WO2022222971A1 - Oral enteric-coated corticosteroids pharmaceutical composition - Google Patents

Abstract

Disclosed is an oral enteric-coated corticosteroids pharmaceutical composition, including: a) a sustained release component, wherein the sustained release component contains a drug-containing core, an isolation layer and a sustained-release coating layer, and the drug-containing core contains corticosteroids such as budesonide and hydroxypropyl methyl cellulose, and b) a delayed release component, wherein the delayed release component protects the composition to be basically released in the intestinal tract after oral administration.

Description

A pharmaceutical composition for oral enteric-coated corticosteroids

This application claims the priority of Chinese patent application 2021104235951 with a filing date of April 20, 2021. This application cites the full text of the above Chinese patent application.

technical field

The present disclosure belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of oral enteric-coated corticosteroids.

Background technique

Corticosteroids, such as budesonide, are used to treat intestinal inflammatory diseases, such as Crohn's disease, ulcerative colitis, by inhibiting the action of the inflammatory response. Oral or intravenous corticosteroids can also be used to treat glomerulonephritis, but long-term systemic exposure to corticosteroids can cause serious side effects, such as Cushing's syndrome and osteoporosis,

Ideally, to minimize systemic exposure to corticosteroids, one approach is by means of rectal administration such as suppositories or enemas. The other is to use the method of intestinal targeted delivery, that is, to make enteric-coated formulations, so that corticosteroids are only released in the intestinal tract. Relevant literature can be found in WO1995035100, WO2003080032, CN101108171, US5643602 and US10172802.

CN102088962 discloses an oral preparation of budesonide with sustained/sustained release in the intestinal tract. It uses aminoethyl cellulose such as

can be formed for the purpose of sustained/sustained release components, and then also found

Alkaline sustained-release materials will affect the stability of corticosteroids. Even if an isolation layer (or additional coating layer) is added between the drug-containing core and the sustained-release coating layer, it still cannot be solved, and the isolation layer (or additional coating layer) must be added. A stable pharmaceutical composition can be obtained by adding an additional acid, preferably a weak acid, such as citric acid, to the coating layer).

Quality by design means that the quality of a drug product is produced by good design, not by control of the production process. Enteric coatings can be solved using acid-containing coating solutions

The problem of interaction with budesonide, but the use of additional excipients does not bring additional drug quality control risks and quality control costs. Accordingly, the design and development of new enteric-coated sustained-release corticosteroid pharmaceutical compositions are still pursued by formulators.

SUMMARY OF THE INVENTION

The present disclosure provides a pharmaceutical composition comprising:

a) a sustained-release component, comprising a drug-containing core, an isolation layer, and a sustained-release coating layer, the drug-containing core is coated by the isolation layer, and the isolation layer is coated by the sustained-release coating layer, wherein the drug-containing core is coated The core contains corticosteroid and hydroxypropylmethylcellulose, and the weight ratio of hydroxypropylmethylcellulose to corticosteroid is at least 2.5:1;

and b) a delayed release component. The delayed release component, after oral administration, substantially blocks release of the sustained release component until the composition reaches the intestine, allowing the corticosteroid drug to reach the area to be treated, such as the inflamed portion of the intestine, in sufficient concentration, where it is The area lasts long enough to provide a localized treatment effect.

Some embodiments provide a schematic diagram of the sustained release component structure in the pharmaceutical composition, as shown in FIG. 1 .

The use of ethyl cellulose as a coating can control the drug release rate. However, ethyl cellulose is a hydrophobic polymer that, while forming an excellent barrier to drug diffusion, is insoluble in water and can only form solutions in organic solvents such as chloroform and tetrahydrofuran. Alkali ethyl cellulose containing materials such as

As a class of water-soluble slow-release materials, it can realize a fully formulated slow-release aqueous coating system. In some embodiments, the alkali-containing ethyl cellulose is an ammonia-containing ethyl cellulose material. In some embodiments, the alkali-containing ethyl cellulose is

It is produced by mixing ethyl cellulose with oleic acid and dibutyl sebacate, followed by extrusion and dissolution. In some embodiments, the sustained release coating layer comprising the controlled release material is an alkali ethylcellulose-containing material, preferably an aminoethylcellulose-containing material, such as

However

Because the basic polymer has poor compatibility with the acidic drug contacting excipients, for example, CN102088962 has found that its alkalinity can cause the degradation of corticosteroids. Adding an isolation layer is a strategy to solve stability, however, only adding an isolation layer cannot obtain a stable corticosteroid pharmaceutical composition, and an additional acid such as a weak acid needs to be added to the isolation layer. In the present application, it is hoped that the stability of the composition can be achieved without adding additional acid, and for this purpose, various types of excipients such as lactose, cyclodextrin, mannitol, glyceryl behenate and the like are screened. It was unexpectedly found that hydroxypropyl methylcellulose can excellently alleviate the degradation of budesonide due to the presence of alkaline reagents, so that the pharmaceutical preparation has an excellent shelf life.

In some embodiments, the hydroxypropyl methylcellulose in the drug-containing core is added in the form of "free state", or in the form of a composite adjuvant, but not only in the form of a composite adjuvant. In some embodiments, the drug-containing core contains budesonide, Opadry I, and hypromellose. In some embodiments, the medicated core contains budesonide and hypromellose.

In some embodiments, the weight ratio of hydroxypropylmethylcellulose to corticosteroid in the drug-containing core is 2.5:1 to 8:1, and can be 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0: 1, 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4.0:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5.0:1, 5.1:1, 5.2:1, 5.3:1, 5.4:1, 5.5: 1, 5.6:1, 5.7:1, 5.8:1, 5.9:1, 6.0:1, 6.1:1, 6.2:1, 6.3:1, 6.4:1, 6.5:1, 6.6:1, 6.7:1, 6.8:1, 6.9:1, 7.0:1, 7.1:1, 7.2:1, 7.3:1, 7.4:1, 7.5:1, 7.6:1, 7.7:1, 7.8:1, 7.9:1, 8.0: 1 or any value in between.

