Corticosteroid-containing pharmaceutical composition and preparation method therefor

Abstract

A corticosteroid-containing pharmaceutical composition and a preparation method therefor. The composition comprises an immediate-release component and a delayed / sustained-release component. The delayed / sustained-release component comprises a core containing a corticosteroid drug, an isolation layer, and an enteric layer; and after oral administration, the immediate-release component is dissolved in the stomach, thereby effectively eliminating the effect of gastric emptying. Furthermore, by means of the enteric layer to which the delayed / sustained-release component is applied, the composition has an immediate-release function and / or a sustained-release function, such that the drug release rate of the composition in the intestinal tract can be effectively controlled, the plasma concentration of a corticosteroid drug in the body is maintained, the bioavailability is improved, and the drug release risk and the individual difference in the body are reduced; and the preparation process is simplified.

Description

A pharmaceutical composition containing corticosteroids and its preparation method Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular 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, exhibiting 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 allergy-reactive mediators such as histamine. It can also alleviate the enzymatic processes stimulated by antigen-antibody binding, inhibit the synthesis and release of bronchoconstrictor substances, and alleviate smooth muscle contractile responses. Clinically, budesonide aerosols, sprays, and powders are widely used for glucocorticoid-dependent or -independent bronchial asthma and asthmatic bronchitis. In addition, studies have shown that budesonide is effective in treating inflammatory bowel diseases such as ulcerative colitis and collagenous colitis. The budesonide preparations currently available in China include aerosols, sprays, nasal preparations, powder inhalers, etc., and there are currently no oral preparations.

[0003] In October 2001, the U.S. FDA approved its enteric-coated micropellet capsules for the maintenance of mild to moderate Crohn's disease involving the ileum and / or ascending colon. Based on the primary pathogenesis model, the formulation is designed to deliver the drug to the Peyer's patch area of ​​the lower small intestine, where the disease originates. The U.S. Food and Drug Administration (FDA) has accepted the Swedish biopharmaceutical company Calliditas Therapeutics' new drug application (NDA) for the oral patented formulation Nefecon (budesonide) and granted priority review. This is a new oral formulation of budesonide, an IgA1 downregulator that treats IgA nephropathy (IgAN) by targeting IgA1 downregulation. Nefecon is derived from TARGIT technology, which allows substances to pass through the stomach and intestines without being absorbed and is released in a pulsed manner only when it reaches the lower 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 approved drug in the world for reducing proteinuria in IgA nephropathy, and it is expensive. The preparation is an enteric-coated capsule filled with sustained-release microcapsules. The sustained-release microcapsules 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 blocking the gastric emptying of the drug through the pylorus, and there are large individual differences in the body.

[0005] CN101108171A discloses a budesonide enteric-coated sustained-release micropill and a preparation method thereof, which comprises a drug-containing immediate-release pellet core, a sustained-release layer, and an enteric layer. This patent only considers the release rate of the drug itself, and achieves the effect of controlling drug release through a sustained-release layer + a sustained-release material; however, it does not consider the release pattern of the prepared drug and the reference preparation (original drug), 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.

[0007] Summary of the Invention

[0008] To address the shortcomings of the original formulation, TARPEYO budesonide enteric-coated pellets, such as gastric drug release and large individual variability, the present invention provides a pharmaceutical composition that allows budesonide to reach the desired area, such as an inflamed portion of the intestine, at a sufficient concentration and persist in that area for a sufficient period of time to provide a localized therapeutic effect. The prior art uses sustained-release components to control sustained release, and the processed capsule shell achieves targeted release, so that after oral administration, the sustained-release component is first released from the capsule in the intestine, a portion of the intestine, or a specific portion of the intestine. However, the capsule shell has problems such as complex preparation processes, irregular emptying and release from the body, and other issues. To address this problem of the prior art, the present invention provides an enteric layer on the outermost layer of the budesonide composition. On the one hand, by timely releasing components, the composition containing budesonide is ensured to be released in the stomach, making the gastric emptying time more regular. The composition with the enteric layer does not release the drug in the stomach. When it reaches the intestine, part of the intestine, or a specific part of the intestine, the delayed-release portion (enteric layer) dissolves or decomposes to achieve continuous localized release in the intestine, 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, but begin 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, achieving a release pattern similar to that of the original drug, thereby improving 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 begins to release slowly after entering the small intestine. Most of the drug is released in diseased areas such as the distal small intestine, ileocecal region, and colon, and the release pattern is similar to that of the reference preparation.

[0009] Furthermore, the budesonide composition provided by the present invention also utilizes an extended-release component and a sustained-release component. These components are two components with different drug release durations / times, resulting in the composition having both immediate-release and sustained-release functions. This allows for controlled release rate of the composition within the intestinal tract, a portion of the intestinal tract, or a specific portion of the intestinal tract, thereby maintaining budesonide blood concentration in the body, improving bioavailability, and reducing drug release risks and individual variability in the body. The preparation process provided by the present invention simplifies the formulation process.

[0010] In one aspect, the present invention provides a pharmaceutical composition containing a corticosteroid, which achieves controlled / sustained release of the drug, comprising an immediate release component and a delayed / sustained release component.

[0011] Furthermore, the delayed / sustained release component comprises a core containing a corticosteroid, a separating layer and an enteric layer;

[0012] In the present invention, the immediate release component dissolves in the stomach after oral administration.

[0013] Furthermore, the immediate release component is a capsule shell, that is, the capsule shell is a gastric-soluble capsule, which 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.

[0014] In the present invention, the gastric soluble capsule is a prior art. For example, the material of the capsule shell is selected from starch, hypromellose, PVA, pullulan or gelatin.

[0015] Furthermore, the core containing the corticosteroid is coated with an isolation layer, and the isolation layer is coated with an enteric layer.

[0016] Furthermore, the core containing corticosteroid refers to a blank core coated with corticosteroid.

[0017] In the present invention, the blank core is the prior art.

[0018] Preferably, the blank core can be a pill core, a tablet core, etc., preferably a pill core.

