Pharmaceutical composition containing corticosteroid and preparation method thereof

Abstract

The invention provides a corticosteroid-containing pharmaceutical composition and a preparation method thereof. The corticosteroid-containing pharmaceutical composition comprises a timely release component and a delayed / sustained release component. The delayed / sustained release component comprises a core containing a corticosteroid drug, an isolating layer and an enteric layer; the timely-released components are dissolved in the stomach after being orally taken, so that the influence of gastric emptying is effectively eliminated. In addition, by applying the enteric layer of the delayed / sustained release component, the composition has a quick release or / and sustained release function, and the purposes of effectively controlling the drug release speed of the composition in the intestinal tract, maintaining the in-vivo blood concentration of the corticosteroid drug, improving the bioavailability and reducing the drug release risk and the in-vivo individual difference can be achieved; the invention also realizes simplification of the preparation process.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to a pharmaceutical composition containing corticosteroids and a preparation method thereof. Background Art

[0002] Corticosteroids such as budesonide treat intestinal inflammatory diseases such as Crohn's disease and ulcerative colitis by inhibiting the inflammatory response.Budesonide is a glucocorticoid with a highly effective local anti-inflammatory effect, which has anti-inflammatory, anti-allergic, antipruritic and anti-exudative effects.Budesonide can enhance the stability of endothelial cells, smooth muscle cells and lysosomal membranes, inhibit immune responses and reduce antibody synthesis, thereby reducing the release and activity of allergic active mediators such as histamine, and can reduce the enzymatic process stimulated by antigen-antibody binding, inhibit the synthesis and release of bronchial contractile substances and reduce the contractile reaction of smooth muscle.Budesonide's aerosols, sprays, powder sprays, etc. are widely used in clinical glucocorticoid-dependent or non-dependent bronchial asthma and asthmatic bronchitis. In addition, studies have shown that the effect of budesonide in treating inflammatory bowel diseases such as ulcerative colitis and collagenous colitis is worthy of recognition.

[0003] In October 2001, the US FDA approved its enteric-coated micropellet capsules for the maintenance of mild to moderate segmental ileitis, i.e. Crohn's disease, involving the ileum and / or ascending colon. According to the main pathogenesis model, the preparation is designed to deliver drugs to the Peyer's patch area of ​​the lower small intestine where the disease originates. The US Food and Drug Administration (FDA) has accepted the new drug application (NDA) for the oral patented preparation Nefecon (budesonide) of the Swedish biopharmaceutical company Calliditas Therapeutics and granted priority review. This is a new oral preparation of budesonide, which is an IgA1 downregulator that treats IgA nephropathy (IgAN) by targeting downregulation of IgA1. Nefecon is derived from TARGIT technology, which allows substances to pass through the stomach and intestines without being absorbed and can only be released in a pulsed manner when they reach the lower part of the small intestine.

[0004] On December 15, 2021, the U.S. FDA approved TARPEYO (targeted delayed-release budesonide capsules) produced by Calliditas Therapeutics for marketing to reduce urinary protein. This is currently the only drug approved in the world for reducing proteinuria in IgA nephropathy, and it is expensive. The preparation is an enteric-coated capsule filled with sustained-release micropellets. The sustained-release micropellets are coated with three layers from the inside to the outside, namely, a drug-containing layer, an isolation layer, and a sustained-release layer. The enteric function is achieved by an unconventional production process in which the capsule shell is coated with an enteric layer. The preparation process of this product is complex, and the enteric coating of hard capsules is prone to poor sealing. Eliminating the gaps in the capsule seams requires a high coating process, and there is a risk of drug gastric emptying through the pylorus being blocked, and there are large individual differences in the body.

[0005] CN101108171A discloses a budesonide enteric-coated sustained-release pellet and a preparation method thereof, which consists of a drug-containing rapid-release pellet core, a sustained-release layer and an enteric-coated layer. The patent only considers the release rate of the drug itself, and achieves the effect of controlling drug release through a sustained-release layer + sustained-release material; however, the release pattern of the prepared drug and the reference preparation (original drug) is not considered, and the release pattern of the drug directly affects the bioavailability of the drug.

[0006] In view of this, the technical problem solved by the present invention is to provide a pharmaceutical composition of an orally administrable corticosteroid, especially budesonide, and a preparation method thereof. The present invention simplifies the preparation process, makes the gastric emptying time more regular, reduces the risk of gastric drug release, and reduces clinical individual differences. Summary of the invention

[0007] In order to solve the defects of the original formulation TARPEYO budesonide enteric-coated pellets in terms of drug release in the stomach and large individual differences, the present invention provides a pharmaceutical composition that allows budesonide to reach the area to be treated, such as the inflamed part of the intestine, at a sufficient concentration and last in the area for a sufficiently long time to provide a local therapeutic effect. The sustained-release component used in the prior art controls the sustained release, and the processed capsule shell achieves the localized release, so that after the composition is taken orally, the sustained-release component is first released from the capsule in the intestine or a part of the intestine or a specific part of the intestine. The capsule shell has the problems of complex preparation process, irregular emptying and release in the human body, etc. In view of this problem of the prior art, the present invention sets an enteric layer on the outermost layer of the budesonide composition. On the one hand, by timely releasing components, it is ensured that the composition containing budesonide is released in the stomach, so that the gastric emptying time is more regular and the composition with the enteric layer will not release the drug in the stomach. When reaching the intestine or a part of the intestine or a specific part of the intestine, the delayed release part (enteric layer) dissolves or decomposes to achieve continuous positioning release in the intestine or a part of the intestine or a specific part of the intestine; on the other hand, by screening different enteric materials and adopting different coating conditions, the prepared compositions are not released in the stomach, and start to release slowly after entering the small intestine, and the release is uniform; the release rate of the composition is also controlled by screening the material composition of different enteric layers, so as to achieve a law similar to that of the original drug release, and improve the bioavailability of the drug. The enteric composition of the present invention can effectively control the drug from being released in the stomach, and only starts to release slowly after entering the small intestine, and most of the drugs are released in diseased areas such as the distal end of the small intestine, the ileocecal part, and the colon, and the release law is similar to that of the reference preparation.

[0008] Furthermore, the budesonide composition provided by the present invention also uses a delayed release component and a sustained release component, which are components with different drug release durations / times, so that the composition has quick-release and sustained-release functions, so as to control the drug release rate of the composition in the intestinal tract or in a part of the intestinal tract or in a specific part of the intestinal tract, maintain the blood concentration of budesonide in the body, improve bioavailability, reduce the risk of drug release and the purpose of individual differences in the body. The preparation process provided by the present invention simplifies the preparation process.

[0009] In one aspect, the present invention provides a pharmaceutical composition containing corticosteroids, which achieves controlled / sustained release of the drug, and comprises a timely release component and a delayed / sustained release component.

[0010] Further, the delayed / sustained release component comprises a core containing a corticosteroid, a separation layer and an enteric layer;

[0011] In the present invention, the immediate release component dissolves in the stomach after oral administration.

[0012] Furthermore, the timely release component is a capsule shell, that is, the capsule shell is a gastric soluble capsule, and the capsule shell dissolves in the stomach to release the delayed / sustained release component. Therefore, the preparation of the present application is not affected by gastric emptying, the peak is more regular, and the inter-individual and intra-individual variations are reduced.

[0013] In the present invention, the gastric soluble capsule is a prior art. For example, the material of the capsule shell is selected from starch, hydroxypropyl methylcellulose, PVA, pullulan or gelatin.

[0014] Furthermore, the core containing the corticosteroid is coated with a separation layer, and the separation layer is coated with an enteric layer.

[0015] Furthermore, the core containing corticosteroid refers to a blank core coated with corticosteroid.

[0016] In the present invention, the blank core is the prior art.

[0017] Preferably, the blank core may be a pill core, a tablet core, etc., preferably a pill core.

[0018] Furthermore, the blank core refers to a sucrose core, a lactose core, a starch core or a microcrystalline cellulose core, etc., and the blank core can be purchased commercially.

[0019] Further, the corticosteroid drugs include but are not limited to any one or more combinations of alclomethasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, methylprednisolone, mometasone, prednisolone, triamcinolone, fluticasone, ciclesonide, fludrocortisone and budesonide.

[0020] Preferably, the corticosteroid is budesonide.

[0021] Furthermore, the corticosteroid-containing core may further contain a first binder and a first anti-adhesive agent.

[0022] Furthermore, the corticosteroid-containing core may further contain a defoaming agent for eliminating foam during the preparation of the corticosteroid-containing core and maintaining the regularity and stability of subsequent drug release.

[0023] Furthermore, the isolation layer comprises a second adhesive and a second anti-adhesive agent. The isolation layer is mainly used to prevent the enteric layer from directly contacting the core containing the corticosteroid, thereby achieving an isolation effect.

[0024] Furthermore, the isolation layer may further include a stabilizer. The stabilizer is mainly used to stabilize corticosteroids such as budesonide in order to create an acidic environment and improve the stability of the drug during storage.

[0025] Furthermore, the enteric layer comprises an enteric material, a plasticizer and a third anti-adhesive agent.

[0026] Furthermore, in the pharmaceutical composition, by weight, the corticosteroid accounts for 0.1 to 5 parts, the blank pill core accounts for 40 to 90 parts, the first adhesive accounts for 1 to 10 parts, the first anti-adhesive agent accounts for 0.1 to 10 parts, the second adhesive accounts for 1 to 10 parts, the second anti-adhesive agent accounts for 0.1 to 10 parts, the third anti-adhesive agent accounts for 0.1 to 10 parts, the enteric material accounts for 5 to 70 parts, and the plasticizer accounts for 0.1 to 5 parts.

[0027] Furthermore, the pharmaceutical composition further comprises, by weight, 0.01 to 0.1 parts of a defoaming agent and 0.05 to 0.5 parts of a stabilizer.

[0028] Further preferably, in the pharmaceutical composition, by weight, the corticosteroid accounts for 0.5 to 2 parts, the blank pill core accounts for 45 to 85 parts, the first binder accounts for 3 to 9 parts, the first anti-adhesive agent accounts for 1 to 4 parts, the second binder accounts for 1 to 5 parts, the second anti-adhesive agent accounts for 0.5 to 2 parts, the third anti-adhesive agent accounts for 4 to 10 parts, the enteric material accounts for 5 to 60 parts, and the plasticizer accounts for 0.5 to 3.5 parts.

