side effects is reduced; the addition of silicon dioxide improves the stability of the coating layer and prevents the degradation and deterioration of the drug during storage and transportation; at the same time, the synergistic effect of the inner and outer sustained-release coatings extends the shelf life of the drug.

[0029] Example 4: Example 3 further optimizes the release curve by different silica particle sizes in the mannitol solution in the inner and outer sustained-release coatings. In order to optimize the release process, further improvements are made on the basis of Example 3.

[0030] The silicon dioxide contained in the mannitol solution of the inner sustained-release coating is a combination of silicon dioxide particles having large particle sizes and small particle sizes, wherein the mass ratio of large particle size to small particle silicon dioxide is 5:1.

[0031] The technical solutions in the above embodiments of the present application have at least the following technical effects or advantages: The combined silica particles containing large and small particles can form a multi-layer structure in the inner sustained-release coating. The large-sized silica particles provide skeleton support, while the small-sized silica particles fill the gaps between the skeletons, thereby increasing the density and adsorption performance of the coating layer. In addition, in the inner sustained-release film, the presence of large particles will cause gaps to appear around the large particles, thereby increasing the release of the drug and preventing the low release rate caused by the double-layer sustained-release layer. When the outer sustained-release coating completely fails, the adsorption of the small-sized particles in the inner sustained-release coating maintains a certain sustained-release capacity, and the generation of gaps can also allow the outer sustained-release coating material to pass through the gaps, thereby increasing the stability and interface bonding ability between the two layers. This particle size combination allows the mannitol solution in the inner layer of sustained-release coating to maintain a certain release rate (controlled by large-size particles) during the release process, while also delaying the dissolution and release of part of the mannitol through the adsorption of small-size particles, thereby achieving a more complex sustained-release effect; the outer layer of sustained-release coating still uses a mannitol solution containing small-size silica to provide a long-lasting sustained-release effect.

[0032] The combination of large and small silica particles forms a multi-layered structure in the mannitol solution. The large-sized particles act as a skeleton, providing stable structural support; the small-sized particles fill the gaps between the skeletons, increasing the density and adsorption performance of the coating layer. This combination of particle sizes requires mannitol molecules to overcome more physical obstacles (such as the adsorption of small-sized particles) during the release process, thereby slowing down the dissolution and release rate of mannitol.

[0033] The small-sized silica particles in the outer layer of sustained-release coating significantly slow down the dissolution and release rate of mannitol through close adsorption, achieving a long-lasting sustained-release effect. The large-sized and small-sized silica particles in the inner layer of sustained-release coating not only ensure the initial drug release, but also achieve a more refined controlled-release regulation through the combination of particle sizes. As the inner layer of mannitol gradually dissolves and releases, the outer layer of mannitol continues to provide a long-lasting sustained-release effect.

[0034] Prepare pellets with 60 mg of the main drug per pellet, and use 900 mL of 0.05 M sodium dihydrogen phosphate buffer solution with a pH value of 6.0 as the release medium, preheat to 37°C, take 10 mL of the solution at 30, 300 and 600 min, filter, accurately measure 5 mL of the filtrate, add 1 mL of 0.25 M sodium hydroxide solution, shake thoroughly, and obtain the sample solution to be tested; Taking the formula of Experiment 1 as the experiment, 100 mg of the extract of the main drug was taken as the reference substance, and the content of the main drug was calculated. 10 mL of anhydrous ethanol was added to a phosphate buffer solution with a pH value of 6.0 to make the volume to 100 mL, fully shaken, filtered, 5 mL of the filtrate was taken, and a phosphate buffer solution with a pH value of 6.0 was added to make the volume to 50 mL, fully shaken, filtered, 5 mL of the filtrate was taken, 1 mL of 0.25 M sodium hydroxide solution was added, and fully shaken to obtain a reference substance solution; the test solution and the reference substance solution were respectively taken to measure the absorbance at 225 nm under ultraviolet light, and the content was calculated. The results are shown in Table 3;

[0035] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A pellet for treating ankylosing spondylitis, characterized in that: It includes a pellet core and a coating, wherein the coating includes a sustained-release coating and an enteric coating; The pellet core includes the main drug and microcrystalline cellulose; the microcrystalline cellulose accounts for 3% of the total mass of the pellet core; the sustained-release coating includes a sustained-release layer and mannitol; and the enteric coating is made by spraying an enteric solution.