[0019] 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.

[0020] Furthermore, the corticosteroid drugs include but are not limited to any one or more combinations of alclometasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, methylprednisolone, mometasone, prednisolone, triamcinolone, fluticasone, ciclesonide, fludrocortisone and budesonide.

[0021] Preferably, the corticosteroid is budesonide.

[0022] Furthermore, the corticosteroid-containing core may further contain a first binder and a first anti-adhesive agent.

[0023] Furthermore, the corticosteroid-containing core may further contain a defoaming agent for eliminating foam during the preparation of the corticosteroid-containing core and maintaining regularity and stability of subsequent drug release.

[0024] 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.

[0025] Furthermore, the isolation layer may further include a stabilizer. The stabilizer is mainly used to stabilize corticosteroids such as budesonide, create an acidic environment during the release process in the body, and further ensure a continuous, regular and stable drug release process.

[0026] Furthermore, the enteric layer includes an enteric material, a plasticizer and a third anti-adhesive agent.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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%.

[0031] Furthermore, in the pharmaceutical composition, 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 pellet core 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%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, the first anti-adhesive ratio can be selected from 0.5%, 1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 2%, 2.5%, 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 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 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%. Furthermore, 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 accounts for 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%.

[0032] Furthermore, the pharmaceutical composition is pH-dependent; after reaching a specific pH portion of the intestinal tract, the enteric material of the outer layer of the composition dissolves, and the active pharmaceutical ingredient is released and absorbed.

[0033] 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 corn gluten.

[0034] 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.

[0035] Furthermore, the defoaming agent is selected from one or more of silicone, silane, polydimethylsiloxane (PDMS), hydrophobic silica, dimethyl silicone oil, simethicone, and n-octanol.

[0036] 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.

[0037] 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, hydroxypropylethylcellulose phthalate, carboxymethyl ethylcellulose, cellulose acetate trioctyl ester, cellulose acetate phthalate, polyvinyl acetate phthalate, and hydroxypropyl methylcellulose phthalate.

[0038] 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.

[0039] 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.

[0040] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, hydroxypropyl cellulose, talc, triethyl citrate, and a methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0041] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, povidone K30, talc, hydroxypropyl cellulose, polyethylene glycol 6000, and a methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0042] Furthermore, the pharmaceutical composition comprises budesonide, a lactose core, ethyl cellulose, stearic acid, dibutyl sebacate, and an aqueous dispersion of a methacrylic acid and ethyl acrylate copolymer.

[0043] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, povidone K30, talc, triethyl citrate, and a methacrylic acid-ethyl acrylate copolymer aqueous dispersion.

[0044] 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.

[0045] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, hypromellose, talc, polyethylene glycol 6000, and methacrylic acid copolymer type B.

[0046] Furthermore, the pharmaceutical composition comprises budesonide, starch core, ethyl cellulose, glyceryl monostearate, polyethylene glycol 6000, and methacrylic acid copolymer type C.

[0047] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, sodium carboxymethylcellulose, talc, tributyl citrate, and methacrylic acid copolymer type A.

[0048] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, povidone K30, talc, polyethylene glycol 6000, and methacrylic acid copolymer type B.

[0049] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, povidone K30, talc, hypromellose, magnesium stearate, diethyl sebacate, and methacrylic acid copolymer type B.

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

[0052] 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.

[0053] 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.

[0054] Furthermore, in the delayed-release component, the enteric layer comprises a first enteric material, a plasticizer and a third anti-adhesive agent;

[0055] 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.

[0056] The plasticizer, the third anti-sticking agent, the stabilizer and the defoaming agent are as described in the present invention.

[0057] Furthermore, the delayed-release component, by weight percentage, comprises 0.5-1.5% of the corticosteroid, 45-55% of the blank pellet core, 3-6% of the first binder, 0.8-1.5% of the first anti-adhesive agent, 1-2% of the second binder, 0.4-1% of the second anti-adhesive agent, 3.5-6.5% of the third anti-adhesive agent, 25-45% of the enteric material, and 0.5-1.5% of the plasticizer.

[0058] Furthermore, in the delayed-release component, the proportion of corticosteroids, by weight percentage, 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%.

[0059] Furthermore, in the sustained-release component, the enteric layer comprises a second enteric material, a plasticizer and a third anti-adhesive agent;

[0060] 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.

[0061] The plasticizer, the third anti-sticking agent, the stabilizer and the defoaming agent are as described in the present invention.

[0062] Furthermore, the sustained-release component, by weight percentage, comprises 0.5-1.5% of the corticosteroid, 60-70% of the 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.

[0063] Furthermore, in the sustained-release component, the proportion of corticosteroids can be selected from 0.5%, 1%, and 1.5%, the proportion of blank pill cores can be selected from 60%, 65%, and 70%, the proportion of the first adhesive can be selected from 5.5%, 6%, 6.5%, 7%, and 7.5%, the proportion of the first anti-adhesive agent can be selected from 1%, 1.5%, and 2%, the proportion of the second adhesive can be selected from 1.5%, 2%, 2.5%, and 3%, the proportion of the second anti-adhesive agent can be selected from 0.4%, 0.6%, 0.8%, and 1%, the proportion of the third anti-adhesive agent can be selected from 3%, 4%, and 5%, the proportion of enteric material can be selected from 7%, 5%, 10%, 15%, and 20%, and the proportion of plasticizer can 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 methacrylic acid copolymer type B.

[0064] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, povidone K30, talc, triethyl citrate, a methacrylic acid-ethyl acrylate copolymer aqueous dispersion, polyethylene glycol 6000, and methacrylic acid copolymer type B.

[0065] Furthermore, the pharmaceutical composition comprises budesonide, a sucrose core, povidone K30, hypromellose, talc, hydroxypropyl cellulose, triethyl citrate, cellulose acetate propionate, dibutyl sebacate, and methacrylic acid copolymer type B.

[0066] Further preferably, the gastric-soluble capsule is a gelatin capsule.