[0029] Furthermore, in the pharmaceutical composition, by weight percentage, the corticosteroid accounts for 0.4-2%, the blank pill core accounts for 35-75%, the first adhesive accounts for 2-7.5%, the first anti-adhesive agent accounts for 0.5-3.5%, the second adhesive accounts for 0.5-4.5%, the second anti-adhesive agent accounts for 0.4-2%, the third anti-adhesive agent accounts for 3-8.5%, the enteric material accounts for 4-50%, and the plasticizer accounts for 0.4-3%.

[0030] Furthermore, in the pharmaceutical composition, the proportion of corticosteroids can be selected from 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.5%, 1.7%, 2%, the proportion of blank pill cores can be selected from 35%, 40%, 45%, 50%, 52%, 55%, 58%, 60%, 63%, 65%, 67%, 69%, 70%, 75%, and the proportion of the first adhesive can be selected from 2%, 3%, 4% and 5%. 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, the first anti-adhesive agent ratio can be selected from 0.5%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2%, 2.5%, 3%, 3.5%, the second adhesive ratio can be selected from 0.5%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2% , 2.2%, 2.3%, 2.5%, 2.8%, 3%, 3.5%, 4%, 4.5%, the second anti-adhesive agent ratio can be selected from 0.4%, 0.45%, 0.47%, 0.5%, 0.55%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2%, the third anti-adhesive agent ratio can be selected from 3%, 3.5%, 4% , 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, the proportion of enteric material can be selected from 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, the proportion of plasticizer can be selected from 0.4%, 0.5%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2%, 2.5%, 3%. Further, the pharmaceutical composition also includes a defoaming agent accounting for 0.01% to 0.1%, and a stabilizer accounting for 0.05 to 0.5%. Furthermore, the pharmaceutical composition further includes, by weight percentage, a defoaming agent which may be selected from 0.01%, 0.02%, 0.03%, 0.05%, 0.06%, 0.08%, and 0.1%, and a stabilizer which may be 0.05%, 0.06%, 0.08%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, and 0.5%.

[0031] Furthermore, the pharmaceutical composition is pH-dependent; after reaching a specific pH position in the intestine, the enteric material of the outer layer of the composition dissolves, and the active pharmaceutical ingredient is released and absorbed.

[0032] Furthermore, the first binder and the second binder are each independently selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, povidone (e.g., povidone K30), Opadry, starch, polymethacrylates, polyvinyl pyrrolidone, gelatin, gum arabic, and zein.

[0033] Furthermore, the first anti-adhesive agent, the second anti-adhesive agent and the third anti-adhesive agent are each independently selected from one or more of talc, stearic acid, magnesium stearate, glyceryl monostearate and silicon dioxide.

[0034] Furthermore, the defoaming agent is selected from one or more of silicone, silane, polydimethylsiloxane (PDMS), hydrophobic silica, dimethyl silicone oil, simethicone, and n-octanol.

[0035] Furthermore, the stabilizer is selected from one or more of calcium carbonate, sodium carbonate, sodium bicarbonate, calcium oxide, calcium hydroxide, arginine, meglumine, magnesium oxide, magnesium hydroxide, disodium hydrogen phosphate, sodium phosphate, polysorbate, poloxamer, phosphoric acid, potassium dihydrogen phosphate, citric acid, malic acid, citric acid, and sodium bicarbonate.

[0036] Furthermore, the enteric material is selected from one or more of methacrylic acid copolymer type A (a copolymer of methacrylic acid and methyl methacrylate (1:1)), methacrylic acid copolymer type B (a copolymer of methacrylic acid and methyl methacrylate (1:2)), methacrylic acid copolymer type C, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, cellulose acetate propionate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl ethylcellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate trioctyl ester, cellulose acetate phthalate, polyvinyl acetate phthalate, and hydroxypropyl methylcellulose phthalate.

[0037] Furthermore, the enteric material is a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B in a mass ratio of 1:0.6 to 3, preferably a mixture of 1:0.8 to 2, for example, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3 and the like.

[0038] Furthermore, the plasticizer is selected from one or more of triethyl citrate, polyethylene glycol 6000, dibutyl sebacate, diethyl sebacate, 1,2-propylene glycol, tributyl citrate, dimethyl phthalate, diethyl phthalate, and dibutyl phthalate.

[0039] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, hydroxypropyl cellulose, talc, triethyl citrate, and a methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0040] Furthermore, the pharmaceutical composition comprises budesonide, sucrose core, povidone K30, talc, hydroxypropyl cellulose, polyethylene glycol 6000, and methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0041] Furthermore, the pharmaceutical composition comprises budesonide, a lactose core, ethyl cellulose, stearic acid, dibutyl sebacate, and an aqueous dispersion of a methacrylic acid ethyl acrylate copolymer.

[0042] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, povidone K30, talc, triethyl citrate, and a methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0043] Furthermore, the pharmaceutical composition comprises budesonide, microcrystalline cellulose core, starch, magnesium stearate, talc, sodium carboxymethylcellulose, triethyl citrate, and methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0044] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, hypromellose, talc, polyethylene glycol 6000, and methacrylic acid copolymer type B.

[0045] Furthermore, the pharmaceutical composition comprises budesonide, starch core, ethyl cellulose, glyceryl monostearate, polyethylene glycol 6000, and methacrylic acid copolymer type C.

[0046] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, sodium carboxymethylcellulose, talc, tributyl citrate, and methacrylic acid copolymer type A.

[0047] Furthermore, the pharmaceutical composition comprises budesonide, sucrose core, povidone K30, talc, polyethylene glycol 6000, and methacrylic acid copolymer type B.

[0048] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, povidone K30, talc, hypromellose, magnesium stearate, diethyl sebacate, and methacrylic acid copolymer type B.

[0049] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, talc, hypromellose, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B.

[0050] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, talc, hypromellose, dimethicone, citric acid, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B.

[0051] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, talc, hypromellose, simethicone, potassium dihydrogen phosphate, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B.

[0052] Furthermore, in the pharmaceutical composition, the delayed / sustained release component is selected from one or both of a sustained release component and a delayed release component. Furthermore, when the delayed / sustained release component is a mixture of a sustained release component and a delayed release component, the ratio of the sustained release component to the delayed release component is 1-10:1-10, preferably 1:1, 2:1, 1:2, 1:3, 3:1, 1:4, 4:1, 1:5, 5:1, 1:6, 6:1, 1:9, 9:1, etc.

[0053] Furthermore, in the delayed-release component, the enteric layer comprises a first enteric material, a plasticizer and a third anti-adhesive agent;

[0054] The first enteric material is selected from methacrylic acid-ethyl acrylate copolymer aqueous dispersion, a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion and methacrylic acid copolymer type A, a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion and methacrylic acid copolymer type B, a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion and methacrylic acid copolymer type C, and a mixture of methacrylic acid copolymer type B and methacrylic acid copolymer type A.

[0055] The plasticizer, the third anti-sticking agent, the stabilizer and the defoaming agent are as described in the present invention.

[0056] Furthermore, the delayed-release component, by weight percentage, comprises 0.5-1.5% of corticosteroid, 45-55% of blank pill core, 3-6% of first adhesive, 0.8-1.5% of first anti-adhesive, 1-2% of second adhesive, 0.4-1% of second anti-adhesive, 3.5-6.5% of third anti-adhesive, 25-45% of enteric material, and 0.5-1.5% of plasticizer.

[0057] Furthermore, in the delayed-release component, by weight percentage, the proportion of corticosteroids may be selected from 0.5%, 1%, and 1.5%, the proportion of blank pill cores may be selected from 45%, 50%, and 55%, the proportion of the first adhesive may be selected from 3%, 4%, 5%, and 6%, the proportion of the first anti-adhesive may be selected from 0.8%, 1%, 1.2%, 1.4%, and 1.5%, the proportion of the second adhesive may be selected from 1%, 1.5%, and 2%, the proportion of the second anti-adhesive may be selected from 0.4%, 0.5%, and 1%, the proportion of the third anti-adhesive may be selected from 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, and 6.5%, the proportion of enteric material may be selected from 25%, 30%, 35%, 40%, and 45%, and the proportion of plasticizer may be selected from 0.5%, 1%, and 1.5%.

[0058] Furthermore, in the sustained-release component, the enteric layer includes a second enteric material, a plasticizer and a third anti-adhesive agent;

[0059] The second enteric material is selected from methacrylic acid copolymer type A, methacrylic acid copolymer type B, methacrylic acid copolymer type C, a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B, a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type C, a mixture of methacrylic acid copolymer type B and methacrylic acid copolymer type B, and a mixture of methacrylic acid copolymer type B and methacrylic acid copolymer type A.

[0060] The plasticizer, the third anti-sticking agent, the stabilizer and the defoaming agent are as described in the present invention.

[0061] Furthermore, the sustained-release component, by weight percentage, comprises 0.5-1.5% of corticosteroid, 60-70% of blank pill core, 5.5-7.5% of the first adhesive, 1-2% of the first anti-adhesive, 1.5-3% of the second adhesive, 0.4-1% of the second anti-adhesive, 3-5% of the third anti-adhesive, 7-20% of the enteric material, and 1-3% of the plasticizer.

[0062] Furthermore, in the sustained-release component, by weight percentage, the proportion of corticosteroids may be selected from 0.5%, 1%, and 1.5%, the proportion of blank pill cores may be selected from 60%, 65%, and 70%, the proportion of the first adhesive may be selected from 5.5%, 6%, 6.5%, 7%, and 7.5%, the proportion of the first anti-adhesive may be selected from 1%, 1.5%, and 2%, the proportion of the second adhesive may be selected from 1.5%, 2%, 2.5%, and 3%, the proportion of the second anti-adhesive may be selected from 0.4%, 0.6%, 0.8%, and 1%, the proportion of the third anti-adhesive may be selected from 3%, 4%, and 5%, the proportion of enteric material may be selected from 7%, 5%, 10%, 15%, and 20%, and the proportion of plasticizer may be selected from 1%, 1.5%, 2%, 2.5%, and 3%. Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, hypromellose, talc, triethyl citrate, a methacrylic acid-ethyl acrylate copolymer aqueous dispersion, polyethylene glycol 6000, and a methacrylic acid copolymer type B.