2. The micropellet for treating ankylosing spondylitis according to claim 1, characterized in that: The main drugs include, by weight: 30-50 parts of epimedium, 15-30 parts of tripterygium wilfordii, 60-80 parts of atractylodes macrocephala, 30-45 parts of aconite root, 50-70 parts of codonopsis pilosula, 20-40 parts of cornus officinalis, 70-90 parts of eucommia bark, 30-50 parts of rehmannia root, 30-50 parts of tuckahoe, 30-50 parts of cyathula, 30-50 parts of liquorice, 30-50 parts of roasted ginger, 20-30 parts of cinnamon bark, 20-30 parts of pilose antler, 50-70 parts of cibotium bark, 70-90 parts of wolfberry, 40-60 parts of salvia miltiorrhiza, 30-50 parts of chuanxiong, 50-70 parts of dipsaci, 50-70 parts of yam, 50-70 parts of angelica and 30-50 parts of astragalus.

3. The micropellet for treating ankylosing spondylitis according to claim 1, characterized in that: The sustained-release coating is prepared by spraying a sustained-release solution and a mannitol solution. The sustained-release solution is prepared by mixing a modified polylactic acid solution and an ethyl cellulose aqueous dispersion in a mass ratio of 5:1 and stirring at 30° C. for 60 minutes.

4. The micropellet for treating ankylosing spondylitis according to claim 3, characterized in that: The modified polylactic acid solution is prepared by adding a dichloromethane / ethanol mixed solution to gluconic acid and polylactic acid, high-speed shearing, adding silicon dioxide and mixing, ultrasonication, adding tocopherol, and reacting in a water bath to obtain the modified polylactic acid solution; the mass ratio of the gluconic acid, polylactic acid, the dichloromethane / ethanol mixed solution, the silicon dioxide and the tocopherol is 2:6:30:5:0.1; and the particle size of the silicon dioxide is 50-100 nm.

5. The micropellet for treating ankylosing spondylitis according to claim 1, characterized in that: The enteric solution is prepared by dissolving hydroxypropyl methylcellulose and talc in a mass ratio of 1:1 in purified water and stirring for 30 minutes.

6. The micropellet for treating ankylosing spondylitis according to claim 1, characterized in that: The mass ratio of main drug: sustained-release coating: enteric coating is 4:10:1, and the mass ratio of modified polylactic acid solution, ethyl cellulose aqueous dispersion, mannitol, main drug, dimethicone, hydroxypropyl methylcellulose and talc is 45-48:9-12:20-28:30-38:8-10:4-6:4-8.

7. A method for preparing micropellets for treating ankylosing spondylitis according to any one of claims 1 to 6, characterized in that: The preparation method is specifically as follows: S1, the main drug component is prepared according to the formula and then ground into powder, and then extracted by continuous reflux to obtain a water extract, and then the water extract is placed in a centrifuge for centrifugation at a speed of 4000 revolutions per minute, and a supernatant is obtained after centrifugation for 15 minutes; the supernatant is placed in a rotary evaporator to evaporate and remove water to obtain an extract with a water content of 60%, the extract is dried to obtain a dry extract, and then microcrystalline cellulose is added, and the extract is squeezed into particles with a 15-mesh sieve, and then spread and placed in an oven for drying to make its water content 5%, and a pill core is obtained; S2. Spray the sustained-release liquid and the mannitol solution onto the pellet cores by alternating spraying. One alternating cycle is to first spray 2% of the total amount of the sustained-release liquid and then spray 4% of the weight of the mannitol solution. The volume ratio of the sustained-release liquid to the mannitol solution is 1:

2. After spraying, the pellet cores are dried at 50° C. for 60 minutes to obtain the sustained-release coated pellet cores. S3. Spray the pellet core containing the sustained-release coating with an enteric solution, and then dry it at 50° C. for 30 minutes to obtain micropellets for treating ankylosing spondylitis.

8. The method for preparing micropellets for treating ankylosing spondylitis according to claim 7, characterized in that: The sustained-release coating also includes an inner sustained-release coating and an outer sustained-release coating, wherein the mannitol solution in the outer sustained-release coating also includes silicon dioxide particles, which account for 1% of the mass of the mannitol solution in the outer sustained-release coating.

9. The method for preparing micropellets for treating ankylosing spondylitis according to claim 8, characterized in that: The mannitol solution in the inner sustained-release coating also includes silicon dioxide particles, which account for 1% of the mass of the mannitol solution in the outer sustained-release coating; The particle size of the silicon dioxide particles in the mannitol solution in the inner sustained-release coating is 300-500 nm; The particle size of silicon dioxide particles in the mannitol solution in the outer sustained-release coating is 10-50 nm.

10. The method for preparing micropellets for treating ankylosing spondylitis according to claim 9, characterized in that: The silicon dioxide contained in the mannitol solution of the inner sustained-release coating is a combination of silicon dioxide particles having large particle sizes and small particle sizes, wherein the mass ratio of large particle size to small particle silicon dioxide is 5:1.

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