On the other hand, in view of the poor compatibility between titanium dioxide and budesonide in direct contact, in some embodiments, it is not recommended to add titanium dioxide or an auxiliary material containing titanium dioxide to the drug-containing core. In addition, the compatibility of polyethylene glycol and budesonide in direct contact is also not good. In some embodiments, it is not recommended to add polyethylene glycol or adjuvants containing polyethylene glycol to the drug-containing core. In some embodiments, polyethylene glycol is absent from the sustained release component. Further, in other embodiments, the sustained release component does not contain titanium dioxide.

In some embodiments, the hydroxypropyl methylcellulose in the drug-containing core is only added in the form of "free state", not in the form of a composite adjuvant, such as Opadry I (product code Y-1- 7000), which contains about 62.5% hypromellose, polyethylene glycol and titanium dioxide.

In other embodiments, the drug-containing core does not contain Opadry I.

In another aspect, the present disclosure also provides a pharmaceutical composition comprising:

a) a sustained-release component, comprising a drug-containing core, an isolation layer, and a sustained-release coating layer, the drug-containing core is coated by the isolation layer, and the isolation layer is coated by the sustained-release coating layer, wherein the drug-containing core is coated The core does not contain Opadry I;

and b) a delayed release component.

Some embodiments provide that the drug-containing core in the pharmaceutical composition is free of polyethylene glycol. Other embodiments provide that the drug-containing core in the pharmaceutical composition does not contain titanium dioxide.

On the other hand, the addition of such as lactose or SBE-β-CD to the drug-containing core can also obtain the expected stable budesonide drug. The present disclosure also provides a pharmaceutical composition comprising a) a sustained-release component, comprising a drug-containing core, an isolation layer and a sustained-release coating layer, the pellet core is coated by the isolation layer, and the isolation layer is a sustained-release coating layer coating, wherein the drug-containing core contains a corticosteroid and at least one selected from lactose or SBE-β-CD; and b) a delayed-release component.

In some embodiments, the weight ratio of lactose to corticosteroid in the drug-containing core is 2.5:1 to 8:1, which can be 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0:1, 3.1:1 , 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4.0:1, 4.1:1, 4.2:1, 4.3:1, 4.4 :1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5.0:1, 5.1:1, 5.2:1, 5.3:1, 5.4:1, 5.5:1, 5.6:1 , 5.7:1, 5.8:1, 5.9:1, 6.0:1, 6.1:1, 6.2:1, 6.3:1, 6.4:1, 6.5:1, 6.6:1, 6.7:1, 6.8:1, 6.9 :1, 7.0:1, 7.1:1, 7.2:1, 7.3:1, 7.4:1, 7.5:1, 7.6:1, 7.7:1, 7.8:1, 7.9:1, 8.0:1 or any two between values.

In some embodiments, the weight ratio of SBE-β-CD to corticosteroid in the drug-containing core is 2.5:1 to 8:1, which can be 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0:1 , 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4.0:1, 4.1:1, 4.2:1, 4.3 :1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5.0:1, 5.1:1, 5.2:1, 5.3:1, 5.4:1, 5.5:1 , 5.6:1, 5.7:1, 5.8:1, 5.9:1, 6.0:1, 6.1:1, 6.2:1, 6.3:1, 6.4:1, 6.5:1, 6.6:1, 6.7:1, 6.8 :1, 6.9:1, 7.0:1, 7.1:1, 7.2:1, 7.3:1, 7.4:1, 7.5:1, 7.6:1, 7.7:1, 7.8:1, 7.9:1, 8.0:1 or any value between two numbers.

In other embodiments, a pharmaceutical composition of the present disclosure comprises a) a sustained release component comprising a drug-containing core, a barrier layer, and a sustained-release coating layer, the drug-containing core is coated by the barrier layer, and the The isolation layer is coated with a sustained-release coating layer, wherein the drug-containing core contains corticosteroid and at least one selected from lactose or SBE-β-CD, and the isolation layer does not contain acid; and b) a delayed-release group point.

In some embodiments, the corticosteroid in the pharmaceutical composition is budesonide, (16α,17-[(1RS)-butylenedioxy]-11β,21-dihydroxypregna-1,4-diene -3,20-dione),

On the other hand, suitable corticosteroid drugs also include, but are not limited to, aclomethasone, beclomethasone, betamethasone, clobetasol, hydrocortisone, dexamethasone, flunisolide, methylprednisolone, Metasone, prednisone, triamcinolone, budesonide, fluticasone, ciclesonide, and fludrocortisone.

In other embodiments, the amount (content) of hydroxypropylmethylcellulose in the drug-containing core accounts for 4-20% of the total weight of the drug-containing core, and can be 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0% , 14.5%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, 20.0% or any value in between. In the solution, the amount (content) of hypromellose in the sustained-release component accounts for 6-18% of the total weight of the sustained-release component, for example, 12% or 13%.

In the present disclosure, "the total weight of the drug-containing core" or "based on the total weight of the drug-containing core" refers to the numerical range of the amount of active ingredients or other types of pharmaceutical excipients calculated by the weight of the core without the isolation layer or coating.

Further, some embodiments provide a pharmaceutical composition in which the isolation layer comprises hydroxypropyl methylcellulose and does not contain organic acids, such as citric acid, glutamic acid, lactic acid, tartaric acid, fumaric acid, malic acid and sodium dihydrogen phosphate . In other embodiments, the isolation layer does not contain acid. The "does not contain" or "substantially do not contain" means that no additional addition is made. It should be noted that, as long as it is confirmed that, for example, the stability of the pharmaceutical composition is not caused by the addition of an acid. In exemplary embodiments, the barrier layer of the pharmaceutical composition of the present disclosure does not require additional additions such as citric acid to ensure stability of the drug.

In another aspect, some embodiments provide that the drug-containing core further contains one or more of a filler, an anti-adherent, and a lubricant. In alternative embodiments, the drug-containing cores comprise coated pellets, coated granules, or coated tablets. In some embodiments, a drug-containing layer is coated on the surface of the blank pellet core to form a drug-containing core. In other embodiments, a drug-containing layer is applied to the surface of the particle.

Further, in some embodiments, the filler in the drug-containing core is selected from lactose, sucrose, starch or microcrystalline cellulose. Extrusion-spheronization is a known process that can be used to form uncoated spherical particles (or blank cores). Additionally, methods for producing cores or granules include, but are not limited to, granulation, microencapsulation, and tableting. In some embodiments, sucrose pellet cores (which may be referred to as sucrose blank pellet cores) are prepared using known processes.

