Budesonide enteric-coated sustained-release pellet and preparation method thereof

Abstract

The invention discloses budesonide enteric-coated sustained-release pellets and a preparation method thereof, and belongs to the technical field of biological medicines. The budesonide enteric-coated and sustained-release pellet sequentially comprises a medicine-containing pellet core, a sustained-release layer and an enteric-coated layer from inside to outside, the drug-containing pill core comprises budesonide, a filler, an adhesive, an acidic agent and a lubricant; the sustained-release layer comprises the following components: a retardant, a plasticizer and an anti-sticking agent; the enteric-coated layer comprises the following components: an enteric-coated material, a plasticizer and an anti-sticking agent. The budesonide enteric-coated sustained-release pellet is prepared by the following steps: preparing budesonide and auxiliary materials into a drug-containing pellet core through an extrusion rolling process, and then coating the drug-containing pellet core with a sustained-release layer and an enteric-coated layer in sequence through a fluidized bed coating, thereby obtaining the budesonide enteric-coated sustained-release pellet. The budesonide enteric-coated and sustained-release pellet cannot be released and absorbed in the stomach, the effect gradually starts after the budesonide enteric-coated and sustained-release pellet reaches the intestinal tract, and the budesonide enteric-coated and sustained-release pellet keeps a proper concentration level in in-vivo blood, so that targeted continuous treatment of inflammatory intestinal diseases is facilitated.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a budesonide enteric-soluble sustained-release pellet and a preparation method thereof. BACKGROUND

[0002] Budesonide is a glucocorticoid with high local anti-inflammatory effect, and has the effects of anti-inflammatory, anti-allergic, antipruritic and anti-exudation. In October 2001, the FDA of the United States approved the enteric-soluble pellet capsule of budesonide for the maintenance treatment of mild to moderate segmental ileitis involving the ileum and / or ascending colon, i.e. Crohn's disease. Currently, the marketed oral budesonide is mainly used for the treatment of intestinal inflammatory diseases, such as Crohn's disease and ulcerative colitis, and it mainly plays a role in inhibiting inflammatory response; at the same time, it is also suitable for reducing the proteinuria level of adult patients with primary immunoglobulin A nephropathy (IgAN).

[0003] Crohn's disease is a chronic nonspecific digestive tract inflammatory disease, which belongs to inflammatory bowel disease. It is prone to occur in the terminal ileum and ascending colon, and can also affect extraintestinal sites such as joints, skin, oral cavity and eyes. Crohn's disease causes chronic inflammation of the digestive tract, destroys the digestive tract, and mucosal inflammation causes further damage. If not timely controlled, intestinal ulcers, stenosis and penetrating lesions will occur. Patients will have intestinal inflammatory symptoms, and ulcers are unevenly distributed. The symptoms of Crohn's disease include abdominal pain, diarrhea, fever, malnutrition, etc., and the onset in childhood can also cause growth and development retardation.

[0004] Since the onset site of Crohn's disease and other diseases is in the ileum and colon, in order to improve the targeting of the drug, budesonide is generally an enteric-soluble preparation, which can prevent the drug from being released in the stomach, and the drug is released at the terminal ileum to target the inflammatory disease site and regulate local intestinal mucosal immune abnormalities, thereby intervening the disease from the source and improving the treatment effect. In addition, budesonide is a glucocorticoid, which has anti-inflammatory and immunosuppressive effects. If an ordinary preparation is taken orally, most of the drug will enter the blood circulation after being absorbed in the gastrointestinal tract, which can cause systemic side effects of glucocorticoids, such as Cushing's syndrome, osteoporosis, elevated blood sugar, etc. The enteric-soluble preparation makes the drug release locally in the intestine and play a role, and most of the drug is metabolized in the intestine, so the amount of drug entering the systemic circulation is reduced, thereby reducing the risk of systemic side effects.

[0005] Currently, there is only NEFECON (4mg) on the domestic market, which is used for treating adult patients with primary immunoglobulin A nephropathy (IgAN) with a risk of progression and reducing the proteinuria level, and there is no budesonide enteric-soluble sustained-release preparation (3mg) for treating Crohn's disease on the market.

