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WO2021223480A1 - Comprimé de ticagrélor à libération contrôlée et son procédé de préparation - Google Patents

Comprimé de ticagrélor à libération contrôlée et son procédé de préparation Download PDF

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Publication number
WO2021223480A1
WO2021223480A1 PCT/CN2021/075842 CN2021075842W WO2021223480A1 WO 2021223480 A1 WO2021223480 A1 WO 2021223480A1 CN 2021075842 W CN2021075842 W CN 2021075842W WO 2021223480 A1 WO2021223480 A1 WO 2021223480A1
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Prior art keywords
release
controlled
tablet
ticagrelor
drug
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Ceased
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PCT/CN2021/075842
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English (en)
Chinese (zh)
Inventor
舒欣
董海红
陈磊
陆平波
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Jiangsu Alicorn Pharmatech Co Ltd
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Jiangsu Alicorn Pharmatech Co Ltd
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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the invention relates to an oral controlled-release preparation of ticagrelor and a preparation method thereof.
  • the controlled-release preparation is a single-chamber osmotic pump controlled-release preparation with multiple drug release holes.
  • Ticagrelor is a new selective anticoagulant and the first reversibly bound P2Y12 adenosine diphosphate receptor (ADP) antagonist, which can reversibly act on vascular smooth muscle cells (VSMC)
  • ADP adenosine diphosphate receptor
  • VSMC vascular smooth muscle cells
  • the purine 2 receptor subtype P2Y12 on P2Y12 has a significant inhibitory effect on platelet aggregation caused by ADP and can effectively improve the symptoms of patients with acute coronary heart disease.
  • the chemical structure is shown in formula I:
  • Ticagrelor is an oral antiplatelet agglutination drug developed by AstraZeneca. It was approved for marketing in the European Union in December 2010, under the trade name Brilique. It was approved by the U.S. FDA in July 2011 and launched in Japan in 2016. Its clinical efficacy and safety are significantly better than clopidogrel, so it is listed in the first-line recommendation by many domestic and foreign guidelines, and the European guidelines list the recommended level of ticagrelor before clopidogrel in the past two years, and it is impossible to take ticagrel Only patients with Reluo can use clopidogrel.
  • Ticagrelor is rapidly absorbed after oral administration, with a median Tmax of approximately 1.5 hours. Because ticagrelor is a non-prodrug, it directly acts on the P2Y12 receptor and does not need to be activated by liver metabolism, and can quickly produce its main circulating metabolite ARC124910XX. The drug itself and its metabolites are active, so it can not only quickly and strongly inhibit ADP-mediated platelet aggregation, but the effectiveness is not affected by liver CYP2C19 gene polymorphism. The pharmacokinetics of ticagrelor is linear (within a dose of 1260 mg), and the exposure of ticagrelor and active metabolites (ARC124910XX) is basically proportional to the dose.
  • ticagrelor has shown superiority over clopidogrel in clinical studies, there is also an obvious disadvantage that the average T 1/2 of ticagrelor is about 7 hours, and the active metabolite is 9 hours, both of which are less than 12. Therefore, after 12 hours, the dose of ticagrelor and active metabolite will be reduced to half, so it must be administered twice a day.
  • Ticagrelor is white or off-white to pale pink powder. At pH 7.4, log P(n-octanol/water) is about 4.5. In a physiological pH environment between pH1.0 and pH7.4, its solubility is not affected by pH, all around 10 ⁇ g/ml, which is a poorly soluble drug; studies have shown that the permeability of this product in the body is about 51%. It belongs to medium permeability, but because it is less than 90%, it belongs to the BCSIV category (low solubility and low permeability).
  • the conventional formulation of ticagrelor is 90 mg twice a day. If a once-a-day controlled-release preparation is designed, the dose needs to be 180 mg, and the dose number is 72 according to the conversion of biological pharmacology. Generally speaking, preparations with oral drug dosages exceeding 20 are difficult to develop, while controlled-release preparations are more difficult to develop.
  • Patent CN101505754A discloses a composition suitable for oral administration including triazolo[4,5-d]pyrimidine derivatives, and the pharmaceutical composition comprises ticagrelor and other pharmaceutically acceptable excipients.
  • the original research agent that has been on the market is prepared using the examples in the patent, and its auxiliary materials include: mannitol, dibasic calcium phosphate dihydrate, hydroxypropyl cellulose, sodium starch carboxyacetate and magnesium stearate.
  • the preparation is prepared by a wet method. Granule technology, the specification is 90mg.