Further, the content of filler in the drug-containing core is 36-80% of the total weight of the drug-containing core, which can be 36%, 38%, 40%, 42%, 44%, 46%, 48%, 50%, 52% %, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, or any value in between .

On the other hand, the pellets or granules are preferably commercially viable sucrose pellets. Sucrose ball cores include sucrose with the addition of smaller amounts of other materials, such as starch. Suppliers of cane sugar pellets include Paulaur Corporation (USA), Chr. Hansen (Denmark), NP Pharm (France), Emilio Castelli (Italy) and JRS Pharma (Germany). Sucrose pellet cores can have a wide variety of diameters, typically in the range of about 0.2 mm to about 5 mm.

The following is a non-limiting example of a method of coating a drug onto blank pellet cores. The blank pellet cores are placed in a coating pan or chamber in which the pellet cores are in continuous motion and exposed to a stream of warm air. The corticosteroid drug and hypromellose are dissolved/or suspended in a volatile liquid medium and then applied to the pellet core, preferably in the form of a fine mist. The liquid medium evaporates in a stream of warm air and leaves a precipitate of solid material on the surface of the pellet core. The liquid medium is preferably water, although anhydrous solvents such as ethanol, isopropanol and ethyl acetate can also be used.

In other embodiments, the medicated core further contains an anti-adherent agent, including but not limited to one or more of talc, silicon dioxide, magnesium stearate or glycerol monostearate. In some embodiments, the anti-adherent agent in the drug-containing core is selected from talc.

In other embodiments, the content of the anti-adhesive agent in the drug-containing core is 10-35% of the total weight of the drug-containing core, which can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32% , 33%, 34%, 35% or any value in between.

The lubricants described in the present disclosure are selected from one or more of magnesium stearate, stearic acid, silicon dioxide or talc. In some embodiments, the content of the lubricant in the drug-containing core is 0-10% of the total weight of the drug-containing core, which can be 0%, 1%, 2%, 3%, 4%, 5%, 6% , 7%, 8%, 9%, 10% or any value in between.

On the other hand, the content of the corticosteroids described in the present disclosure is 0.1-10%, preferably 0.1-5% of the total weight of the drug-containing core, and can be 0.1%, 0.3%, 0.5%, 0.7%, 0.9%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.1%, 2.3%, 2.5%, 2.7%, 2.9%, 3.1%, 3.3%, 3.5%, 3.7%, 3.9%, 4.1%, 4.3%, 4.5% , 4.7%, 4.9%, 5.0% or any value in between.

Further, some embodiments provide that the drug-containing core in the pharmaceutical composition contains 0.1-10% corticosteroid, 4-20% hydroxypropylmethyl cellulose, 36-80% filler and 10-35% anti-adherent, to The total weight of the drug-containing core.

On the other hand, the weight ratio of hydroxypropyl methylcellulose to corticosteroid in the drug-containing core of the present disclosure is 2.5:1 to 8:1, which can be 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3.0: 1, 3.1:1, 3.2:1, 3.3:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9:1, 4.0:1, 4.1:1, 4.2:1, 4.3:1, 4.4:1, 4.5:1, 4.6:1, 4.7:1, 4.8:1, 4.9:1, 5.0:1, 5.1:1, 5.2:1, 5.3:1, 5.4:1, 5.5: 1, 5.6:1, 5.7:1, 5.8:1, 5.9:1, 6.0:1, 6.1:1, 6.2:1, 6.3:1, 6.4:1, 6.5:1, 6.6:1, 6.7:1, 6.8:1, 6.9:1, 7.0:1, 7.1:1, 7.2:1, 7.3:1, 7.4:1, 7.5:1, 7.6:1, 7.7:1, 7.8:1, 7.9:1, 8.0: 1 or any value in between. In some embodiments, the weight ratio of hypromellose to corticosteroid in the drug-containing core is 3:1 to 6:1, eg, 5:1.

The isolation layer mainly prevents the enteric layer (or sustained-release layer) from being in direct contact with the drug-containing core, and on the other hand, can play the role of rapid disintegration. A suitable barrier layer of the present disclosure facilitates the production of suitable barrier layer pellets without compromising content while reducing particle agglomeration. In addition, after the enteric layer is coated, it can play a role of isolation between the drug-containing layer and the enteric layer.

In some embodiments, the barrier coating causes the pill-containing weight gain by 3-20%, which can be 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11% , 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% or any value in between. In some embodiments, the release layer solution concentration is 4%. In some embodiments, the dosage of the barrier layer in a unit prescription is 1.6 mg to 2.0 mg, which can achieve the barrier effect without affecting the particle content and avoid particle aggregation during barrier coating.

In some embodiments, the barrier coating containing hydroxypropyl methyl cellulose is used, and considering the viscosity of the barrier layer coating liquid, suitable plasticizers, anti-sticking agents or colorants can be added to the barrier layer coating liquid . In some embodiments, the release layer further contains one or more of a plasticizer, an anti-adherent, and a colorant.

The plasticizer described in the present disclosure is selected from, but is not limited to, one or more of triethyl citrate, tributyl citrate, dibutyl sebacate, dimethyl phthalate, and polyethylene glycol .

The anti-sticking agent of the present disclosure is selected from one or more of talc, silicon dioxide, magnesium stearate and glycerol monostearate. The colorant described in this disclosure is selected from titanium dioxide.

In some embodiments, the release layer contains hypromellose. In other embodiments, the content of hydroxypropyl methylcellulose in the insulating layer is 50-100% of the total weight of the coating (solid) of the insulating layer, which can be 50%, 52%, 54%, 56%, 58% %, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92%, 94%, 96%, 98%, 100% or any number in between. For example, in some embodiments the release layer contains hypromellose and talc. In other embodiments, the release layer contains hydroxypropyl methylcellulose and Opadry I. In some embodiments, the release layer contains Opadry I (Product Code Y-1-7000, Colorcon) containing about 62.5% hypromellose, polyethylene glycol, and titanium dioxide. In other embodiments, the release layer contains Opadry I, hypromellose, and talc. In other embodiments, the release layer contains hydroxypropyl methylcellulose and talc.