[0006] Patent CN102088962A discloses a composition for oral administration of corticosteroids, wherein the budesonide enteric sustained-release capsule (4mg) contains a sustained-release component and a delayed-release component, the sustained-release component contains budesonide, sulfoxide and acid; the preparation process is relatively complex, including: ① fluidized bed bottom spraying of blank sucrose pill core, ② acid sealing layer, ③ containing aminoethyl cellulose sustained-release layer, ④ capsule filling, ⑤ enteric coating layer, etc. Among them, the fluidized bed bottom spraying time is long, the drug loading efficiency is generally more than 75%, which will cause waste of drug; and the enteric coating layer of the capsule has potential risk of dose pouring due to capsule rupture or unevenness, the sustained-release effect cannot be guaranteed after the enteric barrier is destroyed, and systemic side effects of glucocorticoids may occur. The prior art finds that the alkalinity of sulfoxide can cause degradation of budesonide, and the addition of acid-containing layer can reduce this phenomenon.

[0007] Patent CN105663091A discloses a budesonide enteric sustained-release capsule and a preparation method thereof, which is prepared by using a wet granulation process (high-speed shearing machine) to prepare drug-containing sustained-release pellets, and then enteric coating. However, the granules obtained by the wet granulation process are loose and fragile, and have poor roundness, which may cause uneven sustained-release coating and enteric coating, and the acid resistance cannot be guaranteed, so it is not suitable for coating as the core.

[0008] Patent CN101108171A discloses a budesonide enteric sustained-release pellet and a preparation method thereof, which is composed of drug-containing immediate-release pellet core, sustained-release layer and enteric layer, and budesonide is used as the active pharmaceutical ingredient, and pharmaceutical carrier excipients are used. However, it does not consider the instability of budesonide in alkaline environment, the sustained-release layer uses amino-containing ethyl cellulose (Surlease) or weakly alkaline sodium dodecyl sulfate, and no acid agent or acid sealing layer is added. SUMMARY

[0009] One of the purposes of the present application is to provide a budesonide enteric sustained-release pellet, which comprises drug-containing pellet core, sustained-release layer and enteric layer from inside to outside, and the mass ratio of the drug-containing pellet core, sustained-release layer and enteric layer is (200-300):(30-40):(38-52);

[0010] The components of the drug-containing pellet core include budesonide, filler, binder, acid agent and lubricant;

[0011] The components of the sustained-release layer include retarder, plasticizer and anti-adhesive;

[0012] The components of the enteric layer include enteric material, plasticizer and anti-adhesive.

[0013] Further, in the drug-containing pill core, the mass ratio of the budesonide, the filler, the binder, the acidic agent, and the lubricant is (3-9):(170-215):(18-26):(0.25-0.5):(8-12);

[0014] The filler is selected from microcrystalline cellulose, povidone, mannitol, sorbitol, dextrin, corn starch, sucrose, lactose, colloidal silicon dioxide, sodium lauryl sulfate;

[0015] The binder is selected from povidone, hypromellose, hydroxypropyl cellulose, methyl cellulose, sodium carboxymethyl cellulose;

[0016] The acidic agent is selected from citric acid, tartaric acid, ascorbic acid, anhydrous citric acid, lactic acid, malic acid, fumaric acid, maleic acid, oleic acid, stearic acid;

[0017] The lubricant is selected from talc, silicon dioxide, magnesium stearate, glyceryl monostearate, polyethylene glycol.

[0018] In a specific embodiment of the present application, the filler is a mixture of microcrystalline cellulose and lactose, and the mass ratio of the two is (140-180):(40-70). Microcrystalline cellulose, lactose, starch, dextrin, etc. are often used as fillers when preparing pellets by extrusion and rolling. Microcrystalline cellulose is called a spheroidizing agent because it is good at forming pellets. However, the spheroidization rate of microcrystalline cellulose alone is low. This is because cellulose compounds have strong water absorption, and a large amount of solvent needs to be added when preparing a soft material. The prepared soft material is hard and is easy to block the extrusion die when entering the extruder. Lactose, starch, and dextrin all belong to sugar compounds. When preparing a soft material, these excipients will show a certain viscosity. However, the extrudate formed by using these excipients alone is too soft and has no plasticity, and the hardness of the formed pellets is small, resulting in a low pellet yield. Therefore, microcrystalline cellulose is usually mixed with lactose, starch, dextrin, etc. to ensure smooth extrusion, and the extrudate has plasticity and humidity, so that the spheroidization rate is relatively high during rolling.