[0067] Furthermore, the pharmaceutical composition of the present invention is in the form of tablets, microtablets, granules, pills, etc., or the sustained-release component and the delayed-release component are in the form of tablets, microtablets, granules, pills, etc., and are further coated with the timely-release component.

[0068] In another aspect, the present invention provides a pharmaceutical composition containing a corticosteroid, comprising or consisting of the following components: an immediate-release component and a delayed-release component. Furthermore, the delayed-release component comprises a core containing the corticosteroid, a separating layer, and an enteric layer; and the immediate-release component dissolves in the stomach after oral administration.

[0069] In the present invention, the corticosteroid includes one or more of alclometasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, methylprednisolone, mometasone, prednisolone, triamcinolone, fluticasone, ciclesonide, fludrocortisone or budesonide.

[0070] Furthermore, the immediate-release component is a capsule shell, i.e., the capsule shell is a gastric-soluble capsule that dissolves in the stomach and releases the delayed-release component. Therefore, the preparation of the present application is not affected by gastric emptying, reaches a more regular peak, and reduces both inter- and intra-individual variability. The material of the capsule shell is selected from starch, hypromellose, PVA, pullulan, or gelatin.

[0071] Furthermore, the core containing the corticosteroid is coated with an isolation layer, and the isolation layer is coated with an enteric layer.

[0072] Furthermore, the corticosteroid-containing core 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. 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 commercially available.

[0073] Furthermore, the corticosteroid drug is budesonide.

[0074] Furthermore, the corticosteroid-containing core may further comprise a first binder, a defoaming agent, and a first anti-adherent. Furthermore, the isolation layer comprises a second binder, a stabilizer, and a second anti-adherent. Furthermore, the enteric layer comprises an enteric material, a plasticizer, and a third anti-adherent.

[0075] 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 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%, 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%.

[0076] Furthermore, in the pharmaceutical composition, the proportion of corticosteroid can be selected from 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.5%, 1.7%, and 2% by weight; the proportion of blank pellet core can be selected from 35%, 40%, 45%, 50%, 52%, 55%, 58%, 60%, 63%, 65%, 67%, 69%, 70%, and 75%; the proportion of the first adhesive can be selected from 2%, 3%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, and 7.5% by weight. The proportion of the first anti-adhesive agent 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 proportion of the second adhesive 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 proportion of the second anti-adhesive agent 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 proportion can be selected from 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, the enteric material proportion can be selected from 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, the plasticizer accounts for 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%, and 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%.

[0077] 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.

[0078] Furthermore, the first anti-sticking agent, the second anti-sticking agent and the third anti-sticking agent are each independently selected from one or more of talc, stearic acid and magnesium stearate.

[0079] Furthermore, the defoaming agent is selected from one or more of hydrophobic silica, dimethyl silicone oil, and simethicone. Furthermore, the stabilizer is selected from one or more of citric acid, malic acid, and citric acid.

[0080] 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.

[0081] Furthermore, the plasticizer is selected from one or more of triethyl citrate and polyethylene glycol 6000.

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

[0084] 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.

[0085] Furthermore, the enteric material is a mixture of methacrylic acid copolymer type A and methacrylic acid copolymer type B.

[0086] The inventors further discovered through experiments that the release of drugs can be effectively controlled by selecting the materials for the enteric layer, for example, the release of drugs in a designated position in the intestine can be controlled, and the total release time can be controlled. However, enteric materials composed of different materials have different release amounts of drugs in different time periods. For example, drugs coated with some enteric materials (such as methacrylic acid copolymer type A) are released quickly after entering the designated position, while drugs coated with some enteric materials (methacrylic acid copolymer type B) are released slowly after entering the designated position. Therefore, the specific selection of enteric materials is also targeted.

[0087] 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 (total release time, release rate, and release amount at different stages) as the original drug, the inventors further studied and experimented on enteric materials. 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.

[0088] Furthermore, the pharmaceutical composition comprises, by weight percentage, 0.5-1.5% budesonide, 65-70% sucrose core, 5-10% talc, 5-10% hypromellose, 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.

[0089] On the other hand, the method for preparing the pharmaceutical composition of the present invention comprises: preparing a core containing a corticosteroid drug, coating the core containing the corticosteroid drug with a separating layer, and coating the core containing the enteric layer with the separating layer; and further comprises the step of mixing a delayed-release component and a sustained-release component.

[0090] Furthermore, the method comprises the following steps:

[0091] Step 1: preparing a first suspension containing a corticosteroid drug, a first binder and a first anti-adhesive agent; coating the first suspension on a blank pellet core to form a core containing the corticosteroid drug;

[0092] Step 2: preparing a second solution with a second adhesive and a second anti-adhesive agent, and coating the core containing the corticosteroid drug with the second solution to form an isolation layer;

[0093] Step 3: prepare a third solution by combining the enteric material, plasticizer and anti-adhesive agent; coat the third solution to form an enteric layer to obtain a delayed / sustained release component.

[0094] 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.

[0095] Furthermore, the second solution also contains a stabilizer, which is mainly used to stabilize corticosteroids such as budesonide, creating an acidic environment for storage stability.

[0096] Furthermore, the prepared delayed / sustained release component is coated in the immediate release component to obtain a pharmaceutical composition. Still further, 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.

[0097] In another aspect, the present invention provides 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 glomerulonephritis. Furthermore, the inflammatory disease of the gastrointestinal tract is glomerulonephritis, and the glomerulonephritis is adapted to provide sustained drug release for 2 to 6 hours. Furthermore, the glomerulonephritis is Crohn's disease or ulcerative colitis.

[0098] In the present invention, hydroxypropyl cellulose (CAS No. 9004-64-2), hypromellose (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-sticking 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.