On the other hand, the sustained-release coating layer further contains one or more of a binder, a plasticizer, an anti-sticking agent and a coloring agent. In some embodiments, the content of the controlled-release material in the sustained-release coating layer is 50-98% of the total weight of the sustained-release coating (solid), which can be 50%, 52%, 54%, 56%, 58% , 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80%, 82%, 84%, 86%, 88%, 90%, 92 %, 94%, 96%, 98% or any number in between.

In other embodiments, the content of the binder in the sustained-release coating layer is 1-25% of the total weight of the sustained-release coating (solid), which can be 1%, 2%, 3%, 4%, 5% %, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% or any number in between.

In other embodiments, the content of plasticizer in the sustained-release coating layer is 0-8% of the total weight of the sustained-release coating (solid), which can be 0%, 1%, 2%, 3%, 4% %, 5%, 6%, 7%, 8% or any value in between.

In other embodiments, the content of the anti-sticking agent in the sustained-release coating layer is 0-8% of the total weight of the sustained-release coating (solid), which can be 0%, 1%, 2%, 3%, 4% %, 5%, 6%, 7%, 8% or any value in between.

In other embodiments, the content of the colorant in the sustained-release coating layer is 0-8% of the total weight of the sustained-release coating (solid), which can be 0%, 1%, 2%, 3%, 4% , 5%, 6%, 7%, 8% or any value in between.

In some embodiments, the extended release coating layer contains aminoethyl cellulose such as

and adhesive. In some embodiments, the extended release coating layer contains aminoethyl cellulose such as

and hydroxypropyl methylcellulose. In some embodiments, the extended release coating layer contains aminoethyl cellulose such as

and Opadry I. In some embodiments, the extended release coating layer contains aminoethyl cellulose such as

Hypromellose and Opadry I. In some embodiments, the extended release coating layer contains aminoethyl cellulose such as

Hypromellose and talc.

In some embodiments, the extended release coating layer contains aminoethyl cellulose such as

and Opadry I.

On the other hand, the amount of slow-release material used is also critical. In some embodiments, the sustained release coating increases the weight of the drug-containing core containing the barrier layer by 3-20%, which can be 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% or any number in between.

Some embodiments provide pharmaceutical compositions comprising:

a) a sustained-release component, comprising a drug-containing core, an isolation layer, and a sustained-release coating layer, the drug-containing core is coated by the isolation layer, and the isolation layer is coated by the sustained-release coating layer, wherein the The medicated core contains 0.1-10% corticosteroid, 4-20% hydroxypropylmethylcellulose, 36-80% sucrose and 10-35% talc, and the weight ratio of hydroxypropylmethylcellulose to corticosteroid is at least 2.5:1;

and b) a delayed release component.

Some embodiments provide pharmaceutical compositions comprising:

a) a sustained-release component, comprising a drug-containing core, an isolation layer, and a sustained-release coating layer, the drug-containing core is coated by the isolation layer, and the isolation layer is coated by the sustained-release coating layer, wherein the The drug-containing core contains 0.1-10% corticosteroid, 4-20% hypromellose, 36-80% sucrose and 10-35% Opadry I, and the weight ratio of hypromellose to corticosteroid at least 2.5:1;

and b) a delayed release component.

Further, the aforementioned sustained-release components are preferably filled into hard capsules. For example, gelatin, hydroxypropylmethylcellulose, pullulan or starch capsules, preferably starch capsules. In other embodiments, the aforementioned sustained release components are filled into hypromellose capsules. To achieve extended release of the sustained release component, the sustained release component or capsule comprising the sustained release component is reprocessed, for example coated with a polymer having enteric properties, to ensure that the composition reaches the intestines (for example, at the bottom of the small intestine).

The enteric polymers described in this disclosure can be pH-dependent, insoluble in the low pH stomach but soluble in the high pH intestinal environment, or the polymer can be broken down by enzymes or bacteria present in the intestinal tract. Further, the enteric polymers include, but are not limited to, cellulose acetate trioctyl (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP) , cellulose acetate phthalate (CAP) and copolymers of methacrylic acid and methyl methacrylate. In some embodiments, the commercial sources of methacrylic acid-methyl methacrylate copolymer (1:1) and methacrylic acid-methyl methacrylate copolymer (1:2) are Eudragit L100 and Eudragit, respectively Odd S100 (Degussa, Germany). In an alternative embodiment, different ratios of Eudragit L100 and Eudragit S100 are selected to be mixed to prepare enteric coatings that dissolve between pH 6-7.

Further, in order to ensure the coating uniformity of the enteric layer, the delayed release component of the present disclosure further contains one or more of a binder, a plasticizer, an anti-sticking agent and a coloring agent.

Plasticizers in some embodiments include, but are not limited to, triethyl citrate, tributyl citrate, dibutyl sebacate, dimethyl phthalate, diethyl phthalate, or phthalic acid dibutyl ester.

Binders in some embodiments include, but are not limited to, mannitol, glucose, sucrose, polyethylene glycol, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, triacetin, and polyvinyl alcohol. Water-soluble material.

In other embodiments, the anti-sticking agent in the extended release component is selected from the group consisting of talc, magnesium stearate, or glycerol monostearate.

In some embodiments, the content of the enteric polymer (material) in the delayed release component is 50-80% of the total weight of the delayed release component (solid), and may be 50%, 52%, 54%, 56%, 58%, 60%, 62%, 64%, 66%, 68%, 70%, 72%, 74%, 76%, 78%, 80% or any value in between.

In some embodiments, the content of the plasticizer in the delayed release component is 5-15% of the total weight of the delayed release component (solid), which can be 5%, 6%, 7%, 8%, 9% %, 10%, 11%, 12% or any value in between.

In some embodiments, the content of the binder in the delayed release component is 0-15% of the total weight of the delayed release component (solids), and can be 0, 1%, 2%, 3%, 4% , 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% or any value in between.

In some embodiments, the content of the anti-sticking agent in the delayed-release component is 5-35% of the total weight of the delayed-release component (solid), which can be 5%, 6%, 7%, 8%, 9% %, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35% or any value in between.

In other embodiments, the content of the colorant in the delayed release component is 0-8% of the total weight of the delayed release component (solid), which can be 0%, 1%, 2%, 3%, 4% %, 5%, 6%, 7%, 8% or any value in between.