  • Patent CN102657629 A discloses the ticagrelor controlled-release tablet system and its preparation method. This invention controls the particle size of the raw material drug and mixes it with a certain amount of high-molecular polymer at the same time, through the wet granulation method, to make a framework-type control Release the film.
  • Patent CN103860504 A provides a sustained and controlled release formulation of ticagrelor for oral administration.
  • This invention prepares matrix-type controlled-release tablets, controlled-release coated tablets, and controlled-release pellet capsules by adding matrix materials or by coating technology, and explains The release rate is used as the evaluation index and the release rate measurement method, but the release rate results of each example are not published.
  • the patents CN103520164A and CN105998026A relate to a controlled-release preparation composed of ticagrelor, medicinal controlled-release materials and other medicinal excipients.
  • the controlled-release preparation is divided into two parts: immediate-release and controlled-release. It can be a double-layer tablet compressed by a double-layer tablet press, or a tablet with a controlled-release drug as the core and an immediate-release drug as the outer part of the coating. , Or a controlled-release capsule composed of two-part pellets: immediate release and controlled release.
  • Patent CN103520164A also relates to the use of ⁇ -cyclodextrin inclusion to improve drug solubility and improve bioavailability.
  • the controlled-release preparations of these inventions can not only make the drug take effect quickly, but also can maintain the effective concentration of the drug for a long time, and have a more ideal therapeutic effect.
  • the technical prescription process is complicated and requires a double-layer tablet press or a double-station. High-end equipment such as capsule fillers is not conducive to mass production.
  • Patent CN108210498A discloses a breakable ticagrelor controlled-release preparation.
  • the controlled-release preparation is suitable for oral administration once a day.
  • the tablet can achieve rapid drug release after destruction.
  • the tablet core is the same as the original one.
  • the controlled release layer, enteric layer and drug-containing layer are respectively wrapped on the outer layer.
  • the technology is very complicated and the overall process time is long, which is also not conducive to large-scale production.
  • Ticagrelor is a poorly soluble drug.
  • its solubility and bioavailability should be improved first. Due to the large dose of the designed controlled release formulation, ⁇ -cyclodextrin inclusion or solid dispersion technology should be used. , The required amount of ⁇ -cyclodextrin or solid solvent is generally 1-10 times the weight of the active ingredient, which causes the product formulation size to be too large, which is obviously inappropriate.
  • the osmotic pump formulations of poorly soluble drugs usually adopt double-chamber osmotic pump formulations, which are composed of a drug layer and a pushing layer. The weight ratio of the general drug layer: pushing layer is 1:2 ⁇ 1:3, which also cannot achieve the desired formulation size.
  • the dual-chamber osmotic pump preparation is more suitable for small doses of poorly soluble drugs. Therefore, it is necessary to develop a controlled release formulation suitable for large doses of poorly soluble drug ticagrelor to achieve an ideal and stable slow drug release rate.
  • the existing ticagrelor formulations have excessive release speed, not long-lasting, incomplete release, multiple daily doses, large doses, and cannot be consistent with different crystal forms of ticagrelor.
  • the release effect meanwhile, the existing ticagrelor preparation is unstable, cannot be stored for a long time, and the preparation process of the preparation is complicated, which is not conducive to large-scale industrial production.
  • the present invention provides a controlled-release ticagrelor tablet.
  • the controlled-release ticagrelor tablet has a mild and long-lasting release. Reluo has a good release effect, and the controlled release tablet has stable performance, can be stored for a long time, has a simple preparation process, and is suitable for industrial production.
  • the present invention provides a controlled-release tablet of ticagrelor.
  • the controlled-release tablet includes a tablet core and a film-controlled coating system.
  • the tablet core comprises 30-60wt% of the total weight of the core.
  • the controlled release tablet has more than two drug release holes.
  • the tablet core further includes a penetration enhancer and an osmotic pressure active agent.
  • the content of ticagrelor is 150-200 mg, and the particle size is 50 ⁇ m or less.
  • the film-controlling coating system includes a film-forming material and a plasticizer, the film-forming material accounts for 1-30% of the mass percentage of the controlled-release tablet, and the plasticizer accounts for 1-30% of the mass percentage of the controlled-release tablet. 0.1 ⁇ 10%. More preferably, the film-forming material is selected from one or more of cellulose acetate, ethyl cellulose and polyacrylic resin, preferably cellulose acetate; the plasticizer is selected from polyethylene glycol, oil One or more of the acid and triethyl citrate is preferably polyethylene glycol.
  • the penetration enhancer is selected from hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, non-cellulosic polysaccharides, polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose One or more of its salts, alginic acid and its salts, polyoxyethylene and hydroxymethyl cellulose, preferably hydroxyethyl cellulose.