[0099] In the present invention, the CAS number of methacrylic acid copolymer type A is 25806-15-1, and its pharmaceutical excipient approval number is F20140016. The CAS number of methacrylic acid copolymer type B is 25086-15-1, and its pharmaceutical excipient approval number is F20140017. The CAS number of methacrylic acid copolymer type C is 25212-88-8, and its pharmaceutical excipient approval number is F20170010. The CAS number of methacrylic acid-ethyl acrylate copolymer aqueous dispersion is 25212-88-8, and its pharmaceutical excipient approval number is F20150007. The CAS number of cellulose acetate propionate (also known as cellulose propionate) is 9004-39-1. The CAS number of hydropropyl methylcellulose acetate succinate (also known as cellulose 2-hydroxypropyl methyl ether acetate-esterified succinate-hydrogen) is 71138-97-1. The CAS number for Hydroxypropyl methylcellulose phthalate is 9050-31-1. The CAS number for Carboxymethyl ethylcellulose is 9032-42-2. The CAS number for Cellulose acetate phthalate is 9004-38-0. The CAS number for Polyvinyl acetate phthalate is 34481-48-6. The CAS number for Hydroxypropyl methylcellulose phthalate is 9050-31-1.

[0100] 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 (approximately 250,000); the mass concentration of the methacrylic acid-ethyl acrylate copolymer aqueous dispersion is 20-40% (e.g., 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. Methacrylic acid copolymer type A has an average molecular weight of 90,000 to 180,000, preferably 100,000 to 150,000 (e.g., an average molecular weight of 135,000). Methacrylic acid copolymer type B has an average molecular weight greater than 100,000, preferably 100,000 to 200,000, more preferably 120,000 to 180,000 (e.g., an average molecular weight of 150,000). Methacrylic acid copolymer type C has an average molecular weight of 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.

[0101] Compared with the prior art, the present invention has the following beneficial effects:

[0102] (1) The pharmaceutical composition of the present invention utilizes two components with different drug release times, thereby enabling the composition to have both rapid-release and sustained-release functions, thereby controlling the drug release rate of the composition in vivo, maintaining the blood drug concentration in vivo, improving bioavailability, and reducing the risk of drug release and individual differences in vivo. Alternatively, the pharmaceutical composition of the present invention utilizes a combination of one, two, or even multiple different enteric materials to achieve targeted drug release in vivo, and by controlling the selection of specific materials for different enteric layers, controls the drug release rate in vivo, 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.

[0103] (2) The pharmaceutical composition of the present invention is loaded with a gastric-soluble capsule shell, which dissolves in the stomach and releases the composition. Therefore, the preparation of the present application is not affected by gastric emptying, reaches a peak more regularly, and reduces both inter-individual and intra-individual variations.

[0104] (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.

[0105] (4) The preparation process of the pharmaceutical composition of the present invention is simpler than that of the original formulation, and the capsule coating step is omitted, so the production cost is lower. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. 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 any creative work.

[0107] Figure 1 Dissolution curve of Example 1.

[0108] Figure 2 shows the dissolution curve of Example 5.

[0109] Figure 3 Dissolution curve of Example 11.

[0110] Figure 4 shows the dissolution curve of Example 14.

[0111] Figure 5 shows the dissolution curve of Example 15.

[0112] FIG6 is a comparison of the dissolution curves of Examples 28, 30-33 and the reference preparation.

[0113] FIG7 is a comparison of the dissolution curves of Examples 35-39, Comparative Examples, and a reference preparation.

[0114] FIG8 is a drug-time curve diagram of Example 28 and the reference preparation under fasting conditions of 0 to 24 hours.

[0115] FIG9 is a drug-time curve diagram of Example 28 and the reference preparation under fasting conditions of 0 to 48 hours. DETAILED DESCRIPTION

[0116] 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 illustrate the present invention and are not intended to limit the scope of the present invention.

[0117] If no specific techniques or conditions are specified in the examples, the experiments were carried out according to the techniques or conditions described in the literature in the field or according to the product instructions. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0118] 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.

[0119] In the examples, all materials are of pharmaceutical grade, and each example is a prescription for 1,000 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., micronized 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 High-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 pellets, 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 High-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.

[0120] Preparation Example 1

[0121] Step 1: preparing a suspension containing a corticosteroid such as budesonide, a first adhesive and a first anti-adhesive agent in a certain proportion;

[0122] Step 2: spray the suspension in step 1 into the fluidized bed with blank cores at the bottom, set the coating temperature and coating speed to form drug-containing cores with a drug-containing layer;

[0123] Step 3: preparing a second adhesive and a second anti-adhesive agent into a solution;

[0124] Step 4: Spray the solution in step 3 into the fluidized bed containing the drug-containing cores prepared in step 2 at the bottom, set the coating temperature and coating speed to form drug-containing cores with an isolation layer;

[0125] Step 5: preparing an enteric material, a plasticizer and a third anti-adhesive agent into a suspension;

[0126] Step 6: Spray the suspension in step 5 into the fluidized bed containing the drug-containing core with the isolation layer prepared in step 4 at the bottom, set the coating temperature and coating speed to form the drug-containing core with the enteric layer, and put it into ordinary capsules.

[0127] Preparation Example 2

[0128] Steps 1 and 4 are the same as those in Preparation Example 1.

[0129] 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, enteric layer drug-containing core 1 and drug-containing core 2 with different release effects are prepared respectively;

[0130] Step 6: Mix the drug-containing core 1 and the drug-containing core 2 in proportion and put them into ordinary capsules.

[0131] Preparation Example 3:

[0132] Step 1: Prepare a first adhesive into a 5-15% aqueous solution, then homogeneously disperse a first anti-adhesive agent and a corticosteroid (e.g., budesonide) in the aqueous solution of the first adhesive to prepare a desired suspension for later use;

[0133] Step 2: Add the blank cores to the fluidized bed, preheat, and spray the suspension prepared in step 1 into the fluidized bed at a coating temperature of 35-40°C, an inlet air temperature of 30-55°C, a material temperature of 20-40°C, and an atomization pressure of 1.0-2.0 bar to prepare drug-containing cores containing a corticosteroid (e.g., budesonide);

[0134] Step 3: Prepare the second adhesive into a 5-15% aqueous solution, and then homogeneously disperse the second anti-adhesive agent in the aqueous solution of the second adhesive to prepare the desired suspension for later use;

[0135] 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°C, and the atomization pressure is 1.0-2.0 bar to obtain the drug-containing core with the isolation layer;

[0136] Step 5: mixing a third anti-adherent agent and purified water in a mass ratio of 1:2 and uniformly dispersing the mixture, then adding a plasticizer and stirring the mixture 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 an enteric material, adding purified water to obtain a suspension with a solid content of 10-30%, and setting aside;

[0137] Step 6: Add the drug-containing core with the isolation layer to 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 placed in a gelatin capsule.