In certain embodiments, the delayed release component comprises Eudragit L100 and Eudragit S100, and the weight ratio of L100 to S100 is 10:1 to 1:1, and can be 10:1, 9:1, 8:1, 7:1 , 6:1, 5:1, 4:1, 3:1, 2:1, 1:1 or any value between two numbers, preferably 5:1-2:1.

On the other hand, ordinary capsules, such as hydroxypropyl methylcellulose capsules, have gaps or steps after the body and the cap are locked, and the capsules filled with delayed release components alone cannot achieve the expected purpose well. There is a risk of side leakage. The capsule can be pre-coated with a coating agent containing hydrophilic small molecules such as sucrose before the delayed-release component is coated in the capsule. In this way, the risk of side leakage of the capsule shell can be avoided, and the coated capsule is less prone to cracks than the coating/precoating without hydrophilic small molecules such as HPC, and the additional coating will not. affects the overall release of the drug.

In an optional embodiment, after the aforementioned sustained-release component is filled into a hydroxypropyl methylcellulose capsule, the capsule is sequentially coated with a coating (1) containing a hydrophilic small molecule and a delayed-release component . In some embodiments, the coating (1) of the hydrophilic small molecules further contains one or more of a binder, a plasticizer, an anti-sticking agent, and a coloring agent. In some embodiments, the hydrophilic small molecule coating (1) also contains hypromellose. In some embodiments, the coating (1) of the hydrophilic small molecule contains a mixture of sucrose and polyvinyl alcohol and polyethylene glycol, such as a commercial excipient Opadry II (product code 85G68918, Colorcon).

In another aspect, the present disclosure also provides a capsule pharmaceutical composition comprising a sustained release component, the capsule is coated with a coating layer (1) containing a hydrophilic molecule, and the coating layer containing sucrose is coated with The delayed release component is layered.

Hydrophilic molecules refer to molecules with polar groups that have greater affinity for water, can attract water molecules, or are easily soluble in water. In some embodiments, the release layer hydrophilic molecule is selected from, but not limited to, at least one of sucrose, lactose, mannitol, starch, and sorbitol.

In other embodiments, the capsule does not contain a parafilm between the body and the cap of the capsule.

In some embodiments, the hydrophilic molecule-containing coating layer (1) further contains at least one of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, and polyethylene glycol . In other embodiments, the sucrose-containing coating layer contains a mixture of polyvinyl alcohol and polyethylene glycol, such as the commercial excipient Opadry II (product code 85G68918, Colorcon).

Further, in some embodiments, the capsule is filled with a budesonide-containing pharmaceutical composition comprising a sustained-release component of a drug-containing core, an isolation layer and a sustained-release coating layer, the drug-containing core being coated by the isolation layer and the release layer is coated with a sustained-release coating layer, wherein the drug-containing core contains corticosteroid and hydroxypropylmethylcellulose, and the weight ratio of hydroxypropylmethylcellulose to corticosteroid is at least 2.5:1.

Further, the Chinese Pharmacopoeia dissolution method basket method was used to detect the release of the pharmaceutical composition of the present disclosure, that is, 900 mL of dissolution medium was used, firstly measured in a medium of pH=1.0 for 2 hours, and then put into a phosphate buffer of pH6.8 Continue to measure for 4 hours, the temperature of the dissolution medium is 37±0.5° C., the speed is 100 rpm, and when measured by high performance liquid chromatography, the release characteristics of the composition are obtained.

In certain embodiments, the pharmaceutical compositions of the present disclosure release no more than 10% by weight of budesonide within 2 hours, preferably no more than 0%, 1%, 2%, 3%, 4%, 5%, 6% %, 7%, 8%, 9%, 10% by weight of budesonide.

In certain embodiments, the pharmaceutical compositions of the present disclosure release 5-50% by weight of budesonide within 3 hours, preferably 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28% , 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45 %, 46%, 47%, 48%, 49%, 50% by weight of budesonide.

In certain embodiments, the pharmaceutical composition of the present disclosure releases 50-95% by weight of budesonide within 4 hours, preferably 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73% , 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90 %, 91%, 92%, 93%, 94%, 95% budesonide by weight.

In certain embodiments, the pharmaceutical compositions of the present disclosure release at least 90% by weight of budesonide within 6 hours, preferably at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 100% budesonide by weight.

In certain embodiments, the Chinese Pharmacopoeia Dissolution Determination Method Basket Method is used to detect the release of the pharmaceutical composition of the present disclosure, using 900 mL of dissolution medium, first for 2 hours in a pH=1.0 medium, and then into a pH6.8 phosphate Continue to measure in the buffer solution for 4h, the temperature of the dissolution medium is 37±0.5℃, the speed is 100rpm, and when measured by high performance liquid chromatography, the release characteristics are:

release not more than 10% by weight of budesonide within 2 hours,

Release at least 90% by weight of budesonide within 6 hours.

In some embodiments, the Chinese Pharmacopoeia dissolution assay method basket method is used to detect the release of the pharmaceutical composition of the present disclosure, using 900 mL of dissolution medium, first assayed in a pH=1.0 medium for 2 hours, and then placed in a pH6.8 phosphate buffer Continue to measure in the liquid for 4h, the temperature of the dissolution medium is 37±0.5℃, the speed is 100rpm, and when measured by high performance liquid chromatography, the release characteristics are:

release not more than 10% by weight of budesonide within 2 hours,

5-50% by weight of budesonide is released within 3 hours,

50-95% by weight of budesonide is released within 4 hours,

Release at least 90% by weight of budesonide within 6 hours.

In certain embodiments, the budesonide enteric-coated capsules have an in vitro release characteristic of being acid-resistant and not substantially released within 2 hours, sustained release in the intestinal tract for 3-4 hours, and completely released within 6 hours.

The present disclosure also provides a method for preparing the aforementioned pharmaceutical composition, comprising:

Method 1) the step of coating the solution containing corticosteroid and hydroxypropyl methylcellulose on the surface of blank pellet core;

Alternatively, method 2) corticosteroids are mixed with filler followed by addition of one or more of hypromellose, anti-adherent and lubricant, using rolling or extrusion-spheronization or centrifugation- The steps of preparing pellets by fluidized pelletizing method.

