WO2022222971A1 - Composition pharmaceutique orale de corticostéroïdes à enrobage entérique - Google Patents

Composition pharmaceutique orale de corticostéroïdes à enrobage entérique Download PDF

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WO2022222971A1
WO2022222971A1 PCT/CN2022/087990 CN2022087990W WO2022222971A1 WO 2022222971 A1 WO2022222971 A1 WO 2022222971A1 CN 2022087990 W CN2022087990 W CN 2022087990W WO 2022222971 A1 WO2022222971 A1 WO 2022222971A1
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pharmaceutical composition
drug
release
sustained
coated
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PCT/CN2022/087990
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English (en)
Chinese (zh)
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王伟
王捷
曹笑立
孙海锋
郭辰宁
潘凯
袁萍
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江苏恒瑞医药股份有限公司
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Priority to CN202280028895.2A priority Critical patent/CN117157079A/zh
Publication of WO2022222971A1 publication Critical patent/WO2022222971A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present disclosure belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition of oral enteric-coated corticosteroids.
  • Corticosteroids such as budesonide
  • intestinal inflammatory diseases such as Crohn's disease, ulcerative colitis
  • 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,
  • one approach is by means of rectal administration such as suppositories or enemas.
  • 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).
  • composition comprising:
  • 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;
  • 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 .
  • 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.
  • the alkali-containing ethyl cellulose is an ammonia-containing ethyl cellulose material.
  • the alkali-containing ethyl cellulose is It is produced by mixing ethyl cellulose with oleic acid and dibutyl sebacate, followed by extrusion and dissolution.
  • the sustained release coating layer comprising the controlled release material is an alkali ethylcellulose-containing material, preferably an aminoethylcellulose-containing material, such as
  • 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.
  • an additional acid such as a weak acid needs to be added to the isolation layer.
  • 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.
  • 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.
  • the drug-containing core contains budesonide, Opadry I, and hypromellose.
  • the medicated core contains budesonide and hypromellose.
  • 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.
  • a composite adjuvant such as Opadry I (product code Y-1- 7000), which contains about 62.5% hypromellose, polyethylene glycol and titanium dioxide.
  • the drug-containing core does not contain Opadry I.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • 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;
  • the drug-containing core in the pharmaceutical composition is free of polyethylene glycol.
  • the drug-containing core in the pharmaceutical composition does not contain titanium dioxide.
  • the addition of such as lactose or SBE- ⁇ -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- ⁇ -CD; and b) a delayed-release component.
  • 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.
  • the weight ratio of SBE- ⁇ -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:
  • 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- ⁇ -CD, and the isolation layer does not contain acid; and b) a delayed-release group point.
  • the corticosteroid in the pharmaceutical composition is budesonide, (16 ⁇ ,17-[(1RS)-butylenedioxy]-11 ⁇ ,21-dihydroxypregna-1,4-diene -3,20-dione),
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • the drug-containing core further contains one or more of a filler, an anti-adherent, and a lubricant.
  • the drug-containing cores comprise coated pellets, coated granules, or coated tablets.
  • a drug-containing layer is coated on the surface of the blank pellet core to form a drug-containing core.
  • a drug-containing layer is applied to the surface of the particle.
  • 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).
  • methods for producing cores or granules include, but are not limited to, granulation, microencapsulation, and tableting.
  • sucrose pellet cores (which may be referred to as sucrose blank pellet cores) are prepared using known processes.
  • 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 .
  • 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.
  • 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.
  • an anti-adherent agent in the drug-containing core is selected from talc.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • the enteric layer after the enteric layer is coated, it can play a role of isolation between the drug-containing layer and the enteric layer.
  • 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.
  • the release layer solution concentration is 4%.
  • 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.
  • 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 .
  • 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.
  • the release layer contains hypromellose.
  • 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.
  • the release layer contains hypromellose and talc.
  • the release layer contains hydroxypropyl methylcellulose and Opadry I.
  • 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.
  • Opadry I Product Code Y-1-7000, Colorcon