  • the osmotic pressure active agent is selected from sugar osmotic pressure active agents and/or salt osmotic pressure active agents, and the sugar osmotic pressure active agent is selected from mannitol, xylitol, glucose, sorbitol, fructose One or more of sucrose and starch oligomerization ponds, preferably sorbitol; the salt osmotic pressure active agent is selected from one or two of sodium chloride, potassium chloride, sulfate and phosphatekind of the above mixture.
  • the tablet core further includes a binder and a lubricant
  • the binder is selected from one or more of cellulose ether, polyvinylpyrrolidone and hydroxypropylmethylcellulose succinate, preferably Copovidone
  • the lubricant is selected from one or more of stearic acid, magnesium stearate, and calcium stearate, preferably magnesium stearate.
  • the drug release hole is located on the front, back or side of the controlled release tablet, and there is one and only one drug release hole on the same surface, and the diameter of the drug release hole is 0.3-1.2 mm.
  • the controlled release tablet is a ticagrelor single-chamber osmotic pump controlled release tablet.
  • the present invention also provides a preparation method of ticagrelor controlled-release tablets, the method comprising:
  • the invention uses single-chamber osmotic pump technology to control the rate of water entering the tablet core through a membrane-controlled coating system.
  • the osmotic pressure enhancer absorbs water to make the osmotic pressure in the tablet core higher than the external medium environment, thereby generating permeation
  • the pressure difference further promotes the penetration of water, the penetration enhancer absorbs water and swells, and the drug forms a suspension and is pushed out from the drug release hole, thereby controlling the release of the drug.
  • the design of multiple drug release holes is adopted to ensure the complete release of the drug as much as possible, and at the same time alleviate the excessive osmotic pressure inside the tablet core, and can avoid the rupture of the coating film.
  • the ticagrelor controlled-release tablet provided by the present invention has a mild and long-lasting release, can be released almost completely within 20 hours, and can have a good release effect on ticagrelor of different crystal forms.
  • the controlled-release tablet The performance is stable, can be stored for a long time, and the preparation process is simple, which is suitable for industrial production.
  • the present invention provides a controlled-release ticagrelor tablet.
  • the controlled-release tablet comprises a core and a film-controlled coating system.
  • the core comprises 30-60wt% of the total weight of the core.
  • the controlled release tablet has more than two drug release holes.
  • the ticagrelor may exist in four different fully crystalline forms, namely polymorphs I, II, III, and IV, the melting points between the polymorphs and between the amorphous forms , Solubility and bioavailability are different, and the crystal form II is the original research crystal form.
  • the present invention is selected from crystalline or amorphous forms, and the content of ticagrelor in the controlled release tablet is in the range of 150-200 mg, preferably 160-190 mg, more preferably 180 mg.
  • the particle size of the active ingredient ticagrelor (the particle size D90 calculated by volume) is controlled at 50 ⁇ m or less, preferably 15 ⁇ m or less.
  • the tablet core further includes a penetration enhancer and an osmotic pressure active agent.
  • the penetration enhancer refers to the penetration enhancer that can swell after contacting water to push the drug solution or drug suspension out of the drug release hole. Water-soluble or water-insoluble penetration enhancers can be selected. The penetration enhancer accounts for 10% of the total weight of the tablet core. ⁇ 50%, preferably 10-30%.
  • the osmotic pressure active agent is a mixture of one or more compounds that produces a higher osmotic pressure after absorbing water.
  • the osmotic pressure active agent accounts for 20 to 80% of the total weight of the tablet core, preferably 30 to 50%.
  • the penetration enhancer is selected from hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, non-cellulosic polysaccharides (such as gum arabic, trehalose, Pregelatinized starch, etc.), polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethyl cellulose and its salts, alginic acid and its salts, polyoxyethylene, hydroxymethyl cellulose, etc. Species, preferably hydroxyethyl cellulose.
  • the osmotic pressure active agent is selected from sugar osmotic pressure active agents and/or salt osmotic pressure active agents, and the sugar osmotic pressure active agent is selected from mannitol, xylitol, glucose, sorbitol, fructose, One or more of sucrose and starch oligomerization, the salt osmotic pressure active agent is selected from one or a mixture of two or more of sodium chloride, potassium chloride, sulfate, and phosphate, preferably Sorbitol.
  • the film-controlling coating system includes a film-forming material and a plasticizer, the film-forming material is preferably water-insoluble, and the mass percentage of the film-forming material in the controlled-release tablet is 1 to 30%, preferably 2 to 15%, more preferably 3 to 10%.
  • the mass percentage of the plasticizer in the controlled release tablet is 0.1 to 10%, preferably 0.5 to 5%, more preferably 1 to 3%.