In some embodiments, the preparation method 1) further includes the step of preparing blank pellet cores. In other embodiments, the blank pellet cores used to prepare the pellets are commercially available, as previously described. In some embodiments, sucrose blank pellet cores are used as the inert core drug loading.

The pharmaceutical composition or capsule pharmaceutical composition provided by the present disclosure can be used to treat intestinal inflammatory disease, glomerulonephritis disease or autoimmune liver disease, and the intestinal inflammatory disease is preferably Crohn's disease or ulcerative Colitis, the autoimmune liver disease preferably autoimmune hepatitis.

"Intestine" as used herein refers to the digestive tract from the pylorus of the stomach to the anus. The mammalian intestine includes the small intestine and the large intestine. The human small intestine includes the duodenum, jejunum, and ileum; the large intestine includes the cecum and colon.

"Substantially released in the intestinal tract" as used herein generally means that after oral administration of the pharmaceutical composition, the active substance is not substantially released before reaching the intestinal tract, and the release of the drug begins after reaching the intestinal tract. For example, no more than 15%, preferably no more than 10%, and most preferably no more than 5% of the drug is released from the pharmaceutical composition before reaching the intestinal tract. Usually drug release begins with the small intestine. Drug release may also be delayed until the drug composition reaches a specific part of the intestine, such as the duodenum, colon, ileum, cecum.

"Sustained release" as used herein means that when the delayed release component dissolves or decomposes, not all of the drug is released immediately, and the drug is released after a period of time. The release time of this drug can be controlled, and the length of this drug release time depends, or in part, on the processing of the drug.

The numerical values in the present disclosure are the measured values or the calculated values after the instrument measurement, and there is a certain degree of error. Generally speaking, plus or minus 10% is within a reasonable error range. Of course, it is necessary to consider the context in which the value is used, for example, the content of total impurities. Plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%.

HPLC detection conditions:

Chromatographic column: octadecylsilane bonded silica gel as filler (Agilent Eclipse XDB-C18, 4.6mm×150mm, 3.5μm); mobile phase: potassium phosphate (pH 4.0)-acetonitrile (30:70); detection wavelength: 240nm. According to the external standard method, the dissolution rate in each capsule was calculated by the peak area.

Description of drawings

Figure 1 is a schematic diagram of the structure of the sustained release component in the pharmaceutical composition.

Detailed ways

The following are specific embodiments of the present disclosure, which are for further describing the present disclosure rather than limiting the present disclosure, and all technical solutions equivalent to the present disclosure belong to the protection scope of the present disclosure.

Example 1:

Table 1

1) Solution containing drug

Lactose and Opadry I (product code Y-1-7000) were weighed and dispersed in 319.2 g of purified water according to the recipe quantity, followed by adding 5.4 g of budesonide, fully stirring to form a homogeneous suspension, for later use.

2) isolation layer solution

8.0 g of Opadry I (product code Y-1-7000) was weighed, added to 80.0 g of purified water, fully stirred for uniformity, and used for later use.

3) Coating drug and isolation layer

In the coating chamber of the fluidized bed (FLZB-0.5, Chuangzhi Electromechanical), fill 150g of sucrose blank pellets (0.71-0.85mm, Hangzhou Gaocheng), set the fluidized bed parameters (inlet air temperature 55 ℃, atomization pressure 1.2 bar), weigh 300.0 g of the aforementioned drug-containing solution for coating at a rate of about 8 g/min, after coating, dry and granulate the coated pellets.

Subsequently, the isolation layer solution is coated at a rate of about 8 g/min, and after the coating is completed, it is dried, and the coated pellets are granulated.

4) Sustained release coating layer

Disperse 72.0g of Suisse water dispersion and 3.6g of Opadry coating mixture in 44.4g of purified water, and slowly mix the dispersed Opadry coating solution into Surelease water dispersion to form a controlled release layer coating solution .

Under the condition of fluidized bed (inlet air temperature 55°C, atomization pressure 1.2 bar), the controlled release layer coating solution is coated on the granules (or drug-loaded pellet cores) obtained in step 3 at a rate of about 8 g/min, and the fluidized Dry and granulate the coated pellets.

The micropellets in step 2 are coated in a fluidized bed to obtain sustained-release pellets.

Example 2

Table 2

Note: Labrasol Caprylic Caprate Macrogolglyceride; SBE-β-CD Sulfobutyl Beta Cyclodextrin Sodium; Opadry I (Product Code Y-1-7000).

Referring to the steps of drug-containing solution→isolation layer solution→coating drug and isolation layer→sustained-release coating layer in Example 1, the sustained-release budesonide pills of different prescriptions were prepared with the material dosage in Table 2.

Comparative Example 1:

table 3

Referring to the steps of drug-containing solution→isolation layer solution→coating drug and isolation layer→controlled release layer in Example 1, the sustained-release budesonide pills of different prescriptions were prepared with the material dosage in Table 3.

Test Example 1

The aforementioned prescriptions 1 to 7 and comparative prescriptions 1 to 4 were placed in an open glass bottle, stored in a 60°C incubator, and the content of impurities in the budesonide pellets was detected by high performance liquid chromatography and the relative content of the budesonide in 1 month. Impurity growth on day 0. The relevant data are shown in Table 4.

Table 4

It is not difficult to find from it that, taking comparative prescription 1 (containing an acid-free isolation layer) as a reference, the formula with additional excipients in the drug-containing layer and the formula containing the acid-containing isolation layer have slow impurity growth rates at 60 ° C, indicating that both All can slow down the degradation of budesonide in the pharmaceutical composition to a certain extent. At the same time, taking the types of added excipients as a reference, the growth of the related substances was particularly slow under accelerated conditions in the prescription with additional hydroxypropyl methylcellulose and cyclodextrin added to the drug-containing layer. Considering the potential side effects of cyclodextrin, such as the recently reported cyclodextrin sodium can cause abnormal renal function, metabolic acidosis and hyperchloremia, it is not considered to improve the stability of the composition for the time being.

Example 3

table 5

1) Solution containing drug

Weigh .30g hydroxypropyl methylcellulose (HPMC E5 LV), 4.5g talc and 6g budesonide according to the recipe quantity and disperse in 465.75g purified water, fully stir to form a homogeneous suspension for subsequent use.