[0019] Further, in the sustained-release layer, the mass ratio of the retarder, the plasticizer, and the anti-adhesive agent is (20-30):(3-5):(5-7);

[0020] The retarder is selected from Eudragit RL, Eudragit RS, Eudragit NE30D, ethyl cellulose, Eudostar TM , Kollicoat SR30D, polymethyl methacrylate, cellulose acetate phthalate, hydroxypropyl cellulose acrylate copolymer;

[0021] The plasticizer is selected from triethyl citrate, polyethylene glycol, tributyl citrate, dibutyl sebacate;

[0022] The anti-adhesion agent is selected from talc, silicon dioxide, magnesium stearate and glycerol monostearate.

[0023] In one embodiment of the present application, the retardant is a mixture of Eudragit RL and Eudragit RS, with a mass ratio of (10-15):(10-15). The Eudragit RL / RS used is insoluble in water but can swell to form pores in the coating film. The pore diameter of Eudragit RL is 1-5 μm and that of Eudragit RS is 0.1-0.6 μm. The drug inside the coating is released through these pores. By adjusting the ratio of the two materials and the coating amount, the release rate of the drug can be adjusted. The hydrophilicity of Eudragit RL / RS is independent of pH in the physiological pH range (pH 1-8), so the release rate of the sustained-release preparation is independent of the pH difference in the gastrointestinal tract of different human bodies. The coating composition copolymer without alkali can avoid the contact of budesonide with alkali coating materials, and it also contains a large number of carboxyl groups, which can resist the introduction of alkaline factors in the prescription and process.

[0024] Further, in the enteric layer, the mass ratio of the enteric material, the plasticizer and the anti-adhesion agent is (20-28):(2-2.8):(10-14);

[0025] The enteric material is selected from methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, cellulose acetate phthalate and hydroxypropyl methyl cellulose succinate;

[0026] The plasticizer is selected from triethyl citrate, dibutyl sebacate and propylene glycol;

[0027] The anti-adhesion agent is selected from glycerol monostearate, talc and magnesium stearate.

[0028] In one embodiment of the present application, the enteric material is methacrylic acid-ethyl acrylate copolymer. The methacrylic acid-ethyl acrylate copolymer can form a uniform and dense film on the surface of the budesonide sustained-release pellet, improving the integrity and stability of the coating. It is stable and does not dissolve in the gastric acid environment (pH <5.5), which can effectively protect the drug from damage by gastric acid; it dissolves quickly in the intestinal environment (pH ≥5.5), achieving precise drug release in the intestine and ensuring that budesonide can play a role in the appropriate site. In addition, the methacrylic acid-ethyl acrylate copolymer has water dispersion and powder forms to choose from, which is convenient for application in different production processes and easy to operate with high production efficiency.

[0029] The second object of the present application is to provide a preparation method of the budesonide enteric sustained-release pellet as described above, which comprises the following steps:

[0030] Step 1, micronize budesonide raw material to an average particle size of 1-5 μm. Budesonide has poor water solubility, and micronization can increase the specific surface area of the drug, accelerate dissolution, and improve the rate and extent of absorption in vivo. In addition, budesonide has a small size and a small proportion in the composition, and the particle size distribution is more uniform after micronization, which can reduce the problems of aggregation and caking caused by uneven particle size, and improve the stability and uniformity of the preparation.

[0031] Step 2, mix the micronized budesonide, filler, binder, acidifying agent and lubricant, add a wetting agent to prepare a soft material, use the extrusion-spheronization method to prepare a budesonide-containing pellet core, dry to a water content of less than 3%, and sieve to obtain a drug-containing pellet core of 0.4-0.8 mm. The speed of rolling into pellets is 1000-1500 rpm, and the time is 2-6 minutes.

[0032] Step 3, add the retardant, plasticizer and anti-adhesive to the solvent to obtain a sustained-release layer coating liquid, use the fluidized bed to coat the drug-containing pellet core, and dry to a water content of less than 2%. The spraying rate of coating is 0.5-1.5 mL / min, the air flow rate is 10-20 cubic meters / hour, and the air inlet temperature is 30-40℃.

[0033] Step 4, add the enteric material, plasticizer and anti-adhesive to the solvent to obtain an enteric layer coating liquid, use the fluidized bed to coat the pellet core of step 3, and dry to a water content of less than 3% to obtain the budesonide enteric sustained-release pellet. The spraying rate of coating is 0.5-2 mL / min, the air flow rate is 15-25 cubic meters / hour, and the air inlet temperature is 35-45℃.