[0063] Furthermore, the pharmaceutical composition comprises budesonide, sucrose core, povidone K30, talc, triethyl citrate, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, polyethylene glycol 6000, and methacrylic acid copolymer type B.

[0064] Furthermore, the pharmaceutical composition comprises budesonide, sucrose core, povidone K30, hydroxypropyl methylcellulose, talc, hydroxypropyl cellulose, triethyl citrate, cellulose acetate propionate, dibutyl sebacate, and methacrylic acid copolymer type B.

[0065] Further preferably, the gastric soluble capsule is a gelatin capsule.

[0066] Furthermore, the pharmaceutical composition of the present invention is in the form of tablets, microtablets, granules, pills, etc., or the sustained-release component and delayed-release component are in the form of tablets, microtablets, granules, pills, etc., and the timely-release component is further coated.

[0067] In another aspect, the present invention provides a pharmaceutical composition containing corticosteroids, comprising or consisting of the following components: an immediate release component and a delayed release component. Further, the delayed release component comprises a core containing corticosteroids, a separation layer and an enteric layer; and the immediate release component dissolves in the stomach after oral administration.

[0068] In the present invention, the corticosteroid includes one or more of alclomethasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, methylprednisolone, mometasone, prednisolone, triamcinolone, fluticasone, ciclesonide, fludrocortisone or budesonide.

[0069] Furthermore, the timely release component is a capsule shell, that is, the capsule shell is a gastric soluble capsule, the capsule shell dissolves in the stomach, and releases the delayed release component, so the preparation of the present application is not affected by gastric emptying, the peak is more regular, and the inter-individual and intra-individual variations are reduced. The material of the capsule shell is selected from starch, hydroxypropyl methylcellulose, PVA, pullulan or gelatin.

[0070] Furthermore, the core containing the corticosteroid is coated with a separation layer, and the separation layer is coated with an enteric layer.

[0071] Further, the core containing corticosteroid refers to a corticosteroid coated on a blank core. The blank core can be a pill core, a tablet core, etc., preferably a pill core. Further, the blank core refers to a sucrose core, a lactose core, a starch core or a microcrystalline cellulose core, etc., and the blank core can be commercially available.

[0072] Furthermore, the corticosteroid drug is budesonide.

[0073] Further, the core containing corticosteroid may further contain a first binder, a defoamer and a first anti-adherent. Further, the isolation layer comprises a second binder, a stabilizer and a second anti-adherent. Further, the enteric layer comprises an enteric material, a plasticizer and a third anti-adherent.

[0074] Furthermore, in the pharmaceutical composition, by weight percentage, the corticosteroid accounts for 0.4-2%, the blank pill core accounts for 35-75%, the first adhesive accounts for 2-7.5%, the first anti-adhesive agent accounts for 0.5-3.5%, the second adhesive accounts for 0.5-4.5%, the second anti-adhesive agent accounts for 0.4-2%, the third anti-adhesive agent accounts for 3-8.5%, the enteric material accounts for 4-50%, the plasticizer accounts for 0.4-3%, the defoaming agent accounts for 0.01%-0.1%, and the stabilizer accounts for 0.05-0.5%.

[0075] Further, in the pharmaceutical composition, by weight percentage, the proportion of corticosteroid can be selected from 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.5%, 1.7%, 2%, the proportion of blank pill core can be selected from 35%, 40%, 45%, 50%, 52%, 55%, 58%, 60%, 63%, 65%, 67%, 69%, 70%, 75%, the proportion of the first adhesive can be selected from 2%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, The first anti-adhesive agent ratio can be selected from 0.5%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2%, 2.5%, 3%, 3.5%, the second adhesive ratio can be selected from 0.5%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2%, 2.2%, 2.3%, 2.5%, 2.8%, 3%, 3.5%, 4%, 4.5%, the second anti-adhesive agent ratio can be selected from 0.4%, 0.45%, 0.47% , 0.5%, 0.55%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2%, the third anti-adhesive agent may be selected from 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, the enteric material may be selected from 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, the plasticizer may be selected from The ratio can be selected from 0.4%, 0.5%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2%, 2.5%, 3%; the defoaming agent ratio can be selected from 0.01%, 0.02%, 0.03%, 0.05%, 0.06%, 0.08%, 0.1%; the stabilizer ratio can be selected from 0.05%, 0.06%, 0.08%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%.

[0076] Furthermore, the first binder and the second binder are each independently selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, and ethyl cellulose.

[0077] Furthermore, the first anti-adhesive agent, the second anti-adhesive agent and the third anti-adhesive agent are each independently selected from one or more of talc, stearic acid and magnesium stearate.

[0078] Further, the defoaming agent is selected from one or more of hydrophobic silicon dioxide, dimethyl silicone oil, and simethicone. Further, the stabilizer is selected from one or more of citric acid, malic acid, and citric acid.

[0079] Furthermore, the enteric material is selected from one or more of methacrylic acid copolymer type A, methacrylic acid copolymer type B, and methacrylic acid copolymer type C.

[0080] Furthermore, the plasticizer is selected from one or more of triethyl citrate and polyethylene glycol 6000.

[0081] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, talc, hypromellose, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B.

[0082] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, talc, hypromellose, dimethicone, citric acid, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B.

[0083] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, talc, hypromellose, simethicone, potassium dihydrogen phosphate, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B.

[0084] Furthermore, the enteric material is a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B.

[0085] The inventor further discovered through experiments that the release of the drug can be effectively controlled by selecting the material of the enteric layer, for example, the release of the drug in the designated position of the intestine can be controlled, and the total release time can be controlled. However, the enteric materials composed of different materials have different amounts of drug released in different time periods. For example: the drug coated with some enteric materials (such as methacrylic acid copolymer type A) is released quickly after entering the designated position, and the drug coated with some enteric materials (methacrylic acid copolymer type B) is released slowly after entering the designated position. Therefore, the specific selection of enteric materials is also targeted.

[0086] Furthermore, in order to make the prepared drug as close as possible to the reference preparation (original drug) and maintain the same or similar release pattern as the original drug (total release time, release rate, release amount in different stages), the inventors further studied and experimented on the enteric material. Through experimental verification, a more preferred technical solution was obtained: the enteric material is a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B in a mass ratio of 1:0.6 to 3, preferably a mixture of 1:0.8 to 2. For example, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, etc. Strictly controlling the dosage ratio of methacrylic acid copolymer type A and methacrylic acid copolymer type B in the enteric material can make the release pattern of the prepared drug very close to that of the reference preparation (original drug), achieving the technical effect of reduction, thereby reducing the risk of drug release and individual differences in the body, and improving the bioavailability of the drug.

[0087] Furthermore, the pharmaceutical composition comprises, by weight percentage, 0.5-1.5% budesonide, 65-70% sucrose core, 5-10% talc, 5-10% hydroxypropyl methylcellulose, 0.01-0.1% dimethicone, 0.1-0.2% citric acid, 1.2-2.5% triethyl citrate, 5-10% methacrylic acid copolymer type A, and 5-10% methacrylic acid copolymer type B.

[0088] On the other hand, the method for preparing the pharmaceutical composition of the present invention comprises: the steps of preparing a core containing a corticosteroid drug, coating the core containing a corticosteroid drug with an isolation layer, and coating the isolation layer with an enteric layer; and further comprises the step of mixing a delayed-release component and a sustained-release component.

[0089] Furthermore, the method comprises the following steps:

[0090] Step 1: preparing a first suspension containing a corticosteroid drug, a first adhesive and a first anti-adhesive agent; coating the first suspension on a blank pill core to form a core containing a corticosteroid drug;

[0091] Step 2: a second solution is prepared with a second adhesive and a second anti-adhesive agent, and the second solution is coated on the core containing the corticosteroid drug to form an isolation layer;

[0092] Step 3: prepare a third solution with the enteric material, plasticizer and anti-adhesive agent; coat the third solution to form an enteric layer to obtain a delayed / sustained release component.

[0093] Furthermore, the first suspension also contains a defoaming agent. During the homogenization process of preparing the core containing the corticosteroid drug, a large amount of foam will appear, and the defoaming agent is used to defoam.

[0094] Furthermore, the second solution also contains a stabilizer, which is mainly used to stabilize corticosteroids such as budesonide, create an acidic environment, and facilitate storage stability.

[0095] Furthermore, the prepared delayed / sustained release component is coated in the immediate release component to obtain a pharmaceutical composition. Furthermore, the delayed release component and the sustained release component are mixed in proportion and then coated in the immediate release component to obtain a pharmaceutical composition.

[0096] In another aspect, the present invention provides a use of the pharmaceutical composition of the present invention in the preparation of a medicament for treating an inflammatory disease of the gastrointestinal tract or for treating glomerulonephritis. Further, the inflammatory disease of the gastrointestinal tract refers to glomerulonephritis, and the glomerulonephritis is adapted to provide a sustained drug release for 2 to 6 hours. Further, the glomerulonephritis refers to Crohn's disease or ulcerative colitis.

[0097] In the present invention, hydroxypropyl cellulose (CAS No. 9004-64-2), hydroxypropyl methylcellulose (CAS No. 9004-65-3), sodium carboxymethyl cellulose (CAS No. 9004-32-4), ethyl cellulose (CAS No. 9004-57-3), povidone (CAS No. 9003-39-8), Opadry (CAS No. 9004-35-7), starch (CAS No. 9005-25-8), polyvinyl pyrrolidone (CAS No. 9003-39-8), gelatin (CAS No. 9000-70-8), gum arabic (CAS No. 9000-01-5), and zein (CAS No. 9010-66-6) act as binders. Talc (CAS No. 14807-96-6), stearic acid (CAS No. 57-11-4), magnesium stearate (CAS No. 557-04-0), glyceryl monostearate (CAS No. 31566-31-1), and silicon dioxide (CAS No. 14808-60-7) act as anti-adhesive agents or lubricants. Triethyl citrate (CAS No. 77-93-0), polyethylene glycol (CAS No. 25322-68-3), dibutyl sebacate (CAS No. 109-43-3), diethyl sebacate (CAS No. 110-40-7), 1,2-propylene glycol (CAS No. 57-55-6), tributyl citrate (CAS No. 77-94-1), dimethyl phthalate (CAS No. 131-11-3), diethyl phthalate (CAS No. 84-66-2), dibutyl phthalate (CAS No. 84-74-2), and triethyl citrate (CAS No. 77-93-0) all act as plasticizers. Siloxane (CAS No. 994-49-0), silane (CAS No. 7803-62-5), polydimethylsiloxane (CAS No. 9016-00-6), hydrophobic silica (CAS No. 14808-60-7), dimethyl silicone oil (CAS No. 9006-65-9), simethicone (CAS No. 8050-81-5), and n-octanol (CAS No. 111-87-5) all act as defoaming agents. Arginine (CAS No. 74-79-3), meglumine (CAS No. 6284-40-8), disodium hydrogen phosphate (CAS No. 7558-79-4), tartaric acid (CAS No. 526-83-0), phosphoric acid (CAS No. 7664-38-2), potassium dihydrogen phosphate (CAS No. 7778-77-0), citric acid (also known as citric acid, CAS No. 5949-29-1), malic acid (CAS No. 6915-15-7), and sodium citrate (CAS No. 6132-04-3) all act as stabilizers.