[0138] Preparation Example 4:

[0139] Steps 1 and 4 are the same as those in Preparation Example 3.

[0140] Step 5: dissolving the enteric material and a 60%-90% ethanol solution in a mass ratio of 1:1, adding a plasticizer and stirring to dissolve, to prepare an ethanol solution containing the enteric material and the plasticizer; mixing a third anti-adherent agent with the 60%-90% ethanol solution in a mass ratio of 1:1 and homogeneously dispersing the mixture, to prepare a suspension containing the third anti-adherent agent; adding the suspension containing the third anti-adherent agent to the ethanol solution containing the enteric material and the plasticizer, and adding the 60%-90% ethanol solution to prepare a suspension with a solid content of 5-30%, and setting aside;

[0141] Step 6: Add the drug-containing core with an 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 placed in a gelatin capsule.

[0142] Preparation Example 5:

[0143] The drug-containing cores with enteric layers prepared in Preparation Example 3 and Preparation Example 4 were mixed in proportion and then packed into gelatin capsules to obtain the product.

[0144] Preparation Example 6:

[0145] 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;

[0146] Step 2: spray the suspension in step 1 into the fluidized bed with blank cores at the bottom, set the coating temperature and coating speed to form drug-containing cores with a drug-containing layer;

[0147] Step 3: preparing a solution of the second adhesive, the stabilizer and the second anti-adhesive agent;

[0148] Step 4: Spray the solution in step 3 into the fluidized bed containing the drug-containing cores prepared in step 2 at the bottom, set the coating temperature and coating speed to form drug-containing cores with an isolation layer;

[0149] Steps 5 and 6 are the same as those in Preparation Example 1.

[0150] Preparation Example 7:

[0151] Step 1: Prepare a first adhesive into a 5-15% aqueous solution, then homogeneously disperse a first anti-adhesive agent, a defoaming agent, and a corticosteroid (e.g., budesonide) in the aqueous solution of the first adhesive to prepare a desired suspension for later use;

[0152] Step 2: Add blank cores to a fluidized bed, preheat, and spray the suspension from step 1 into the fluidized bed at a coating temperature of 35-40°C, an inlet air temperature of 30-40°C, a material temperature of 25-30°C, and an atomization pressure of 1.0-2.0 bar to produce drug-containing cores containing a corticosteroid (e.g., budesonide);

[0153] Step 3: Prepare the second adhesive into a 5-15% aqueous solution, then homogeneously disperse the second anti-adhesive agent and stabilizer in the aqueous solution of the second adhesive to prepare the desired suspension for later use;

[0154] 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 30-40°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 the isolation layer:

[0155] Step 5: dissolving the enteric material in ethanol to prepare an enteric material solution; mixing a third anti-adherent agent and purified water in a mass ratio of 1:2 and uniformly dispersing the mixture; then adding a plasticizer and stirring evenly to prepare 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, and adding purified water to prepare a suspension with a solid content of 8 to 30% (preferably 8%), and setting aside;

[0156] Step 6: Add the drug-containing core with the isolation layer to 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 placed in a gelatin capsule.

[0157] Example 1

[0158] Preparation prescription: drug-containing core: budesonide 3.75g, sucrose pellet 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.

[0159] The preparation process was the same as that of Preparation Example 3, wherein the first binder and the second binder were both prepared into 10% aqueous solutions; the solid content of the suspension in step 5 was 10%; and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 30°C, and atomization pressure of 1.5 bar.

[0160] Example 2

[0161] 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 6000 5.625g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 187.5g.

[0162] The preparation process was the same as that of Preparation Example 3, wherein the first binder was prepared into a 10% concentration solution, and the second binder was prepared into a 15% water concentration aqueous solution; the solid content of the suspension in step 5 was 10%; and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 35°C, inlet air temperature of 40°C, material temperature of 30°C, and atomization pressure of 1.2 bar.

[0163] Example 3

[0164] Preparation prescription: drug-containing core: budesonide 7.5g, lactose pellet 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.

[0165] The preparation process was the same as that of Preparation Example 3, wherein the first binder and the second binder were both prepared into 15% aqueous solutions; the solid content of the suspension in step 5 was 20%, and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 35°C, inlet air temperature of 35°C, material temperature of 25°C, and atomization pressure of 2 bar.

[0166] Example 4

[0167] Preparation prescription: Drug-containing core: budesonide 18.75g, sucrose pellet core 337.5g, povidone K30 37.5g, magnesium stearate 11.25g; isolation layer: sodium carboxymethylcellulose 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.

[0168] The preparation process was the same as that of Preparation Example 3, wherein the first binder and the second binder were both prepared into 12% aqueous solutions; the solid content of the suspension in step 5 was 20%; and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 35°C, air inlet temperature of 35°C, material temperature of 28°C, and atomization pressure of 2 bar.

[0169] Example 5

[0170] Preparation prescription: Drug-containing core: budesonide 4.17g, sucrose pellet core 300g, hypromellose 27g, talc 6.75g; isolation layer: hypromellose 10g, talc 2.5g; enteric layer: talc 18.3g, polyethylene glycol 6000 9.15g, methacrylic acid copolymer type B 61g.

[0171] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 10% aqueous solutions; the concentration of the ethanol solution in step 5 was 80%, and the solid content of the suspension was 10%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0172] Example 6

[0173] Preparation prescription: Drug-containing core: budesonide 1.875g, starch pellet 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.