[0034] The third object of the present application is to provide a pharmaceutical composition comprising the above-mentioned budesonide enteric sustained-release pellet. The pellet can be filled in a pharmaceutically acceptable package, and the patient can directly swallow after removing the package; or the pellet can be filled in a capsule alone or mixed with suitable excipients, and the patient can take it in the form of a capsule; or the pellet can be formed into a dry suspension with suitable suspending agents, pH adjusting agents, flavoring agents, etc., and the patient can take it after mixing with an appropriate amount of water.

[0035] The fourth object of the present application is to provide the use of the above-mentioned budesonide enteric sustained-release pellet or the above-mentioned pharmaceutical composition in the preparation of a drug for treating inflammatory diseases of the intestinal tract.

[0036] Further, the inflammatory disease of the intestinal tract is Crohn's disease.

[0037] The budesonide is first prepared into a drug-containing pellet core through an extrusion and rolling process with excipients, and then a sustained-release layer and an enteric layer are coated on the drug-containing pellet core in sequence through a fluidized bed coating to obtain the budesonide enteric sustained-release pellet. The budesonide enteric sustained-release pellet cannot be released and absorbed in the stomach, and the effect gradually starts after reaching the intestine, and a suitable concentration level is maintained in the blood in the body, which is beneficial to the targeted and sustained treatment of inflammatory bowel diseases.

[0038] Compared with the prior art, the budesonide enteric sustained-release pellet has the advantages and beneficial effects that:

[0039] 1. Since the blank pellet core is used as the basis, the fluidized bed bottom is sprayed with the medicine, the material is contacted with the atomized liquid drops in the guide cylinder to complete the coating, and then the material is dried by hot air outside the guide cylinder, and then enters the guide cylinder again for the next coating-drying cycle. The whole process is relatively slow, and a complete coating process may need to last for several hours or even dozens of hours, which seriously restricts the production efficiency. In addition, fluctuations in liquid spraying speed, drying temperature and spraying pressure may cause the medicine liquid to be blown away, resulting in loss of medicine coating, and there are defects of low medicine coating rate and instability between batches. The extrusion and rolling process used in the present application can automatically and continuously produce the drug-containing pellet core by mixing and wetting the medicine and the corresponding excipients, has large production capacity, can greatly shorten the production cycle, improve the production efficiency, reduce the production cost, is suitable for large-scale industrial production, and has high batch consistency.

[0040] 2. In order to avoid the contact between the main drug component and the alkaline coating component, resulting in the degradation and destruction of the component, the present application considers using a coating component without alkali, such as ethyl acrylate, methyl methacrylate and chloromethyl trimethylamine ethyl methacrylate copolymer, so that the main drug component does not contact with the alkaline component; the coating component copolymer without alkali also contains a large amount of carboxyl groups, which can resist the alkaline factors that may be introduced in the prescription and process; at the same time, the addition of acidifying agent in the tablet core can play a multiple protection role and increase the stability of the medicine.

[0041] 3. In order to avoid the situation that the enteric layer is coated on the capsule, the capsule is not uniform due to uneven enteric layer coating, is accidentally damaged or is damaged by the patient, cannot tolerate the acidic environment, and loses the enteric effect, the present application uses enteric pellets as multiple unit preparations, and the defects of individual unit preparations will not cause drug burst release and have less influence on the whole preparation. Compared with the relative unit preparations (such as sustained-release tablets, capsules, etc.), the incidence of adverse reactions is lower. In addition, the pellets are dispersed and distributed in the gastrointestinal tract, the local drug concentration is reduced, and the irritability to the gastrointestinal tract can be effectively reduced.

[0042] 4. The present application controls the weight gain of the sustained-release layer within a reasonable range to adjust the release rate of the drug. If the weight gain is too large, the release of the main drug component inside is too slow, affecting the drug efficacy and bioavailability; if the weight gain is too small, the main drug component cannot be effectively sustained-released. In combination with the onset site of budesonide in the intestinal tract, the inventors set the weight gain of the sustained-release layer at (10%-20%) through optimization experiments; within this weight gain range, budesonide can be continuously and completely released after entering the intestinal tract.