[0098] In the present invention, the CAS number of methacrylic acid copolymer type A is 25806-15-1, and the pharmaceutical excipient approval number is F20140016. The CAS number of methacrylic acid copolymer type B is 25086-15-1, and the pharmaceutical excipient approval number is F20140017. The CAS number of methacrylic acid copolymer type C is 25212-88-8; the pharmaceutical excipient approval number is F20170010. The CAS number of methacrylic acid-ethyl acrylate copolymer aqueous dispersion is 25212-88-8; the pharmaceutical excipient approval number is F20150007. The CAS number of cellulose acetate propionate (alias: cellulose propionate) is 9004-39-1. The CAS number of hydroxypropyl methylcellulose acetate succinate (alias: cellulose-2-hydroxypropyl methyl ether esterified with acetate and hydrogen succinate) is 71138-97-1. The CAS number of Hydroxypropyl methylcellulose phthalate is 9050-31-1. The CAS number of Carboxymethyl ethylcellulose is 9032-42-2. The CAS number of Cellulose acetate phthalate is 9004-38-0. The CAS number of Polyvinyl acetate phthalate is 34481-48-6. The CAS number of Hydroxypropyl methylcellulose phthalate is 9050-31-1.

[0099] In the present invention, the molecular weight of the hypromellose used is 10,000-1,500,000. The average molecular weight of the methacrylic acid-ethyl acrylate copolymer is 200,000-300,000 (about 250,000); the mass concentration of the methacrylic acid-ethyl acrylate copolymer aqueous dispersion is 20-40% (for example, 30%). The molecular weight of povidone is 2,500-3,000,000. The average molecular weight of polyethylene glycol is 190-9,000. The weight average molecular weight of ethyl cellulose is 75,000-215,000. The molecular weight of sodium carboxymethylcellulose is 263.198. The weight average molecular weight of hypromellose is 10,000-1,500,000. The molecular weight of glyceryl monostearate is 358.57. The average molecular weight of methacrylic acid copolymer type A is 90,000 to 180,000, preferably 100,000 to 150,000 (for example, the average molecular weight is 135,000). The average molecular weight of methacrylic acid copolymer type B is greater than 100,000, preferably 100,000 to 200,000, more preferably 120,000 to 180,000 (for example, the average molecular weight is 150,000). The average molecular weight of methacrylic acid copolymer type C is 25,000. The molecular weight of diethyl sebacate is 258.36. The molecular weight of dibutyl sebacate is 314.47. The molecular weight of polyvinyl pyrrolidone is 2,500 to 3,000,000.

[0100] Compared with the prior art, the present invention has the following beneficial effects:

[0101] (1) The pharmaceutical composition of the present invention uses two components with different drug release times, so that the composition has rapid release and sustained release functions, controls the drug release rate of the composition in vivo, maintains the blood drug concentration in vivo, improves bioavailability, reduces the risk of drug release and individual differences in vivo. Alternatively, the pharmaceutical composition of the present invention uses a combination of one, two or even multiple different enteric materials to achieve the localized release of the drug in vivo, controls the drug release rate in vivo by controlling the selection of specific materials for different enteric layers, maintains the blood drug concentration in vivo, thereby reducing the risk of drug release, reducing individual differences in vivo, and improving the bioavailability of the drug.

[0102] (2) The pharmaceutical composition of the present invention is loaded with a gastric soluble capsule shell, which dissolves in the stomach to release the composition. Therefore, the preparation of the present application is not affected by gastric emptying, reaches a more regular peak, and reduces both inter-individual and intra-individual variations.

[0103] (3) The drug composition of the present invention contains a drug core whose release is pH-dependent. After reaching a specific pH position in the intestine, the outer enteric material dissolves, and the drug is released and absorbed. Therefore, the drug release and absorption are not affected by food, thereby improving the patient's medication compliance.

[0104] (4) The preparation process of the pharmaceutical composition of the present invention is simpler than that of the original preparation, and the capsule coating step is omitted, so the production cost is lower. BRIEF DESCRIPTION OF THE DRAWINGS

[0105] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0106] Figure 1 Example 1 Dissolution curve.

[0107] Figure 2 Example 5 Dissolution curve.

[0108] Figure 3 Example 11 Dissolution curve.

[0109] Figure 4 Example 14 Dissolution curve.

[0110] Figure 5 Example 15 Dissolution curve.

[0111] Figure 6 Comparison of dissolution curves of Examples 28, 30-33 and the reference preparation.

[0112] Figure 7Comparison of dissolution curves of Examples 35-39, comparative examples and reference preparations.

[0113] Figure 8 Drug-time curves of Example 28 and the reference preparation under fasting conditions of 0 to 24 hours.

[0114] Fig. 9 Drug-time curves of Example 28 and the reference preparation under fasting conditions of 0 to 48 hours. DETAILED DESCRIPTION

[0115] The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the scope of the present invention.

[0116] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0117] The experimental methods in the examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0118] In the examples, the materials are all of pharmaceutical grade, and each example is a prescription for 1000 tablets. The sources and models of the drugs used in the examples of the present invention are as follows: Budesonide, Jinyao Pharmaceutical Co., Ltd. / Hubei Gedian Renfu Pharmaceutical Co., Ltd., micro powder (D90 <5 μm). Sucrose pellet core, Anhui Shanhe Pharmaceutical Excipients Co., Ltd. / Castelli / Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd., 550-1180 μm / 14-30 mesh. Hydroxypropyl methylcellulose, Ashland, type 2910 (E5). Talc, Imerys Talv Italy SpA, LUZENAC Pharna M. Triethyl citrate, Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd. / Morimura Bros. Inc. Methacrylic acid-ethyl acrylate copolymer aqueous dispersion, Shanghai Changwei Pharmaceutical Excipients Technology Co., Ltd. / Evonik Specialty Chemicals (Shanghai) Co., Ltd., EUDRAGIT L30D-55. Povidone K30, Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd. Hydroxypropyl cellulose, Ashland, HEC-250. Polyethylene glycol 6000, Hunan Jiudian Hongyang Pharmaceutical Co., Ltd. Lactose pellet core, Hangzhou Chengyuan Biotechnology Co., Ltd., 550-1180 μm. Ethyl cellulose, Ashland, EC-N22. Stearic acid, Hunan Jiudian Hongyang Pharmaceutical Co., Ltd. Dibutyl sebacate, Beijing Biolab Technology Co., Ltd. Magnesium stearate, Anhui Shanhe Pharmaceutical Excipients Co., Ltd., SH-YM-M. Sodium carboxymethyl cellulose, Anhui Shanhe Pharmaceutical Excipients Co., Ltd., SH-SJJ-800. Methacrylic acid copolymer type A, Evonik Operations GmbH, Eudragit L100. Methacrylic acid copolymer type B, Evonik Operations GmbH, Eudragit S100. Methacrylic acid copolymer type C, Evonik Operations GmbH, Eudragit L100-55. Glyceryl monostearate, Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd. Cellulose acetate propionate, Zhengzhou Yande Biotechnology Co., Ltd. Dimethicone, Jiangxi Alpha Hi-Tech Pharmaceutical Co., Ltd., viscosity 500. Simethicone (Simethicone), DDP Specialty Electronic Materials US 9, LLC. Citric acid, Hunan Jiudian Hongyang Pharmaceutical Co., Ltd. Potassium dihydrogen phosphate, Hunan Jiudian Hongyang Pharmaceutical Co., Ltd. Reference preparation, Calliditas Therapeutics AB, TARPEYO.

[0119] Preparation Example 1

[0120] Step 1: preparing a suspension containing a corticosteroid such as budesonide, a first adhesive and a first anti-adhesive agent in a certain ratio;

[0121] Step 2: spraying the suspension in step 1 into a fluidized bed containing blank cores at the bottom, setting the coating temperature and coating speed for coating to form drug-containing cores with drug-containing layers;

[0122] Step 3: preparing a second adhesive and a second anti-adhesive agent into a solution;

[0123] Step 4: spray the solution in step 3 into the fluidized bed containing the drug-containing core prepared in step 2 at the bottom, set the coating temperature and coating speed to form the drug-containing core with an isolation layer;

[0124] Step 5: preparing an enteric material, a plasticizer and a third anti-adhesive agent into a suspension;

[0125] Step 6: Spray the suspension in step 5 into the fluidized bed containing the drug-containing core with an isolation layer prepared in step 4 at the bottom, set the coating temperature and coating speed for coating to form a drug-containing core with an enteric layer, and put it into an ordinary capsule.

[0126] Preparation Example 2

[0127] Step 1 and step 4 are the same as those in Preparation Example 1.

[0128] Step 5: by changing the type and component content of the enteric material in the enteric layer or changing the preparation method of the enteric suspension, the enteric layer drug-containing core 1 and the drug-containing core 2 with different release effects are prepared respectively;

[0129] Step 6: Mix the drug-containing core 1 and the drug-containing core 2 according to a certain proportion and put them into a common capsule.