[0174] The preparation process was the same as that of Preparation Example 4, wherein the first binder was prepared into a 15% aqueous solution and the second binder was prepared into a 10% aqueous solution; the concentration of the ethanol solution in step 5 was 90%, and the solid content of the suspension was 15%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 35°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.0 bar.

[0175] Example 7

[0176] 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.

[0177] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 15% aqueous solutions; the concentration of the ethanol solution in step 5 was 70%, and the solid content of the suspension was 10%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 35°C, material temperature of 25°C, and atomization pressure of 1.6 bar.

[0178] Example 8

[0179] Preparation prescription: Drug-containing core: budesonide 1.875g, sucrose pellet 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.

[0180] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 14% aqueous solutions; the concentration of the ethanol solution in step 5 was 80%, and the solid content of the suspension was 10%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 35°C, material temperature of 25°C, and atomization pressure of 1.6 bar.

[0181] Example 9

[0182] Preparation prescription: drug-containing core: budesonide 5.5g, lactose pellet core 325g, povidone K30 30g, talc 7g; isolation layer: hypromellose 10g, glyceryl monostearate 3g; enteric layer: talc 35g, diethyl sebacate 7g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 250g.

[0183] The preparation process was the same as that of Preparation Example 3, wherein the first binder and the second binder were both prepared into 15% aqueous solutions; the solid content of the suspension in step 5 was 15%; and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 30°C, and atomization pressure of 1.5 bar.

[0184] Example 10

[0185] 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.

[0186] The preparation process was the same as that of Preparation Example 3, wherein the first binder and the second binder were both prepared into 15% aqueous solutions; the solid content of the suspension in step 5 was 30%; and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0187] Example 11

[0188] 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 31g, triethyl citrate 7g, methacrylic acid-ethyl acrylate copolymer aqueous dispersion 204g.

[0189] The preparation process was the same as that of Preparation Example 3, wherein the first binder and the second binder were both prepared into 15% aqueous solutions; the solid content of the suspension in step 5 was 10%; and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0190] Example 12

[0191] Preparation prescription: drug-containing core: budesonide 4.5, sucrose pellet 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.

[0192] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 15% aqueous solutions; the concentration of the ethanol solution in step 5 was 80%, and the solid content of the suspension was 20%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0193] Example 13

[0194] Preparation prescription: drug-containing core: budesonide 4g, sucrose pellet core 300g, hypromellose 24g, talc 6.25g; isolation layer: hypromellose 8g, talc 2g; enteric layer: talc 18g, dibutyl sebacate 7.5g, methacrylic acid copolymer type B 70g.

[0195] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 15% aqueous solutions; the concentration of the ethanol solution in step 5 was 90%, and the solid content of the suspension was 10%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0196] Example 14

[0197] 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.

[0198] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 15% aqueous solutions; the concentration of the ethanol solution in step 5 was 70%, and the solid content of the suspension was 20%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0199] Example 15

[0200] 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.

[0201] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 10% aqueous solutions; the concentration of the ethanol solution in step 5 was 90%, and the solid content of the suspension was 30%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0202] Example 16

[0203] 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.

[0204] The preparation process was the same as that of Preparation Example 3, wherein the first binder and the second binder were both prepared into 10% aqueous solutions; the solid content of the suspension in step 5 was 10%; and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0205] Example 17

[0206] 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.

[0207] The preparation process was the same as that of Preparation Example 3, wherein the first binder and the second binder were both prepared into 10% aqueous solutions; the solid content of the suspension in step 5 was 15%; and the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0208] Example 18

[0209] 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.

[0210] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 10% aqueous solutions; the concentration of the ethanol solution in step 5 was 80%, and the solid content of the suspension was 10%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 30°C, material temperature of 25°C, and atomization pressure of 1.5 bar.

[0211] Example 19

[0212] 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.

[0213] The preparation process was the same as that of Preparation Example 4, wherein the first binder and the second binder were both prepared into 10% aqueous solutions; the concentration of the ethanol solution in step 5 was 90%, and the solid content of the suspension was 30%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 30°C, and atomization pressure of 1.5 bar.

[0214] Example 20

[0215] The drug-containing cores with enteric layers prepared in Example 1 and Example 5 were mixed in a ratio of 1:1 and then packed into a gelatin capsule to obtain the product.

[0216] Example 21

[0217] The drug-containing cores with enteric layers prepared in Example 11 and Example 14 were mixed in a ratio of 1:2 and then packed into gelatin capsules to obtain the product.

[0218] Example 22

[0219] The drug-containing cores with enteric layers prepared in Example 11 and Example 15 were mixed in a ratio of 1:1 and then packed into a gelatin capsule to obtain the product.

[0220] Example 23

[0221] The drug-containing cores with enteric layers prepared in Example 10 and Example 13 were mixed in a ratio of 1:3 and then packed into a gelatin capsule to obtain the product.

[0222] Example 24

[0223] 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 gelatin capsules to obtain the product.

[0224] Example 25

[0225] The drug-containing cores with enteric layers prepared in Example 1 and Example 5 were mixed at a ratio of 1:5 and then packed into a gelatin capsule to obtain the product.

[0226] Example 26

[0227] The drug-containing cores with enteric layers prepared in Example 1 and Example 5 were mixed in a ratio of 1:4 and then packed into a gelatin capsule to obtain the product.

[0228] Example 27

[0229] Preparation prescription: drug-containing core: budesonide 4.9g, sucrose pellet core 300g, hypromellose 27g, talc 6.75g; isolation layer: hypromellose 10.43g, talc 2.65g; enteric layer: talc 22.65g, triethyl citrate 7.55g, methacrylic acid copolymer type A 37.76g, methacrylic acid copolymer type B 37.76g.

[0230] The preparation process was the same as that of Preparation Example 7, wherein the first binder and the second binder were both prepared into 10% aqueous solutions; the concentration of the ethanol solution in step 5 was 90%, and the solid content of the suspension was 30%; the parameters in the fluidized bed in steps 2, 4, and 6 were all set as follows: coating temperature of 38°C, inlet air temperature of 40°C, material temperature of 30°C, and atomization pressure of 1.5 bar.