[0043] 5. The present application controls the weight gain of the enteric layer within a reasonable range to ensure the acid resistance of the product: if the weight gain is too large, it is not conducive to the release of the main drug component inside, affecting the drug efficacy; if the weight gain is too small, it cannot effectively resist acid, and the enteric layer is prone to aging, affecting the stability. In combination with the onset site of budesonide in the intestinal tract, the inventors set the weight gain of the enteric layer at (13%-18%) through optimization experiments; within this weight gain range, budesonide can be gradually released after entering the intestinal tract without being released in the stomach. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 The dissolution curve of the budesonide enteric sustained-release pellets. DETAILED DESCRIPTION

[0045] The preferred embodiments of the present application will be described in detail below with reference to the examples. It should be understood that the following examples are given only to illustrate the present application and are not intended to limit the scope of the present application. Those skilled in the art can make various modifications and substitutions to the present application without departing from the spirit and principles of the present application.

[0046] The experimental methods used in the following examples are conventional methods unless otherwise specified.

[0047] The materials, reagents, etc. used in the following examples can be obtained from commercial channels unless otherwise specified.

[0048] Example 1

[0049] The prescription of the budesonide enteric sustained-release pellets of the present embodiment is as follows:

[0050]

[0051] The preparation method comprises the following steps:

[0052] a. The budesonide raw drug is micronized to a particle size of 1-5 μm.

[0053] b. The components of the drug-containing pellet core were weighed according to the prescription amount and mixed for 15 minutes. A suitable amount of water was added as a wetting agent to prepare a soft material. The soft material was extruded through a screen plate (pore size 0.6 mm), and the obtained strip material was placed in a round-up pot to round up into a pellet core. The pellet core was dried at 60°C until the water content was below 3%, and then sieved to obtain the target pellet core containing budesonide of 0.4-0.8 mm. The round-up speed was 1000 rpm, and the round-up time was 4 minutes. The extrusion round-up yield was 92.39%.

[0054] c. Preparation of budesonide sustained-release pellets: triethyl citrate and talc were added to 95% ethanol and homogenized; Eudragit RS100 and Eudragit RL100 were slowly added to the above 95% ethanol in turn and homogenized; and after dissolution, sieved through a 50-mesh sieve. The budesonide pellet core was placed in a fluidized bed and preheated to 30°C. The liquid spray rate was adjusted to about 0.8 mL / min, the air inlet amount was about 15 cubic meters / hour, and the air inlet temperature was about 35°C, so that the coating operation could be continuously carried out. The material temperature was maintained at 20-30°C, and the material flowed smoothly. Then the pellets were dried until the water content was below 2%.

[0055] d. Preparation of budesonide enteric sustained-release pellets: Eudragit L30D-55, propylene glycol and talc were added to water to prepare a suspension with a solid content of 25%, filtered through a 50-mesh sieve, and used as an enteric coating liquid. The budesonide sustained-release pellets were placed in a fluidized bed and preheated to 30°C. The liquid spray rate was adjusted to about 1.1 mL / min, the air inlet amount was about 20 cubic meters / hour, and the air inlet temperature was about 40°C, so that the coating operation could be continuously carried out. The material temperature was maintained at 25-35°C, and the material flowed smoothly. Then the pellets were dried until the water content was below 3%.

[0056] Example 2

[0057] The prescription of the budesonide enteric sustained-release pellets of this example is as follows:

[0058]

[0059]

[0060] The preparation method includes the following steps:

[0061] a. The budesonide raw material was micronized to a particle size of 1-5 μm.

[0062] b. The components in the drug-containing pellet cores were weighed according to the prescription amount and mixed for 15 min. A suitable amount of water was added as a wetting agent to prepare a soft material. The soft material was extruded through a screen plate (pore size 0.6 mm), and the obtained strip material was placed in a round-up pot to round up into pellet cores. The pellet cores were dried at 60°C until the water content was below 3%, and then sieved to obtain the target pellet cores containing budesonide of 0.4-0.8 mm. The round-up speed was 1400 rpm, and the round-up time was 4 min. The extrusion round-up yield was 90.44%.

[0063] c. Preparation of budesonide sustained-release pellets: triethyl citrate and talc were added to 95% ethanol and homogenized; Eudragit RS100 and Eudragit RL100 were slowly added to the above 95% ethanol in turn and homogenized; and after dissolution, sieved through a 50-mesh sieve. The budesonide pellet cores were placed in a fluidized bed and preheated to 30°C. The liquid spraying rate was adjusted to about 0.8 mL / min, the air inlet amount was about 15 cubic meters / hour, and the air inlet temperature was about 35°C, so that the coating operation could be continuously carried out. The material temperature was maintained at 20-30°C, and the material flowed smoothly. Subsequently, the pellets were dried until the water content was below 2%.