2) isolation layer solution

Weigh 12g of hydroxypropyl methylcellulose (HPMC E5 LV) and 1.8g of talc into purified water, stir well to form uniformity, and use for subsequent use.

3) Coating drug and isolation layer

In the coating chamber of the fluidized bed (GPCG 1.1, GLATT, Germany), fill 200 g of sucrose blank pellets (0.71-0.85 mm, Hangzhou Gaocheng), and set the fluidized bed parameters (inlet air temperature 60 °C, atomization pressure 1.5 bar), the aforementioned drug-containing solution is coated at a rate of about 6 g/min, and after coating is completed, it is dried, and the coated pellets are sized.

Subsequently, the isolation layer solution is coated at a rate of about 8 g/min, and after the coating is completed, it is dried, and the coated pellets are granulated.

4) Sustained release coating layer

Disperse 3.75g of hydroxypropyl methylcellulose (HPMC E5 LV) in 40.4g of purified water, add 60g of Suisse water dispersion, stir and mix to form a controlled release layer coating solution.

Under the condition of fluidized bed (inlet air temperature 55°C, atomization pressure 1.5bar), the controlled release layer coating solution is coated on the granules (or drug-loaded pellet cores) obtained in step 3 at a rate of about 5g/min, and fluidized Dry and granulate the coated pellets.

Coating the pellets in step 2 in a fluidized bed to obtain sustained-release pellets.

Test case 2

The formulation 8 samples were placed in sealed aluminum foil bags, respectively, and stored in a 60°C and 40°C incubator respectively. High performance liquid chromatography was used to detect the content of impurities in the budesonide pellets, and the 4-week relative to the 0th was calculated. The growth rate of impurities is as follows:

Table 6

Example 4

Table 7

Referring to the steps of drug-containing solution→isolation layer solution→coating drug and isolation layer→sustained-release coating layer in Example 2, the sustained-release budesonide pills of different prescriptions were prepared with the material dosage in Table 7.

The aforementioned recipe 9 and comparative recipe 5 were stored in a sealed aluminum foil bag, respectively, in a 60°C and 40°C incubator, and a high performance liquid chromatograph was used to detect the content change of impurities in the budesonide pellets. The relevant data are shown in Table 8.

Table 8

Example 5: Budesonide enteric-coated sustained-release capsules

Table 9

Referring to the steps of drug-containing solution→isolation layer solution→coating drug and isolation layer→sustained-release coating layer in Example 1, the sustained-release pills containing budesonide were prepared with the material dosages in Table 9.

1) Preparation of delayed release components

Dissolve 26.8 g of triethyl citrate, 201 g of Eudragit L100, and 67 g of Eudragit S100 in 95% ethanol, then add 53.6 g of talc, and stir uniformly for later use.

2) Preparation of coating layer containing sucrose (1)

40g of sucrose and 400g of Opadry II (product code 85G 68918, Colorcon) were added to 2493.3g of 70% ethanol solution, dispersed evenly, and used for later use.

3) Filling - coating

The budesonide-containing sustained-release pills obtained above were filled into hypromellose capsules (manufacturer: Qingdao Yiqing). Subsequently, in the fluidized bed, the coating solution containing sucrose was applied to the sustained-release pellets containing budesonide at a rate of 20 g/min, and after the coating was completed, it was dried;

Subsequently, the delayed-release component is coated at a rate of about 20 g/min, and after the coating is completed, the budesonide enteric-coated capsules are obtained by drying.

The release of enteric-coated capsules was detected by the basket method of the Chinese Pharmacopoeia dissolution method. 900 mL of dissolution medium was used, and it was first measured in a medium with pH=1.0 for 2 hours, and then put into a phosphate buffer with pH 6.8. The temperature of the dissolution medium was 37 ±0.5°C, the speed is 100rpm, and it is detected by HPLC. The detection results are shown in Table 10 below:

Table 10

time (h)	Dissolution (%)
2	0
2.5	0
3	7
3.5	76
4	92
5	93
6	94

Test case 3

The formulation sample of prescription 11 was placed in a high-density polyethylene bottle, placed in a 40 °C incubator, and the content of impurities in the budesonide pellets was detected by high performance liquid chromatography. The relevant data are as follows:

Table 11

Note: *Impurities less than 0.05% are not counted.

Example 6

Table 12

1) Preparation of coating liquid

Coating liquid of the first coating: mix the purified water of the prescription and the 95% ethanol of the prescription, add Opadry II to fully disperse and wait for use.

Coating solution of the second coating: dissolve the prescribed amount of triethyl citrate in 95% ethanol, add Eudragit L100 and S100 to dissolve, add talc powder to fully disperse and wait for use.

2) Filling - coating

Referring to the steps of drug-containing solution→isolation layer solution→coating drug and isolation layer→sustained-release coating layer in Example 2, the sustained-release budesonide pills of different prescriptions were prepared with the material dosages in Table 12.

The budesonide-containing sustained-release pills obtained above were filled into hypromellose capsules (manufacturer: Qingdao Yiqing). Subsequently, in a fluidized bed, the coating solution containing Opadry is coated on the capsules containing budesonide sustained-release pellets, and after coating is completed, drying;

Subsequently, the delayed release component was coated on the surface of the capsule containing isolation, and the coating weight was increased by 18%. After the coating was completed, the budesonide enteric-coated capsule was obtained by drying.

The release of the above enteric-coated capsules and enteric-coated pellets was detected by the basket method of the Chinese Pharmacopoeia dissolution test method, using 900 mL of dissolution medium, first measured in the medium of pH=1.0 for 2h, and then put into the phosphate buffer of pH6.8 In the liquid, the temperature of the dissolution medium is 37±0.5°C, the speed is 100rpm, and the measurement is carried out by high performance liquid chromatography. The results are shown in the following table.