[0130] Preparation Example 3:

[0131] Step 1: Prepare a first adhesive into a 5-15% aqueous solution, then homogenously disperse a first anti-adhesive agent and a corticosteroid (such as budesonide) in the aqueous solution of the first adhesive to prepare a desired suspension for later use;

[0132] Step 2: Add the blank core into the fluidized bed, preheat, and spray the suspension in step 1 into the fluidized bed. The coating temperature is 35-40°C, the air inlet temperature is 30-55°C, the material temperature is 20-40°C, and the atomization pressure is 1.0-2.0 bar to obtain a drug-containing core containing a corticosteroid (e.g., budesonide);

[0133] Step 3: Prepare the second adhesive into an aqueous solution with a concentration of 5-15%, and then uniformly disperse the second anti-adhesive agent in the aqueous solution of the second adhesive to prepare a desired suspension for later use;

[0134] Step 4: Add the drug-containing core prepared in step 2 to the fluidized bed, preheat, and spray the suspension in step 3 into the fluidized bed. The coating temperature is 35-40°C, the inlet air temperature is 30-55°C, the material temperature is 20-40, and the atomization pressure is 1.0-2.0 bar to obtain the drug-containing core with an isolation layer;

[0135] Step 5: Mix the third anti-adherent agent and purified water in a mass ratio of 1:2 and disperse them uniformly, then add the plasticizer and stir evenly to obtain a suspension containing the third anti-adherent agent and the plasticizer; then slowly pour the suspension containing the third anti-adherent agent and the plasticizer into a container containing an enteric material, add purified water to prepare a suspension with a solid content of 10 to 30%, and set aside;

[0136] Step 6: Add the drug-containing core containing the isolation layer into the fluidized bed, preheat, and spray the suspension in step 5 into the fluidized bed. The coating temperature is 35-40°C, the inlet air temperature is 30-55°C, the material temperature is 20-40, and the atomization pressure is 1.0-2.0 bar; the drug-containing core with an enteric layer is formed and loaded into a gelatin capsule.

[0137] Preparation Example 4:

[0138] Step 1 and step 4 are the same as those in Preparation Example 3.

[0139] Step 5: dissolving the enteric material and the 60%-90% ethanol solution in a mass ratio of 1:1, adding a plasticizer and stirring to dissolve, to obtain an ethanol solution containing the enteric material and the plasticizer; mixing the third anti-adhesive agent and the 60%-90% ethanol solution in a mass ratio of 1:1 and then homogenously dispersing them to obtain a suspension containing the third anti-adhesive agent; adding the suspension containing the third anti-adhesive agent to the ethanol solution containing the enteric material and the plasticizer, adding the 60%-90% ethanol solution to prepare a suspension with a solid content of 5-30%, and setting aside;

[0140] Step 6: Add the drug-containing core containing the isolation layer prepared in step 4 to the fluidized bed, preheat, and spray the suspension in step 5 into the fluidized bed. Start coating at a coating temperature of 30-36°C, an inlet air temperature of 30-55°C, a material temperature of 20-40, and an atomization pressure of 1.0-2.0 bar to obtain a drug-containing core with an enteric layer, which is then loaded into a gelatin capsule.

[0141] Preparation Example 5:

[0142] The drug-containing cores with enteric layers prepared in Preparation Example 3 and Preparation Example 4 are mixed in proportion and then packed into gelatin capsules to obtain the obtained product.

[0143] Preparation Example 6:

[0144] Step 1: preparing a suspension containing a corticosteroid such as budesonide, a defoaming agent, a first adhesive and a first anti-adhesive agent in a certain proportion;

[0145] Step 2: spraying the suspension in step 1 into a fluidized bed containing blank cores at the bottom, setting the coating temperature and coating speed for coating to form drug-containing cores with drug-containing layers;

[0146] Step 3: preparing a solution of a second adhesive, a stabilizer and a second anti-adhesive agent;

[0147] Step 4: spray the solution in step 3 into the fluidized bed containing the drug-containing core prepared in step 2 at the bottom, set the coating temperature and coating speed to form the drug-containing core with an isolation layer;

[0148] Steps 5 and 6 are the same as those in Preparation Example 1.

[0149] Preparation Example 7:

[0150] Step 1: Prepare a first adhesive into an aqueous solution with a concentration of 5-15%, and then homogeneously disperse a first anti-adhesive agent, a defoaming agent, and a corticosteroid (such as budesonide) in the aqueous solution of the first adhesive to prepare a desired suspension for standby use;

[0151] Step 2: Add the blank core into the fluidized bed, preheat, and spray the suspension in step 1 into the fluidized bed. The coating temperature is 35-40°C, the air inlet temperature is 30-40°C, the material temperature is 25-30°C, and the atomization pressure is 1.0-2.0 bar to obtain a drug-containing core containing a corticosteroid (e.g., budesonide);

[0152] Step 3: Prepare the second adhesive into an aqueous solution with a concentration of 5-15%, and then homogeneously disperse the second anti-adhesive agent and the stabilizer in the aqueous solution of the second adhesive to prepare a desired suspension for standby use;

[0153] Step 4: Add the drug-containing core prepared in step 2 into the fluidized bed, preheat, and spray the suspension in step 3 into the fluidized bed. The coating temperature is 35-40°C, the inlet air temperature is 30-40°C, the material temperature is 25-30°C, and the atomization pressure is 1.0-2.0 bar to obtain the drug-containing core with an isolation layer;

[0154] Step 5: dissolving the enteric material with ethanol to obtain an enteric material solution; mixing the third anti-adherent agent and purified water in a mass ratio of 1:2 and uniformly dispersing them, then adding a plasticizer and stirring them evenly to obtain a suspension containing the third anti-adherent agent and the plasticizer; then slowly pouring the suspension containing the third anti-adherent agent and the plasticizer into a container containing the enteric material solution, adding purified water to prepare a suspension with a solid content of 8 to 30% (preferably 8%), and setting aside;

[0155] Step 6: Add the drug-containing core containing the isolation layer into the fluidized bed, preheat, and spray the suspension in step 5 into the fluidized bed. The coating temperature is 20-30°C, the inlet air temperature is 30-40°C, the material temperature is 20-25°C, and the atomization pressure is 1.0-2.0 bar; the drug-containing core with an enteric layer is formed and loaded into a gelatin capsule.

[0156] Example 1

[0157] Preparation prescription: drug-containing core: budesonide 3.75g, sucrose pill core 300g, hypromellose 27g, talc 6.75g; isolation layer: hypromellose 10g, talc 2.5g; enteric layer: talc 30.66g, triethyl citrate 6.9g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 203.25g.

[0158] The preparation process is the same as that of Preparation Example 3, wherein the first adhesive and the second adhesive are both formulated into 10% aqueous solutions; the solid content of the suspension in step 5 is 10%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 30°C, and atomization pressure is 1.5 bar.

[0159] Example 2

[0160] Preparation prescription: drug-containing core: budesonide 1.875g, sucrose pellet core 281.25g, povidone K30 24.5g, talc 5.65; isolation layer: hydroxypropyl cellulose 7.5g, talc 1.875g; enteric layer: talc 26.25g, polyethylene glycol 60005.625g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 187.5g.

[0161] The preparation process is the same as that of Preparation Example 3, wherein the first binder is prepared into a 10% concentration solution, and the second binder is prepared into a 15% water concentration aqueous solution; the solid content of the suspension in step 5 is 10%; the parameters in the fluidized bed of steps 2, 4 and 6 are all set as follows: coating temperature is 35°C, inlet air temperature is 40°C, material temperature is 30°C, and atomization pressure is 1.2 bar.

[0162] Example 3

[0163] Preparation prescription: drug-containing core: budesonide 7.5g, lactose pill core 381.75g, ethyl cellulose 30g, stearic acid 7.5g; isolation layer: ethyl cellulose 11.25g, stearic acid 3.75g; enteric layer: stearic acid 37.5g, dibutyl sebacate 9.4g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 225g.

[0164] The preparation process is the same as that of Preparation Example 3, wherein the first adhesive and the second adhesive are both formulated into 15% aqueous solutions; the solid content of the suspension in step 5 is 20%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 35°C, air inlet temperature is 35°C, material temperature is 25°C, and atomization pressure is 2 bar.

[0165] Example 4

[0166] Preparation prescription: Drug-containing core: budesonide 18.75g, sucrose pill core 337.5g, povidone K30 37.5g, magnesium stearate 11.25g; isolation layer: sodium carboxymethyl cellulose 18.75g, magnesium stearate 5.63g; enteric layer: magnesium stearate 37.5g, polyethylene glycol 6000 18.75g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 262.5g.

[0167] The preparation process is the same as that of Preparation Example 3, wherein the first adhesive and the second adhesive are both formulated into 12% aqueous solutions; the solid content of the suspension in step 5 is 20%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 35°C, air inlet temperature is 35°C, material temperature is 28°C, and atomization pressure is 2 bar.

[0168] Example 5

[0169] Preparation prescription: Drug-containing core: 4.17g budesonide, 300g sucrose pill core, 27g hypromellose, 6.75g talc; isolation layer: 10g hypromellose, 2.5g talc; enteric layer: 18.3g talc, 9.15g polyethylene glycol 6000, 61g methacrylic acid copolymer type B.

[0170] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both formulated into 10% aqueous solutions; the concentration of the ethanol solution in step 5 is 80%, and the solid content of the suspension is 10%; the parameters in the fluidized bed in steps 2, 4, and 6 are all set as follows: coating temperature is 38°C, air inlet temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0171] Example 6

[0172] Preparation prescription: Drug-containing core: budesonide 1.875g, starch pill core 281.25g, ethyl cellulose 24.5g, glyceryl monostearate 5.65g; isolation layer: ethyl cellulose 7.5g, glyceride 1.88g; enteric layer: glyceryl monostearate 3.75g, polyethylene glycol 6000 3.75g, methacrylic acid copolymer type C 37.5g.

[0173] The preparation process is the same as that of Preparation Example 4, wherein the first binder is prepared into an aqueous solution with a concentration of 15%, and the second binder is prepared into an aqueous solution with a concentration of 10%; in step 5, the concentration of the ethanol solution is 90%, and the solid content of the suspension is 15%; the parameters in the fluidized bed of steps 2, 4, and 6 are all set as follows: the coating temperature is 35°C, the inlet air temperature is 40°C, the material temperature is 25°C, and the atomization pressure is 1.0 bar.

[0174] Example 7

[0175] Preparation prescription: Drug-containing core: budesonide 7.5g, sucrose pill core 318.75g, sodium carboxymethyl cellulose 30g, talc 7.5g; isolation layer: sodium carboxymethyl cellulose 11.25g, talc 3.75g; enteric layer: talc 37.5g, tributyl citrate 18.75g, methacrylic acid copolymer type A 93.75g.