[0064] d. Preparation of budesonide enteric sustained-release pellets: Eudragit L30D-55, propylene glycol, and talc were added to water to prepare a suspension with a solid content of 25%, filtered through a 50-mesh sieve, and used as an enteric coating liquid. The budesonide sustained-release pellets were placed in a fluidized bed and preheated to 30°C. The liquid spraying rate was adjusted to about 1.1 mL / min, the air inlet amount was about 20 cubic meters / hour, and the air inlet temperature was about 40°C, so that the coating operation could be continuously carried out. The material temperature was maintained at 25-35°C, and the material flowed smoothly. Subsequently, the pellets were dried until the water content was below 3%.

[0065] Example 3

[0066] The prescription of the budesonide enteric sustained-release pellets of this example is as follows:

[0067]

[0068] The preparation method includes the following steps:

[0069] a. The budesonide raw material was micronized to a particle size of 1-5 μm.

[0070] b. The components in the drug-containing pellet cores were weighed according to the prescription amount and mixed for 15 min. A suitable amount of water was added as a wetting agent to prepare a soft material. The soft material was extruded through a screen plate (pore size 0.6 mm), and the obtained strip material was placed in a round-up pot to round up into pellet cores. The pellet cores were dried at 60°C until the water content was below 3%, and then sieved to obtain the target pellet cores containing budesonide of 0.4-0.8 mm. The round-up speed was 1400 rpm, and the round-up time was 4 min. The extrusion round-up yield was 90.44%.

[0071] c. Preparation of budesonide sustained release pellets: triethyl citrate and talc were added into 95% ethanol and homogenized; Eudragit RS100 and Eudragit RL100 were added into the above 95% ethanol and homogenized; after dissolution, the mixture was passed through a 50 mesh sieve. The budesonide pellet cores were placed in a fluid bed and preheated to 30°C. The spray rate was adjusted to about 0.8 mL / min, the air flow was about 15 cubic meters / hour and the air temperature was about 35°C, so that the coating operation could be continuously carried out. The material temperature was maintained at 20-30°C and the material flowed smoothly. Subsequently, the pellets were dried to a water content of less than 2%.

[0072] d. Preparation of budesonide enteric sustained release pellets: Eudragit L30D-55, propylene glycol and talc were added into water to form a suspension with a solid content of 25%, which was filtered through a 50 mesh sieve and used as the enteric coating solution. The budesonide sustained release pellets were placed in a fluid bed and preheated to 30°C. The spray rate was adjusted to about 1.1 mL / min, the air flow was about 20 cubic meters / hour and the air temperature was about 40°C, so that the coating operation could be continuously carried out. The material temperature was maintained at 25-35°C and the material flowed smoothly. Subsequently, the pellets were dried to a water content of less than 3%.

[0073] Example 4

[0074] The formulation of the budesonide enteric sustained release pellets of this example is as follows:

[0075]

[0076] The preparation method comprises the following steps:

[0077] a. The budesonide raw material was micronized to a particle size of 1-5 μm.

[0078] b. The components in the drug-containing pellet cores were weighed according to the prescription amount and mixed for 15 min. An appropriate amount of water was added as a wetting agent to prepare a soft material, which was extruded through a sieve plate (pore size 0.6 mm). The obtained strip-shaped material was placed in a round-up pot to round up into pellet cores. The pellet cores were dried at 60°C to a water content of less than 3%, and then sieved to obtain budesonide-containing target pellet cores of 0.4-0.8 mm. The round-up speed was 1200 rpm and the round-up time was 3 minutes. The extrusion round-up yield was 91.78%.

[0079] c. Preparation of budesonide sustained release pellets: triethyl citrate and talc were added into 95% ethanol and homogenized; Eudragit RS100 and Eudragit RL100 were added into the above 95% ethanol and homogenized; after dissolution, the mixture was passed through a 50 mesh sieve. The budesonide pellet cores were placed in a fluid bed and preheated to 30°C. The spray rate was adjusted to about 0.8 mL / min, the air flow was about 15 cubic meters / hour and the air temperature was about 35°C, so that the coating operation could be continuously carried out. The material temperature was maintained at 20-30°C and the material flowed smoothly. Then the pellets were dried to less than 2% moisture content.