  • the sustained-release coating layer further contains one or more of a binder, a plasticizer, an anti-sticking agent and a coloring agent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the extended release coating layer contains aminoethyl cellulose such as and Opadry I.
  • 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.
  • 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;
  • 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;
  • the aforementioned sustained-release components are preferably filled into hard capsules.
  • hard capsules for example, gelatin, hydroxypropylmethylcellulose, pullulan or starch capsules, preferably starch capsules.
  • the aforementioned sustained release components are filled into hypromellose capsules.
  • 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.
  • 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.
  • 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).
  • different ratios of Eudragit L100 and Eudragit S100 are selected to be mixed to prepare enteric coatings that dissolve between pH 6-7.
  • 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.
  • the anti-sticking agent in the extended release component is selected from the group consisting of talc, magnesium stearate, or glycerol monostearate.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the capsule is sequentially coated with a coating (1) containing a hydrophilic small molecule and a delayed-release component .
  • 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.
  • the hydrophilic small molecule coating (1) also contains hypromellose.
  • 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).
  • the present disclosure also provides a capsule pharmaceutical composition
  • 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.
  • the release layer hydrophilic molecule is selected from, but not limited to, at least one of sucrose, lactose, mannitol, starch, and sorbitol.
  • the capsule does not contain a parafilm between the body and the cap of the capsule.
  • the hydrophilic molecule-containing coating layer (1) further contains at least one of hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, and polyethylene glycol .
  • 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).
  • the capsule is filled with a budesonide-containing pharmaceutical composition
  • 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
  • the drug-containing core contains corticosteroid and hydroxypropylmethylcellulose, and the weight ratio of hydroxypropylmethylcellulose to corticosteroid is at least 2.5:1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • the preparation method 1) further includes the step of preparing blank pellet cores.
  • the blank pellet cores used to prepare the pellets are commercially available, as previously described.
  • sucrose blank pellet cores are used as the inert core drug loading.
  • Testine 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 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.
  • 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 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.
  • Chromatographic column octadecylsilane bonded silica gel as filler (Agilent Eclipse XDB-C18, 4.6mm ⁇ 150mm, 3.5 ⁇ m); 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.
  • Figure 1 is a schematic diagram of the structure of the sustained release component in the pharmaceutical composition.
  • 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.
  • 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.
  • 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 °C, 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.
  • 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.
  • 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.
  • micropellets in step 2 are coated in a fluidized bed to obtain sustained-release pellets.
  • the sustained-release budesonide pills of different prescriptions were prepared with the material dosage in Table 2.
  • the sustained-release budesonide pills of different prescriptions were prepared with the material dosage in Table 3.
  • 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.
  • 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.
  • 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.
  • step 2 Coating the pellets in step 2 in a fluidized bed to obtain sustained-release pellets.
  • 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:
  • 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.
  • the sustained-release pills containing budesonide were prepared with the material dosages in Table 9.
  • 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;
  • 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 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:
  • 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.
  • 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;
  • 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.

Abstract

Une composition pharmaceutique orale de corticostéroïdes à enrobage entérique est divulguée, ladite composition comprenant : a) un constituant à libération prolongée, le constituant à libération prolongée contenant un noyau contenant un médicament, une couche d'isolation et une couche d'enrobage à libération prolongée, et le noyau contenant un médicament contenant des corticostéroïdes tels que le budésonide et l'hydroxypropyl méthylcellulose, et b) un constituant à libération retardée, le constituant à libération retardée protégeant la composition de sorte qu'elle est fondamentalement libérée dans le tractus intestinal après administration orale.
PCT/CN2022/087990 2021-04-20 2022-04-20 Composition pharmaceutique orale de corticostéroïdes à enrobage entérique WO2022222971A1 (fr)

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