[0231] Example 28

[0232] Preparation prescription: Drug-containing core: budesonide 4.9g, sucrose pill core 300g, hypromellose 27g, talc 6.75g, dimethicone 0.13g; isolation layer: hypromellose 10.43g, talc 2.65g, citric acid 0.63g; enteric layer: talc 22.65g, triethyl citrate 7.55g, methacrylic acid copolymer type A 37.76g, methacrylic acid copolymer type B 37.76g.

[0233] The preparation process is the same as Example 27.

[0234] Example 29

[0235] Preparation prescription: Drug-containing core: budesonide 4.9g, sucrose pill core 300g, hypromellose 27g, talc 6.75g, simethicone 0.15g; isolation layer: hypromellose 10.43g, talc 2.65g, potassium dihydrogen phosphate 0.53g; enteric layer: talc 22.65g, triethyl citrate 7.55g, methacrylic acid copolymer type A 37.76g, methacrylic acid copolymer type B 37.76g.

[0236] The preparation process is the same as Example 27.

[0237] Example 30

[0238] Preparation prescription: Drug-containing core: budesonide 4.5g, sucrose pill core 300g, hypromellose 27g, talc 6.8g, dimethicone 0.11g; isolation layer: hypromellose 10.43g, talc 2.65g, citric acid 0.6g; enteric layer: talc 22.65g, triethyl citrate 7.55g, methacrylic acid copolymer type A 47.76g, methacrylic acid copolymer type B 47.76g.

[0239] The preparation process is the same as Example 27.

[0240] Example 31

[0241] Preparation prescription: Drug-containing core: budesonide 5.2g, sucrose pill core 300g, hypromellose 27g, talc 7.1g, simethicone 0.15g; isolation layer: hypromellose 12.36g, talc 2.86g, potassium dihydrogen phosphate 0.53g; enteric layer: talc 24.35g, triethyl citrate 9.12g, methacrylic acid copolymer type A 22.5g, methacrylic acid copolymer type B 21.5g.

[0242] The preparation process is the same as Example 27.

[0243] Example 32

[0244] Preparation prescription: Drug-containing core: budesonide 4.9g, sucrose pill core 300g, hypromellose 27g, talc 6.75g, dimethicone 0.14g; isolation layer: hypromellose 10.43g, talc 2.61g, citric acid 0.53g; enteric layer: talc 30.21g, triethyl citrate 10.07g, methacrylic acid copolymer type A 50.37g, methacrylic acid copolymer type B 50.37g.

[0245] The preparation process is the same as Example 27.

[0246] Example 33

[0247] Preparation prescription: Drug-containing core: budesonide 4.9g, sucrose pill core 300g, hypromellose 27g, talc 6.75g, dimethicone 0.14g; isolation layer: hypromellose 10.43g, talc 2.61g, citric acid 0.53g; enteric layer: talc 35.87g, triethyl citrate 12.90g, methacrylic acid copolymer type A 63.96g, methacrylic acid copolymer type B 75.23g.

[0248] The preparation process is the same as Example 27.

[0249] Example 34

[0250] 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.

[0251] Example 35

[0252] 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.

[0253] Example 36

[0254] The difference from Example 32 is: enteric layer: magnesium stearate 30.21 g, triethyl citrate 10.07 g, methacrylic acid copolymer type A 20.05 g, methacrylic acid copolymer type B 80.20 g.

[0255] Example 37

[0256] 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.

[0257] Example 38

[0258] 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.

[0259] Example 39

[0260] 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.

[0261] Comparative Example

[0262] After conversion with reference to Example 3 of patent CN101108171A, the specific prescription composition is as follows:

[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 hours, pH 6.8 phosphate buffer from 2 to 8 hours, 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 rate of budesonide in the above preparations within 0 to 2 hours was 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 a 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 in Examples 1 and 11 could rapidly 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 steadily 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%; and the cumulative dissolution rate of budesonide in the pharmaceutical composition prepared in Example 15 at the 4th hour was 90.01%. This indicates that the compositions of Examples 5, 14, and 15 can continuously release budesonide in the intestine, and the release rates of Examples 14 and 15 are slightly faster than that of Example 5.

[0270] From the dissolution test of the pharmaceutical compositions 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, ensuring the dissolution concentration of budesonide and the extension of the dissolution time.

[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 (4 mg) after oral administration of 4 tablets on an empty stomach. The plasma concentration of budesonide at different time points was measured, 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: 21 blood samples were collected from each subject in each cycle, 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] As can be seen from the table above, the delayed-release compositions (Examples 1 and 11) reach peak drug release in vivo earlier than the sustained-release compositions (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 drug release time of Examples 20 and 21, which are a mixture of the delayed-release composition and the sustained-release composition, is between the peak times of the delayed-release composition and the sustained-release composition, indicating that the two can cooperate with each other to control the drug release rate of the pellets in vivo, maintain the blood drug concentration in vivo, and improve bioavailability. 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.

[0278] Effect Example 3

[0279] The dissolution curves of the pharmaceutical compositions prepared from the reference preparation, comparative example, and Examples 28, 30-33, and 35-39 were respectively measured.

[0280] Dissolution method: Paddle method, 100 rpm. Dissolution medium: pH 1.2 hydrochloric acid solution from 0 to 2 hours, pH 6.8 phosphate buffer from 2 to 8 hours. Sampling time points: 0 min, 120 min, 135 min, 150 min, 180 min, 210 min, 240 min, 300 min, 360 min, and 370 min. Dissolution results are shown in Tables 2 and 3 below.

[0281] Table 2

[0282] Table 3

[0283] As shown in Figure 6, the dissolution curves of Examples 28, 30-33 show that under pH 1.2 hydrochloric acid solution conditions (0 min-120 min), the cumulative dissolution of budesonide in the above-mentioned formulations within the first 0-2 hours was less than 0.25%, indicating that the pharmaceutical compositions prepared by the present invention release almost no drug in the stomach. In a pH 6.8 phosphate buffer dissolution medium, approximately 30 min (150 min in the figure), the budesonide in the prepared pharmaceutical compositions was immediately released by 14-20%. At 180 min, the cumulative dissolution of budesonide reached over 60%, maintained over 80% from 210 min to 360 min, and was greater than 90% at 360 min. This indicates that the compositions can continuously and slowly release budesonide in the intestine, and the release rate is substantially consistent with that of the reference formulation.