[0080] d. Preparation of budesonide enteric sustained release pellets: Eudragit L30D-55, propylene glycol and talc were added into water to form a suspension with a solid content of 25%, which was filtered through a 50 mesh sieve and used as the enteric coating solution. The budesonide sustained release pellets were placed in a fluid bed and preheated to 30°C. The spray rate was adjusted to about 1.1 mL / min, the air flow was about 20 cubic meters / hour and the air temperature was about 40°C, so that the coating operation could be continuously carried out. The material temperature was maintained at 25-35°C and the material flowed smoothly. Then the pellets were dried to less than 3% moisture content.

[0081] Comparative Example 1

[0082] The difference between this example and Example 3 is that the drug-containing pellet cores do not contain acidifying agents, and the sustained release layer is coated with Surelease, with a coating weight gain of about 15%. The procedure is as follows:

[0083]

[0084] a. The budesonide raw material was micronized to a particle size of 1-5 μm.

[0085] b. The components in the drug-containing pellet cores were weighed according to the prescription and mixed for 15 min. A suitable amount of water was added as a wetting agent to prepare a soft material, which was extruded through a screen plate (pore size 0.6 mm). The obtained strip material was placed in a rounder pot to round into pellet cores, which were dried at 60°C to less than 3% moisture content, and then sieved to obtain the target budesonide-containing pellet cores of 0.4-0.8 mm. The rounding speed was 1200 rpm and the rounding time was 3 minutes. The extrusion rounding yield was 90.05%.

[0086] c. Preparation of budesonide sustained release pellets: Surelease (aqueous dispersion of ethyl cellulose) was diluted with water to a solid content of about 15%, stirred for at least 30 minutes and passed through a 50 mesh sieve to obtain the sustained release coating solution. The budesonide pellets were placed in a fluid bed and preheated to 40°C. The spray rate was adjusted to about 0.8 mL / min, the air flow to about 15 cubic meters / hour and the air temperature to about 35°C to allow continuous coating operation. The material temperature was maintained between 30-40°C and the material flowed smoothly. The pellets were then dried to a moisture content of less than 2%.

[0087] d. Preparation of budesonide enteric sustained release pellets: Eudragit L30D-55, propylene glycol and talc were mixed with water to a solid content of 25% and filtered through a 50 mesh sieve to obtain the enteric coating solution. The budesonide sustained release pellets were placed in a fluid bed and preheated to 30°C. The spray rate was adjusted to about 1.1 mL / min, the air flow to about 20 cubic meters / hour and the air temperature to about 40°C to allow continuous coating operation. The material temperature was maintained between 25-35°C and the material flowed smoothly. The pellets were then dried to a moisture content of less than 3%.

[0088] Example 5

[0089] Release profile of budesonide enteric sustained release pellets

[0090] The dissolution rate of budesonide enteric sustained release pellets of formulation examples 1-3 was studied at different pH values. The paddle method apparatus of the Chinese Pharmacopoeia 2020 edition was used at 100 rpm and 37°C with 900 mL of dissolution medium. After 2 hours of release testing in pH 1.2 hydrochloric acid solution, the release medium was changed to pH 6.8 phosphate buffer solution containing 0.05% Tween 80 and testing was continued for 8 hours.

[0091] The dissolution rates are provided in Table 1 and shown in the form of curves in Figure 1 .

[0092] Table 1

[0093]

[0094] From the dissolution data and curves it can be concluded that:

[0095] At pH 1.2, budesonide is not released at all;

[0096] After the change in pH to pH 6.8, budesonide is continuously released from the enteric sustained release pellets for more than 6 hours.

[0097] This ensures that budesonide is not released and absorbed in the stomach and after reaching the intestine, the action gradually begins, maintaining suitable blood levels in the body, which is advantageous for the targeted and sustained treatment of inflammatory bowel diseases.

[0098] Example 6

[0099] Stability of budesonide enteric sustained-release pellets

[0100] Table 2 below lists the budesonide in the enteric sustained-release pellets prepared in Examples 3 and 4 and stored in aluminum bags at 40°C / 75% RH for 6 months, detected by high performance liquid chromatography for the related substances in the budesonide enteric sustained-release pellets.

[0101] Total impurity limit: not more than 2%.