[0176] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both prepared into 15% aqueous solution; the concentration of the ethanol solution in step 5 is 70%, and the solid content of the suspension is 10%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 35°C, material temperature is 25°C, and atomization pressure is 1.6 bar.

[0177] Example 8

[0178] Preparation prescription: Drug-containing core: budesonide 1.875g, sucrose pill core 262.5g, povidone K30 18.75g, talc 3.75g; isolation layer: hypromellose 3.75g, talc 0.375g; enteric layer: magnesium stearate 3.75g, diethyl sebacate 3.75g, methacrylic acid copolymer type B 93.75g.

[0179] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both formulated into 14% aqueous solutions; the concentration of the ethanol solution in step 5 is 80%, and the solid content of the suspension is 10%; the parameters in the fluidized bed in steps 2, 4, and 6 are all set as follows: coating temperature is 38°C, air inlet temperature is 35°C, material temperature is 25°C, and atomization pressure is 1.6 bar.

[0180] Example 9

[0181] Preparation prescription: drug-containing core: 5.5g budesonide, 325g lactose pellet core, 30g povidone K30, 7g talc; isolation layer: 10g hydroxypropyl methylcellulose, 3g glyceryl monostearate; enteric layer: 35g talc, 7g diethyl sebacate, 250g methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0182] The preparation process is the same as that of Preparation Example 3, wherein the first adhesive and the second adhesive are both formulated into 15% aqueous solutions; the solid content of the suspension in step 5 is 15%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 30°C, and atomization pressure is 1.5 bar.

[0183] Example 10

[0184] Preparation prescription: drug-containing core: budesonide 2.8g, sucrose pellet core 275g, povidone K30 25g, talc 6.5g; isolation layer: hydroxypropyl cellulose 12g, talc 4g; enteric layer: talc 30g, triethyl citrate 6.5g, cellulose acetate propionate 255g.

[0185] The preparation process is the same as that of Preparation Example 3, wherein the first adhesive and the second adhesive are both formulated into 15% aqueous solutions; the solid content of the suspension in step 5 is 30%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0186] Embodiment 11

[0187] Preparation prescription: drug-containing core: 4g budesonide, 300g sucrose pellet core, 27g povidone K30, 6.75g talc; isolation layer: 10g povidone K30, 2.5g talc; enteric layer: 31g talc, 7g triethyl citrate, 204g methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0188] The preparation process is the same as that of Preparation Example 3, wherein the first adhesive and the second adhesive are both formulated into 15% aqueous solutions; the solid content of the suspension in step 5 is 10%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0189] Example 12

[0190] Preparation prescription: drug-containing core: budesonide 4.5, sucrose pill core 300g, carboxymethylcellulose sodium 26g, magnesium stearate 7.2g; isolation layer: carboxymethylcellulose sodium 8g, talc 2g; enteric layer: talc 20g, polyethylene glycol 6000 10g, methacrylic acid copolymer type A 75g.

[0191] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both prepared into 15% aqueous solution; the concentration of the ethanol solution in step 5 is 80%, and the solid content of the suspension is 20%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0192] Embodiment 13

[0193] Preparation prescription: drug-containing core: 4g budesonide, 300g sucrose pill core, 24g hypromellose, 6.25g talc; isolation layer: 8g hypromellose, 2g talc; enteric layer: 18g talc, 7.5g dibutyl sebacate, 70g methacrylic acid copolymer type B.

[0194] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both prepared into 15% aqueous solution; the concentration of the ethanol solution in step 5 is 90%, and the solid content of the suspension is 10%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, air inlet temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0195] Embodiment 14

[0196] Preparation prescription: drug-containing core: budesonide 4g, sucrose pellet core 300g, povidone K30 27g, talc 6.75g; isolation layer: povidone K30 10g, talc 2.5g; enteric layer: talc 18g, polyethylene glycol 6000 8g, methacrylic acid copolymer type A 45g.

[0197] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both prepared into 15% aqueous solution; the concentration of the ethanol solution in step 5 is 70%, and the solid content of the suspension is 20%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0198] Embodiment 15

[0199] Preparation prescription: drug-containing core: budesonide 4g, sucrose pellet core 300g, povidone K30 27g, talc 6.75g; isolation layer: povidone K30 10g, talc 2.5g; enteric layer: talc 22g, polyethylene glycol 6000 12g, methacrylic acid copolymer type A 80g.

[0200] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both formulated into 10% aqueous solutions; the concentration of the ethanol solution in step 5 is 90%, and the solid content of the suspension is 30%; the parameters in the fluidized bed in steps 2, 4, and 6 are all set as follows: coating temperature is 38°C, air inlet temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0201] Example 16

[0202] Preparation prescription: drug-containing core: budesonide 4.5g, sucrose pellet core 150g, povidone K30 14.5g, talc 6g; isolation layer: povidone K30 5g, talc 2g; enteric layer: talc 16g, triethyl citrate 5.3g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 148g.

[0203] The preparation process is the same as that of Preparation Example 3, wherein the first adhesive and the second adhesive are both formulated into 10% aqueous solutions; the solid content of the suspension in step 5 is 10%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0204] Embodiment 17

[0205] Preparation prescription: drug-containing core: budesonide 3.75g, microcrystalline cellulose pellet core 300g, starch 27g, magnesium stearate 6.75g; isolation layer: sodium carboxymethyl cellulose 10g, talc 2.5g; enteric layer: talc 30.66g, triethyl citrate 6.9g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 204g.

[0206] The preparation process is the same as that of Preparation Example 3, wherein the first adhesive and the second adhesive are both formulated into 10% aqueous solutions; the solid content of the suspension in step 5 is 15%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0207] Embodiment 18

[0208] Preparation prescription: drug-containing core: budesonide 4.5g, sucrose pellet core 150g, povidone K30 14.5g, talc 6g; isolation layer: povidone K30 5g, talc 2g; enteric layer: talc 16g, polyethylene glycol 6000 8g, methacrylic acid copolymer type B 51g.

[0209] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both formulated into 10% aqueous solutions; the concentration of the ethanol solution in step 5 is 80%, and the solid content of the suspension is 10%; the parameters in the fluidized bed in steps 2, 4, and 6 are all set as follows: coating temperature is 38°C, air inlet temperature is 30°C, material temperature is 25°C, and atomization pressure is 1.5 bar.

[0210] Embodiment 19

[0211] Preparation prescription: Drug-containing core: budesonide 2.5g, sucrose pill core 300g, polyvinyl pyrrolidone 27g, talc 6.75g; isolation layer: hypromellose 10g, talc 2.5g; enteric layer: silicon dioxide 18.26g, polyethylene glycol 60009.14g, methacrylic acid copolymer type C 60.94g.

[0212] The preparation process is the same as that of Preparation Example 4, wherein the first adhesive and the second adhesive are both prepared into 10% aqueous solutions; the concentration of the ethanol solution in step 5 is 90%, and the solid content of the suspension is 30%; the parameters in the fluidized bed in steps 2, 4 and 6 are all set as follows: coating temperature is 38°C, inlet air temperature is 40°C, material temperature is 30°C, and atomization pressure is 1.5 bar.

[0213] Embodiment 20

[0214] The drug-containing cores with enteric layers prepared in Example 1 and Example 5 were mixed in a ratio of 1:1 and then filled into a gelatin capsule to obtain a product.

[0215] Embodiment 21

[0216] The drug-containing cores with enteric layers prepared in Example 11 and Example 14 were mixed in a ratio of 1:2 and then filled into a gelatin capsule to obtain the result.

[0217] Embodiment 22

[0218] The drug-containing cores with enteric layers prepared in Example 11 and Example 15 were mixed in a ratio of 1:1 and then filled into a gelatin capsule to obtain a product.

[0219] Embodiment 23

[0220] The drug-containing cores with enteric layers prepared in Example 10 and Example 13 respectively are mixed in a ratio of 1:3 and then packed into a gelatin capsule to obtain the result.

[0221] Embodiment 24

[0222] The drug-containing cores with enteric layers prepared in Example 16 and Example 17 were mixed in a ratio of 3:1 and then packed into a gelatin capsule to obtain the result.

[0223] Embodiment 25

[0224] The drug-containing cores with enteric layers prepared in Example 1 and Example 5 were mixed in a ratio of 1:5 and then filled into a gelatin capsule to obtain a product.

[0225] Embodiment 26

[0226] The drug-containing cores with enteric layers prepared in Example 1 and Example 5 were mixed in a ratio of 1:4 and then filled into a gelatin capsule to obtain a product.

[0227] Embodiment 27

[0228] Preparation prescription: Drug-containing core: 4.9g budesonide, 300g sucrose pill core, 27g hypromellose, 6.75g talc; isolation layer: 10.43g hypromellose, 2.65g talc; enteric layer: 22.65g talc, 7.55g triethyl citrate, 37.76g methacrylic acid copolymer type A, 37.76g methacrylic acid copolymer type B.

[0229] The preparation process is the same as that of Preparation Example 7, wherein the first adhesive and the second adhesive are both formulated into 10% aqueous solutions; the concentration of the ethanol solution in step five is 90%, and the solid content of the suspension is 30%; the parameters in the fluidized bed in steps two, four and six are all set as follows: coating temperature is 38°C, air inlet temperature is 40°C, material temperature is 30°C, and atomization pressure is 1.5 bar.

[0230] Embodiment 28

[0231] Preparation prescription: Drug-containing core: 4.9g budesonide, 300g sucrose pill core, 27g hypromellose, 6.75g talc, 0.13g dimethicone; isolation layer: 10.43g hypromellose, 2.65g talc, 0.63g citric acid; enteric layer: 22.65g talc, 7.55g triethyl citrate, 37.76g methacrylic acid copolymer type A, 37.76g methacrylic acid copolymer type B.

[0232] The preparation process is the same as Example 27.

[0233] Embodiment 29

[0234] Preparation prescription: Drug-containing core: 4.9g budesonide, 300g sucrose pill core, 27g hypromellose, 6.75g talc, 0.15g simethicone; isolation layer: 10.43g hypromellose, 2.65g talc, 0.53g potassium dihydrogen phosphate; enteric layer: 22.65g talc, 7.55g triethyl citrate, 37.76g methacrylic acid copolymer type A, 37.76g methacrylic acid copolymer type B.