Table 12 In vitro release of enteric-coated sustained-release pellets and enteric-coated capsules

Claims (26)

1. A pharmaceutical composition comprising:

   a) a sustained-release component, comprising a drug-containing core, an isolation layer, and a sustained-release coating layer, the drug-containing core is coated by the isolation layer, and the isolation layer is coated by the sustained-release coating layer, wherein the drug-containing core is coated The core contains corticosteroid and hydroxypropylmethylcellulose, and the weight ratio of hydroxypropylmethylcellulose to corticosteroid is at least 2.5:1;

   and b) a delayed release component.
2. The pharmaceutical composition of claim 1, wherein the corticosteroid is budesonide.
3. The pharmaceutical composition according to claim 1 or 2, wherein the sustained release coating layer comprises alkali-containing ethylcellulose, preferably an ammonia-containing ethylcellulose material, more preferably Suisse

   

   .
4. The pharmaceutical composition according to any one of claims 1-3, wherein the content of hydroxypropylmethylcellulose in the drug-containing core is 4-20%, preferably 6-18%, of the total weight of the drug-containing core, for example 12% or 13%.
5. The pharmaceutical composition according to any one of claims 1-4, wherein the drug-containing core does not contain polyethylene glycol.
6. The pharmaceutical composition according to any one of claims 1-5, wherein the drug-containing core does not contain titanium dioxide.
7. The pharmaceutical composition according to any one of claims 1-6, wherein the release layer comprises hydroxypropylmethylcellulose, further, the release layer preferably does not contain organic acids, more preferably does not contain acids.
8. The pharmaceutical composition according to any one of claims 1-7, wherein the sustained release component comprises coated pills, coated granules or coated tablets, preferably coated pills.
9. The pharmaceutical composition according to any one of claims 1-7, wherein the drug-containing core further contains one or more of fillers, anti-adherents and lubricants.
10. The pharmaceutical composition according to claim 9, wherein the filler is selected from lactose, sucrose, starch or microcrystalline cellulose, preferably sucrose; preferably the content of the filler is 36-36% of the total weight of the drug-containing core 80%.
11. The pharmaceutical composition according to claim 9 or 10, wherein the anti-sticking agent is selected from one or more of talc, silicon dioxide, magnesium stearate or glyceryl monostearate, preferably talc ; Preferably, the content of the anti-adherent agent is 10-35% of the total weight of the drug-containing core.
12. The pharmaceutical composition according to any one of claims 9-11, wherein the lubricant is selected from one or more of magnesium stearate, stearic acid, silicon dioxide or talc, preferably the lubricant The content of the drug-containing core is 0-10% of the total weight of the drug-containing core.
13. The pharmaceutical composition according to any one of claims 1-12, wherein the content of the corticosteroid is 0.1-10% of the total weight of the drug-containing core.
14. The pharmaceutical composition according to any one of claims 1-13, wherein the drug-containing core contains 0.1-10% corticosteroid, 4-20% hypromellose, 36-80% filler and 10-35% Anti-adherent, based on the total weight of the medicated core.
15. The pharmaceutical composition according to any one of claims 1-14, wherein the weight ratio of hypromellose to corticosteroid in the drug-containing core is 2.5:1 to 8:1, preferably 3:1 to 6:1: 1.
16. The pharmaceutical composition according to any one of claims 1-15, wherein the release layer further contains one or more of a plasticizer, an anti-sticking agent and a colorant; the plasticizer is selected from citric acid One or more of triethyl ester, tributyl citrate, dibutyl sebacate, dimethyl phthalate and polyethylene glycol, and the anti-sticking agent is selected from talc, silicon dioxide , one or more of magnesium stearate and glycerol monostearate.
17. The pharmaceutical composition of any one of claims 1-16, wherein the release layer contains hydroxypropylmethylcellulose and talc.
18. The pharmaceutical composition according to any one of claims 1-17, wherein the sustained-release coating layer further contains one or more of a binder, a plasticizer, an anti-sticking agent and a coloring agent.
19. The pharmaceutical composition according to any one of claims 1-18, wherein the sustained release component is contained in a capsule, further, the capsule is preferably coated with the delayed release component (b).
20. The pharmaceutical composition according to claim 17, wherein the capsules are selected from starch capsules, hypromellose capsules or gelatin capsules.
21. The pharmaceutical composition of any one of claims 1-20, comprising:

    a) a sustained-release component, comprising a drug-containing core, an isolation layer, and a sustained-release coating layer, the drug-containing core is coated by the isolation layer, and the isolation layer is coated by the sustained-release coating layer, wherein the The medicated core contains 0.1-10% corticosteroid, 4-20% hydroxypropylmethylcellulose, 36-80% sucrose and 10-35% talc, and the weight ratio of hydroxypropylmethylcellulose to corticosteroid is at least 2.5:1;

    and b) a delayed release component.
22. The pharmaceutical composition according to any one of claims 1-21, wherein the release of the pharmaceutical composition is detected by the Chinese Pharmacopoeia dissolution method basket method, 900 mL of dissolution medium is used, and the pH=1.0 medium is first measured for 2 hours, and then Put it into the phosphate buffer of pH 6.8 and continue to measure for 4h, the temperature of the dissolution medium is 37±0.5℃, the speed is 100rpm, and when measured by high performance liquid chromatography, the release characteristics are:

    release not more than 10% by weight of budesonide within 2 hours,

    Release at least 90% by weight of budesonide within 6 hours.
23. A method of preparing the pharmaceutical composition of any one of claims 1-22, comprising:

    Method 1) the step of coating the solution containing corticosteroid and hydroxypropyl methylcellulose on the surface of blank pellet core;

    Alternatively, Method 2) The corticosteroid is mixed with the bulking agent, followed by the addition of one or more of hypromellose, an anti-adherent, and a lubricant, using rolling or extrusion-spheronization or centrifugation- The steps of preparing pellets by fluidized pelletizing method.
24. The method according to claim 23, wherein the method 1) further comprises the step of preparing blank pellets.
25. A capsule pharmaceutical composition comprising a sustained-release component, the capsule is coated with a sucrose-containing coating layer, and the sucrose-containing coating layer is coated with a delayed-release component layer.
26. The pharmaceutical composition according to any one of claims 1-22 or the capsule pharmaceutical composition according to claim 25 is used in the preparation of medicines for the treatment of intestinal inflammatory diseases, glomerulonephritis diseases or autoimmune liver diseases For the use in , the intestinal inflammatory disease is preferably Crohn's disease or ulcerative colitis, and the autoimmune liver disease is preferably autoimmune hepatitis.

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