[0102] Table 2

[0103]

[0104] As shown in the experimental data in the table, the addition of an acidic agent such as citric acid or tartaric acid in the drug-containing pellet core and the use of a sustained-release coating composition without alkali accelerated the degradation of budesonide, with the related substances being 0.53% and 0.59%, respectively, while the total impurity of Comparative Example 1 was 2.14%. This indicates that the direct contact of sulfolane with budesonide causes the degradation of budesonide, and the addition of an acidic agent in the drug-containing pellet layer and the use of a sustained-release coating composition without alkali can significantly reduce the degradation of budesonide.

Claims

1. A budesonide enteric-coated sustained-release microsphere, characterized in that, From the inside out, it includes a drug-containing core, a sustained-release layer, and an enteric coating layer, wherein the mass ratio of the drug-containing core, sustained-release layer, and enteric coating layer is (200-300):(30-40):(38-52); The components of the pill core include budesonide, filler, binder, acidifier, and lubricant; The sustained-release layer comprises a retardant, a plasticizer, and an anti-adhesion agent; The enteric coating consists of enteric materials, plasticizers, and anti-adhesion agents.

2. The budesonide enteric-coated sustained-release microspheres according to claim 1, characterized in that, In the drug-containing pellet core, the mass ratio of budesonide, filler, binder, acidifier, and lubricant is (3-9):(170-215):(18-26):(0.25-0.5):(8-12); The filler is selected from microcrystalline cellulose, povidone, mannitol, sorbitol, dextrin, corn starch, sucrose, lactose, colloidal silica, and sodium lauryl sulfate; The acidic agent is selected from citric acid, tartaric acid, ascorbic acid, anhydrous citric acid, lactic acid, malic acid, fumaric acid, maleic acid, oleic acid, and stearic acid. The adhesive is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and sodium carboxymethyl cellulose. The lubricant is selected from talc, silica, magnesium stearate, glyceryl monostearate, and polyethylene glycol.

3. The budesonide enteric-coated sustained-release microspheres according to claim 1, characterized in that, In the sustained-release layer, the mass ratio of the inhibitor, plasticizer, and anti-adhesion agent is (20-30):(3-5):(5-7); The inhibitor is selected from Eutectic RL, Eutectic RS, Eutectic NE30D, ethyl cellulose, and Aidoxiu. TM KollicoatSR30D, polymethyl methacrylate, cellulose acetate phthalate, hydroxypropyl cellulose acrylate copolymer; The plasticizer is selected from triethyl citrate, polyethylene glycol, tributyl citrate, and dibutyl sebacate; The anti-adhesion agent is selected from talc, silica, magnesium stearate and glyceryl monostearate.

4. The budesonide enteric-coated sustained-release microspheres according to claim 1, characterized in that, In the enteric coating layer, the mass ratio of enteric material, plasticizer, and anti-adhesive is (20-28):(2-2.8):(10-14); The enteric material is selected from methacrylate-ethyl acrylate copolymer, methacrylate-methyl methacrylate copolymer, polyvinyl acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, cellulose acetate phthalate and hydroxypropyl methylcellulose acetate succinate. The plasticizer is selected from triethyl citrate, dibutyl sebacate, and propylene glycol; The anti-adhesion agent is selected from glyceryl monostearate, talc, and magnesium stearate.

5. The method for preparing budesonide enteric-coated sustained-release microspheres according to any one of claims 1-4, characterized in that, Includes the following steps: Step 1: Micronize the budesonide active pharmaceutical ingredient to an average particle size of 1-5 μm; Step 2: Mix the micronized budesonide, filler, binder, acidifier and lubricant, add wetting agent to prepare soft material, use extrusion spheronization method to obtain budesonide-containing pellet core, dry to a moisture content of less than 3%, and sieve to obtain 0.4-0.8 mm drug-containing pellet core; Step 3: Add the inhibitor, plasticizer, and anti-adhesion agent to the organic solvent to obtain the sustained-release coating solution. Coat the drug-containing pellet core using a fluidized bed and dry it until the water content is below 2%. Step 4: Add enteric material, plasticizer, and anti-adhesion agent to solvent to obtain enteric coating solution. Coat the pellet core from Step 3 using a fluidized bed and dry until the moisture content is below 3% to obtain the budesonide enteric sustained-release microspheres.

6. A pharmaceutical composition, characterized in that, Includes the budesonide enteric-coated sustained-release microspheres as described in any one of claims 1-4.

7. The use of the budesonide enteric-coated sustained-release microgranules according to any one of claims 1-4 or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating inflammatory bowel diseases.

8. The application according to claim 7, characterized in that, The inflammatory bowel disease mentioned is Crohn's disease.

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