[0235] The preparation process is the same as Example 27.

[0236] Embodiment 30

[0237] Preparation prescription: Drug-containing core: 4.5g budesonide, 300g sucrose pill core, 27g hypromellose, 6.8g talc, 0.11g dimethicone; isolation layer: 10.43g hypromellose, 2.65g talc, 0.6g citric acid; enteric layer: 22.65g talc, 7.55g triethyl citrate, 47.76g methacrylic acid copolymer type A, 47.76g methacrylic acid copolymer type B.

[0238] The preparation process is the same as Example 27.

[0239] Embodiment 31

[0240] Preparation prescription: Drug-containing core: 5.2g budesonide, 300g sucrose pill core, 27g hypromellose, 7.1g talc, 0.15g simethicone; isolation layer: 12.36g hypromellose, 2.86g talc, 0.53g potassium dihydrogen phosphate; enteric layer: 24.35g talc, 9.12g triethyl citrate, 22.5g methacrylic acid copolymer type A, 21.5g methacrylic acid copolymer type B.

[0241] The preparation process is the same as Example 27.

[0242] Embodiment 32

[0243] Preparation prescription: Drug-containing core: 4.9g budesonide, 300g sucrose pill core, 27g hypromellose, 6.75g talc, 0.14g dimethicone; isolation layer: 10.43g hypromellose, 2.61g talc, 0.53g citric acid; enteric layer: 30.21g talc, 10.07g triethyl citrate, 50.37g methacrylic acid copolymer type A, 50.37g methacrylic acid copolymer type B.

[0244] The preparation process is the same as Example 27.

[0245] Embodiment 33

[0246] Preparation prescription: Drug-containing core: 4.9g budesonide, 300g sucrose pill core, 27g hypromellose, 6.75g talc, 0.14g dimethicone; isolation layer: 10.43g hypromellose, 2.61g talc, 0.53g citric acid; enteric layer: 35.87g talc, 12.90g triethyl citrate, 63.96g methacrylic acid copolymer type A, 75.23g methacrylic acid copolymer type B.

[0247] The preparation process is the same as Example 27.

[0248] Embodiment 34

[0249] The difference from Example 32 is: enteric layer: talc 30.21 g, triethyl citrate 10.07 g, methacrylic acid copolymer type A 20.05 g, methacrylic acid copolymer type B 80.20 g.

[0250] Embodiment 35

[0251] The difference from Example 32 is: Enteric layer: talc 30.21 g, triethyl citrate 10.07 g, methacrylic acid copolymer type A 15.05 g, methacrylic acid copolymer type B 85.20 g.

[0252] Embodiment 36

[0253] The difference from Example 32 is: Enteric layer: 30.21 g of magnesium stearate, 10.07 g of triethyl citrate, 20.05 g of methacrylic acid copolymer type A, and 80.20 g of methacrylic acid copolymer type B.

[0254] Embodiment 37

[0255] The difference from Example 32 is: enteric layer: talc 30.21 g, triethyl citrate 10.07 g, methacrylic acid copolymer type A 82.5 g, methacrylic acid copolymer type B 27.50 g.

[0256] Embodiment 38

[0257] The difference from Example 32 is: Enteric layer: talc 22.65 g, triethyl citrate 7.55 g, methacrylic acid copolymer type A 56.52 g, methacrylic acid copolymer type B 19.02 g.

[0258] Embodiment 39

[0259] The difference from Example 32 is: enteric layer: talc 35.87 g, triethyl citrate 12.90 g, methacrylic acid copolymer type A 95.8 g, methacrylic acid copolymer type B 31.8 g.

[0260] Comparative Example

[0261] After conversion with reference to Example 3 of patent CN101108171A, the specific prescription composition is as follows:

[0262]

[0263] Effect Example 1

[0264] Investigate the dissolution performance of different preparations:

[0265] The dissolution curves of the pharmaceutical compositions prepared in Examples 1, 11, 5, 14, 15, 20, 21 and 22 were measured respectively.

[0266] Dissolution method: paddle method, 100 rpm, dissolution medium: pH 1.2 hydrochloric acid solution from 0 to 2 h, pH 6.8 phosphate buffer from 2 to 8 h, sampling time points: 0 min, 120 min, 135 min, 150 min, 180 min, 210 min, 240 min, 300 min, 360 min, 420 min, 480 min.

[0267] Under the condition of pH 1.2 hydrochloric acid solution, the cumulative dissolution of budesonide in the above preparations within 0 to 2 hours is less than 3.8%, indicating that the pharmaceutical composition prepared by the present invention basically does not release the drug in the stomach.

[0268] In the pH 6.8 phosphate buffer dissolution medium, budesonide in the pharmaceutical compositions prepared in Examples 1 and 11 was immediately released. At 135 min, the cumulative dissolution of budesonide was greater than 95%, indicating that the compositions of Examples 1 and 11 could quickly release budesonide in the intestine.

[0269] In the pH 6.8 phosphate buffer dissolution medium, budesonide in the pharmaceutical compositions prepared in Examples 5, 14, and 15 was slowly and stably released. The cumulative dissolution rate of budesonide in the pharmaceutical composition prepared in Example 5 at the 6th hour was 97.05%; the cumulative dissolution rate of budesonide in the pharmaceutical composition prepared in Example 14 at the 8th hour was 79.26%; the cumulative dissolution rate of budesonide in the pharmaceutical composition prepared in Example 15 at the 4th hour was 90.01%, indicating that the compositions of Examples 5, 14, and 15 can continuously release budesonide in the intestine, and the release rate of Examples 14 and 15 is slightly faster than that of Example 5.

[0270] From the dissolution test of the pharmaceutical composition prepared in Examples 20, 21 and 22, it can be seen that the mixed preparation of the rapid-release and sustained-release pellets can well control the drug release rate and ensure the dissolution concentration and dissolution time of budesonide.

[0271] It can be seen from this that the pharmaceutical composition prepared by the present invention achieves delayed release and / or sustained release of the drug.

[0272] Effect Example 2

[0273] Pharmacokinetic study of budesonide enteric-coated pellets:

[0274] In this study, a two-cycle crossover administration was used to compare the pharmacokinetic properties of the pharmaceutical compositions prepared in Examples 1, 5, 11, 14, 20, and 21 (specification: 4 mg) after oral administration of 4 capsules on an empty stomach; the blood concentration of budesonide in plasma at different time points was detected, and the in vivo pharmacokinetic parameters after oral administration of the pharmaceutical compositions prepared in Examples 1, 5, 11, 14, 20, and 21 were calculated. The results are shown in Table 1.

[0275] Blood collection time: In each cycle, 21 blood samples were collected from each subject, with 3 mL of venous blood collected each time at 0 h before administration and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 8 h, 9 h, 10 h, 12 h, 14 h, and 24 h after administration.

[0276] Table 1 Statistical table of human pharmacokinetic parameters of budesonide drug composition

[0277]

[0278] According to the above table, the delayed release composition (Examples 1 and 11) reaches the peak time of drug release in vivo earlier than the sustained release composition (Examples 5 and 15), indicating that the delayed release composition and the sustained release composition achieve the effects of rapid release and sustained release, respectively. The peak time of drug release in vivo in Examples 20 and 21, which are a mixture of the delayed release composition and the sustained release composition, is between the peak time of the delayed release composition and the sustained release composition, indicating that the control of the in vivo drug release rate of the pellets, the maintenance of the blood drug concentration in vivo, and the improvement of bioavailability can be achieved through the cooperation of the two. In addition, the coefficient of variation of each pharmacokinetic parameter in the above examples is less than 0.54%, and the inter-individual variation of the preparation is significantly reduced.

[0279] Effect Example 3

[0280] The dissolution curves of the reference preparation, comparative example, and pharmaceutical compositions prepared in Examples 28, 30-33, and 35-39 were respectively measured.

[0281] Dissolution method: paddle method, 100rpm, dissolution medium: pH 1.2 hydrochloric acid solution for 0-2h, pH 6.8 phosphate buffer for 2-8h, sampling time points: 0min, 120min, 135min, 150min, 180min, 210min, 240min, 300min, 360min, 370min. The dissolution results are shown in Tables 2 and 3 below.

[0282] Table 2

[0283]

[0284] Table 3

[0285]

[0286] Depend on Figure 6 As shown in the dissolution curves of Examples 28, 30-33, it can be seen that under the condition of pH 1.2 hydrochloric acid solution (0min-120min), the cumulative dissolution of budesonide in the above preparations within 0-2h is less than 0.25%, indicating that the pharmaceutical composition prepared by the present invention hardly releases the drug in the stomach. In the pH 6.8 phosphate buffer dissolution medium for about 30min (150min point in the figure), budesonide in the prepared pharmaceutical composition is immediately released by 14-20%, at 180min, the cumulative dissolution of budesonide reaches more than 60%, and the dissolution is maintained at more than 80% from 210min to 360min, and is greater than 90% at 360min, indicating that the composition can continuously and slowly release budesonide in the intestine, and the release rate is basically consistent with the reference preparation.

[0287] Combined with the dissolution curves of Examples 5, 14, 15, 28, and 30-33, it can be seen that the amount of enteric material is controlled between 10% and 25% of the total amount of the pharmaceutical composition, and a dissolution curve for sustained release of budesonide can be obtained, which is conducive to effectively controlling the requirements of localized drug release and sustained drug release; It can be seen from the dissolution curves of Examples 28 and 30-32 that the thickness of the enteric layer affects the speed of drug release to a certain extent.

[0288] Combining the dissolution curves of Examples 1, 11, 5, 14, 15, 28, and 30-33, it can be seen that different types of enteric materials can effectively meet the control of sustained drug release.

[0289] Depend on Figure 7 As shown, from the dissolution process of the comparative example, Examples 37-39 and the reference preparation, at 180 minutes, the comparative preparation and Examples 37-39 preparations were almost completely dissolved, while the reference preparation was only 16.11% dissolved. At 210 minutes, the reference preparation was only 75.2% dissolved, which shows that the comparative preparation was dissolved too fast.