[0284] 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 targeted drug release and sustained drug release; from the dissolution curves of Examples 28 and 30-32, it can be seen that the thickness of the enteric layer affects the speed of drug release to a certain extent.

[0285] From 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 satisfy the control of sustained drug release.

[0286] As shown in Figure 7, the dissolution process of the comparative example, Examples 37-39, and the reference preparation shows that at 180 minutes, the comparative preparations and Examples 37-39 were almost completely dissolved, while the reference preparation only dissolved 16.11%. At 210 minutes, the reference preparation only dissolved 75.2%, indicating that the comparative preparation dissolves too quickly.

[0287] The inventors discovered through experiments that, after slightly adjusting the enteric layer material ratio in the comparative example to increase the weight content (30-50%), as in Examples 37-39, it was found that the adjustment of the dissolution rate by increasing the weight of the enteric layer was unclear, and the dissolution rate was still too fast. Example 36 adjusted the anti-adherent agent based on Example 27, but still did not achieve the expected dissolution rate. Example 35 adjusted the ratio of the enteric layer excipients, that is, increased the content of methacrylic acid copolymer type B, and the dissolution release rate was significantly slowed.

[0288] Based on Figure 7 , the 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 to methacrylic acid copolymer Type B directly affects the dissolution rate of the drug. When the dosage ratio of methacrylic acid copolymer Type A to 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, consistent with the dissolution trend of the reference preparation, thereby ensuring the bioavailability of the drug.

[0289] Through experiments, the inventors discovered that adjusting the ratio of methacrylic acid copolymer Type A to methacrylic acid copolymer Type B in the enteric layer directly affects the drug dissolution rate. Excessive use of methacrylic acid copolymer Type A results in excessive drug dissolution, while excessive use of methacrylic acid copolymer Type B results in excessive drug dissolution. When the ratio of methacrylic acid copolymer Type A to methacrylic acid copolymer Type B is controlled to be 1:0.6-3 (preferably 1:0.8-2), the resulting drug dissolution rate is close to that of the reference formulation, thereby ensuring the bioavailability of the resulting drug.

[0290] Effect Example 4

[0291] Pharmacokinetic study of budesonide enteric-coated pellets:

[0292] This study employed a two-cycle crossover dosing to compare the pharmacokinetic properties of the pharmaceutical compositions (4 mg) prepared in Examples 28 and 32 and a reference formulation (commercially available budesonide enteric-coated pellets) after oral administration of four capsules on an empty stomach. Plasma budesonide concentrations were measured at different time points, and in vivo pharmacokinetic parameters were calculated after oral administration of the pharmaceutical compositions (4 mg) prepared in Examples 28 and 32 and the reference formulation. The results are shown in Tables 4 to 6. The fasting study was planned to enroll 6 subjects; 6 subjects were actually enrolled. All subjects completed two cycles of dosing and clinical sampling.

[0293] Blood collection time:

[0294] Fasting test: 22 sampling points were collected at 0 h before administration (within 1 h before administration) and 2 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, 8 h, 8.5 h, 9 h, 10 h, 11 h, 12 h, 14 h, 24 h, 36 h, and 48 h after administration. 3 mL of venous blood was collected each time.

[0295] Table 4 Pharmacokinetic parameter statistics of the reference preparation and Example 28

[0296] Table 5 Statistics of human pharmacokinetic parameters of reference preparation and Example 32

[0297] Table 6: Reference Formulation and Example 32 - Absorption Kinetics Consistency Evaluation Data - Fasting

[0298] As shown in Tables 4-6 above, the compositions prepared in Examples 28 and 32 have similar in vivo drug release times compared to the reference formulation. Therefore, as long as the material composition of the enteric layer is controlled, the in vivo drug release time and release rate of the prepared drug can be guaranteed to be close to that of the reference formulation. The release time of Example 28 is slightly faster, while the release time of Example 32 is slightly slower, indicating that the in vivo drug release rate of the pellets can be controlled by adjusting the thickness of the enteric layer, maintaining the blood drug concentration in vivo and improving bioavailability.

[0299] Figures 8-9 illustrate that the drug release behaviors of Examples 28, 32 and the reference formulation in vivo are very similar.

[0300] The consistency evaluation data in Table 6 show that Example 32 and the reference formulation have equivalent AUCs in humans. This indicates that the pharmaceutical composition prepared by the present invention not only achieves the goal of preventing drug release in gastric acid but also, through adjustments in formulation technology, can flexibly achieve both rapid intestinal release and targeted drug release at different intervals. This opens the possibility of treating diseases such as ulcerative colitis, Crohn's disease, and IgA nephropathy, which require drug release at different time intervals.

[0301] The inventors have conducted experiments and found that the present invention provides a solution for optimizing the enteric layer material. By specifically selecting the type and dosage of the enteric layer material, the pharmaceutical composition is released at a designated location in the intestine. Therefore, by controlling the type and / or dosage of the enteric layer material, the pharmaceutical composition prepared can have a release pattern that is the same as or similar to that of the corresponding reference preparation, thereby ensuring the release rate of the drug and thus ensuring the bioavailability of the drug. Alclometasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, methylprednisolone, mometasone, hydroprednisolone, triamcinolone, fluticasone, ciclesonide, and fludrocortisone employ the enteric layer of the specific material of the present invention and a specific dosage ratio, and have similar release characteristics. Since the release patterns are close to those of the corresponding reference preparations, they will not be described in detail herein.

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 arginine, meglumine, disodium hydrogen phosphate, tartaric acid, phosphoric acid, potassium dihydrogen phosphate, citric acid, malic acid, citric acid, One or more of sodium carbonate.

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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