[0290] The inventors found through experiments that after slightly adjusting the proportion of the enteric layer material of the comparative example, the weight content (30-50%) was increased, such as in Examples 37-39, and it was found that the adjustment of the dissolution rate by the weighted enteric layer was unclear, and the dissolution was still too fast. Example 36 adjusted the anti-adhesive agent on the basis of Example 27, but still did not achieve the expected dissolution. Example 35 adjusted the proportion of the enteric layer excipients, that is, increased the content of methacrylic acid copolymer type B, and the dissolution release rate was significantly slowed down.

[0291] based on Figure 7The thickness of the enteric layer of Examples 30-33 was adjusted, and it was found that in the mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B, the dosage ratio of methacrylic acid copolymer type A and methacrylic acid copolymer type B directly affects the dissolution rate of the drug. When the dosage ratio of methacrylic acid copolymer type A and methacrylic acid copolymer type B in the mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B is controlled to be close to 1:1, the dissolution rate of the drug is similar to that of the reference preparation, which is in line with the dissolution trend of the reference preparation, thereby ensuring the bioavailability of the drug.

[0292] The inventors found through experiments that adjusting the dosage ratio of methacrylic acid copolymer type A and methacrylic acid copolymer type B in the enteric layer directly affects the dissolution rate of the drug. If the dosage of methacrylic acid copolymer type A is too much, the dissolution rate of the drug is too fast; if the dosage of methacrylic acid copolymer type B is too much, the dissolution rate of the drug is too slow. When the dosage ratio of methacrylic acid copolymer type A and methacrylic acid copolymer type B is controlled to be 1:0.6-3 (preferably 1:0.8-2), the dissolution rate of the prepared drug can be guaranteed to be close to that of the reference preparation, thereby ensuring the bioavailability of the prepared drug.

[0293] Effect Example 4

[0294] Pharmacokinetic study of budesonide enteric-coated pellets:

[0295] This study used 2-cycle crossover administration to compare the pharmacokinetic properties of the pharmaceutical composition (specification of 4 mg) prepared in Examples 28 and 32 and the reference preparation (commercially available budesonide enteric-coated pellets) after oral administration of 4 capsules on an empty stomach; the blood concentration of budesonide in plasma at different time points was detected, and the in vivo pharmacokinetic parameters after oral administration of the pharmaceutical composition (specification of 4 mg) prepared in Examples 28 and 32 and the reference preparation were calculated. The results are shown in Tables 4 to 6. The fasting test was planned to enroll 6 subjects, and 6 subjects were actually enrolled. All subjects completed two cycles of administration and clinical sampling.

[0296] Blood collection time:

[0297] Fasting test: 0h before administration (within 1h before administration) and 2h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 10h, 11h, 12h, 14h, 24h, 36h, 48h after administration, a total of 22 sampling points. 3mL of venous blood was collected each time.

[0298] Table 4 Statistical table of human pharmacokinetic parameters of reference preparation and Example 28

[0299]

[0300] Table 5 Statistical table of human pharmacokinetic parameters of reference preparation and Example 32

[0301]

[0302] Table 6: Reference formulation and Example 32 - Absorption kinetics consistency evaluation data - fasting

[0303]

[0304] According to Tables 4-6 above, the compositions prepared in Examples 28 and 32 have similar drug release times in vivo compared to the reference preparation. Therefore, as long as the material composition of the enteric layer is controlled, the release time and release rate of the prepared drug in vivo can be guaranteed to be close to the reference preparation. Among them, the release time of Example 28 is slightly faster, and the release time of Example 32 is slightly slower, indicating that the release rate of the micropill in vivo can be controlled by adjusting the thickness of the enteric layer, maintaining the blood drug concentration in vivo, and improving the bioavailability.

[0305] Figure 8-9 This indicates that the drug release behaviors of Examples 28, 32 and the reference preparation in vivo are very similar.

[0306] From the consistency evaluation data in Table 6, it can be seen that the AUC of Example 32 and the reference preparation in human body are equivalent. It can be seen that the pharmaceutical composition prepared by the present invention not only achieves the purpose of not releasing the drug in gastric acid, but also can flexibly achieve the needs of rapid release in the intestine and localized release of the drug in different intervals through the adjustment of the preparation technology, which provides the possibility for the treatment of diseases such as ulcerative colitis, Crohn's disease and IgA nephropathy that meet the requirements of drug release in different time periods.

[0307] The inventor has conducted experiments and found that the solution provided by the present invention is to optimize the enteric layer material, and the enteric layer material type and dosage are specifically selected to release the pharmaceutical composition at a designated position in the intestine. Therefore, as long as the enteric layer material type and / or dosage are controlled, the prepared pharmaceutical composition can have a release pattern that is the same or similar to that of the corresponding reference preparation, and the release rate of the drug can be guaranteed, thereby ensuring the bioavailability of the drug. Alclometasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, methylprednisolone, mometasone, hydroprednisolone, triamcinolone, fluticasone, ciclesonide, and fludrocortisone use the specific materials of the present invention and the enteric layer of the specific dosage ratio, and have similar release characteristics. Since the release pattern is close to that of the corresponding reference preparation, it will not be repeated here.

Claims

1. A pharmaceutical composition containing corticosteroids, characterized in that The pharmaceutical composition comprises or consists of the following components: an immediate release component and a delayed / sustained release component; the delayed / sustained release component comprises a core containing a corticosteroid, a separation layer and an enteric layer; the immediate release component dissolves in the stomach after oral administration.

2. The pharmaceutical composition according to claim 1, characterized in that The corticosteroid includes one or more of alclomethasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, methylprednisolone, mometasone, prednisolone, triamcinolone, fluticasone, ciclesonide, fludrocortisone or budesonide.

3. The pharmaceutical composition according to claim 1, characterized in that The core containing corticosteroid refers to a corticosteroid coated on a blank core; the core containing corticosteroid is coated by an isolation layer, and the isolation layer is coated by an enteric layer; The corticosteroid-containing core includes a first binder and a first anti-adherent agent; The isolation layer includes a second adhesive and a second anti-adhesive agent; The enteric layer comprises an enteric material, a plasticizer and a third anti-adhesive agent.

4. The pharmaceutical composition according to claim 3, characterized in that In terms of weight percentage, the corticosteroid accounts for 0.4-2%, the blank pellet core accounts for 35-75%, the first binder accounts for 2-7.5%, the first anti-adhesive agent accounts for 0.5-3.5%, the second binder accounts for 0.5-4.5%, the second anti-adhesive agent accounts for 0.4-2%, the third anti-adhesive agent accounts for 3-8.5%, the enteric material accounts for 4-50%, and the plasticizer accounts for 0.4-3%; Preferably, the corticosteroid-containing core further comprises an antifoaming agent; and / or the isolation layer further comprises a stabilizer; Preferably, the pharmaceutical composition further comprises, by weight percentage, 0.01% to 0.1% of a defoaming agent and 0.05% to 0.5% of a stabilizer.

5. The pharmaceutical composition according to claim 3, characterized in that The blank core is a pill core or a tablet core; the material of the blank core is selected from one or more of lactose, sucrose, starch or microcrystalline cellulose; The first binder and the second binder are each independently selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, povidone, Opadry, starch, polyvinyl pyrrolidone, gelatin, gum arabic, and zein; The first anti-adhesive agent, the second anti-adhesive agent and the third anti-adhesive agent are each independently selected from one or more of talc, stearic acid, magnesium stearate, glyceryl monostearate and silicon dioxide; The enteric material is selected from one or more of methacrylic acid copolymer type A, methacrylic acid copolymer type B, methacrylic acid copolymer type C, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, cellulose acetate propionate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl ethylcellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate trioctyl ester, cellulose acetate phthalate, polyvinyl acetate phthalate, and hydroxypropyl methylcellulose phthalate; The plasticizer is selected from one or more of triethyl citrate, polyethylene glycol 6000, dibutyl sebacate, diethyl sebacate, 1,2-propylene glycol, tributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and triethyl citrate; The defoaming agent is selected from one or more of siloxane, silane, polydimethylsiloxane, hydrophobic silica, dimethyl silicone oil, simethicone, and n-octanol; The stabilizer is selected from one or more of arginine, meglumine, disodium hydrogen phosphate, tartaric acid, phosphoric acid, potassium dihydrogen phosphate, citric acid, malic acid, and sodium citrate.

6. The pharmaceutical composition according to claim 3, characterized in that In the pharmaceutical composition, the enteric material is a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B; Preferably, the enteric material is a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B in a mass ratio of 1:0.6-3, preferably a mixture of 1:0.8-2.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition comprises budesonide, sucrose core, hypromellose, talc, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, povidone K30, talc, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, hypromellose, talc, polyethylene glycol 6000, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, povidone K30, talc, polyethylene glycol 6000, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, hypromellose, talc, triethyl citrate, polyethylene glycol 6000, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, povidone K30, talc, triethyl citrate, polyethylene glycol 6000, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, povidone K30, hypromellose, talc, hydroxypropyl cellulose, triethyl citrate, cellulose acetate propionate, dibutyl sebacate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, talc, hypromellose, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, talc, hypromellose, dimethicone, citric acid, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B; Or, the pharmaceutical composition comprises budesonide, sucrose core, talc, hypromellose, simethicone, potassium dihydrogen phosphate, triethyl citrate, methacrylic acid copolymer type A, and methacrylic acid copolymer type B.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that In the pharmaceutical composition, the delayed / sustained release component is in the form of tablets, microtablets, granules, and pills, and is further coated with the timely release component.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, characterized in that: The method comprises: the steps of preparing a core containing a corticosteroid drug, coating the core containing the corticosteroid drug with an isolation layer, and coating the isolation layer with an enteric layer; and further comprising the step of mixing a delayed-release component and a sustained-release component; Preferably, the method is as follows: Step 1: preparing a first suspension containing a corticosteroid drug, a first adhesive and a first anti-adhesive agent; coating the first suspension on a blank pill core to form a core containing a corticosteroid drug; Step 2: a second solution is prepared with a second adhesive and a second anti-adhesive agent, and the second solution is coated on the core containing the corticosteroid drug to form an isolation layer; Step 3: prepare a third solution with the enteric material, plasticizer and anti-adhesive agent; coat the third solution to form an enteric layer to obtain a delayed / sustained release component.

10. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for treating inflammatory diseases of the gastrointestinal tract or for treating glomerulonephritis.

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