  • the film-forming material is selected from one or more of cellulose acetate, ethyl cellulose, polyacrylic resin, etc., preferably cellulose acetate.
  • the plasticizer is selected from one or more of polyethylene glycol, oleic acid, triethyl citrate, etc., preferably polyethylene glycol.
  • the semipermeable membrane coating liquid generally selects an organic solvent, such as acetone, ethanol, isopropanol or its aqueous solution, preferably acetone, more preferably an acetone-water solution with a concentration of 90-99%, the coating liquid
  • the solid content should generally be 3-15% (w/v,%), preferably 5-8% (w/v,%).
  • the tablet core further includes a binder and a lubricant
  • the binder is selected from one of cellulose ether, polyvinylpyrrolidone, and hydroxypropylmethylcellulose succinate.
  • the mass percentage of the binder in the total weight of the tablet core is 0.5-10%, preferably 1 to 5%
  • the lubricant is selected from stearic acid, magnesium stearate One or more of calcium stearate, etc., preferably magnesium stearate.
  • the mass percentage of the lubricant in the total weight of the tablet core is 0.1-10%, preferably 0.5-5%.
  • the present invention adopts the technology of multiple drug release holes, and the number of drug release holes is two or more.
  • the position of the holes can be selected on the front, back, and side of the tablet, but different drug-release holes should be on different sides.
  • the diameter of the drug-release hole is generally 0.3-1.2 ⁇ m. It is preferably 0.5 to 0.8 ⁇ m.
  • the controlled release tablet is a ticagrelor single-chamber osmotic pump controlled release tablet.
  • Another object of the present invention is to provide a method for preparing ticagrelor controlled-release tablets, the method comprising:
  • the active ingredient ticagrelor used in the following examples is selected from crystalline or amorphous, and the particle size (the particle size D90 calculated by volume) is controlled below 50 ⁇ m.
  • composition of the initial prescription is shown in Table 2:
  • composition Dosage (mg) Proportion(%) Ticagrelor 180 42.9 Sorbitol 153 36.4 Hydroxyethyl cellulose 55 13.1 Copovidone 8 1.9 Magnesium stearate 4 0.9 Cellulose acetate 14 3.3 Polyethylene glycol 6 1.4 total 420 /
  • the preparation method of ticagrelor controlled-release tablets is as follows:
  • the coated tablet is aged in an oven at 40°C, and a laser hole is drilled at the center of the front of the coated tablet with a diameter of 0.6 mm, and it is obtained.
  • composition Dosage (mg) Proportion(%) Ticagrelor 180 42.9 Sorbitol 153 36.4 Polyoxyethylene 55 13.1 Copovidone 8 1.9 Magnesium stearate 4 0.9 Cellulose acetate 14 3.3 Polyethylene glycol 6 1.4 total 420 /
  • the preparation method of ticagrelor controlled-release tablets is as follows:
  • the coated tablet is aged in an oven at 40°C, and a laser hole is drilled at the center of the front of the coated tablet with a diameter of 0.6 mm, and it is obtained.
  • composition Dosage (mg) Proportion(%) Ticagrelor 180 42.9 Sorbitol 153 36.4 Hydroxyethyl cellulose 55 13.1 Copovidone 8 1.9 Magnesium stearate 4 0.9 Cellulose acetate 15.8 3.8 Hypromellose 4.2 1.0 total 420 /
  • the preparation method of ticagrelor controlled-release tablets is as follows:
  • the coated tablet is aged in an oven at 40°C, and a laser hole is drilled at the center of the front of the coated tablet with a diameter of 0.6 mm, and it is obtained.
  • the chromatographic conditions for the release determination are: octadecylsilane-bonded silica gel is used as the column filler, phosphate buffer [take 1.0mol/L sodium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid) 10ml, Add water to 480ml, shake well]-Acetonitrile (48:52) is the mobile phase; the column temperature is 55°C; the detection wavelength is 242nm.
  • the tailing factor of ticagrelor should not be greater than 1.5, and the number of theoretical plates should not be less than 13,500 based on ticagrelor.
  • the release rate was determined by using 0.2% Tween 80 pH6.8 phosphate dissolution medium to investigate the drug release situation up to 20h. The release situation is shown in Table 5.
  • Example 2 It can be seen from Table 5 that by selecting the ingredients and contents of Example 2, the resulting ticagrelor controlled-release tablet releases mild, long-lasting, and has the highest release rate.
  • Example 6 It can be seen from Table 6 that the single-release drug hole was used in Example 2, and the single-chamber osmotic pump sustained-release tablets obtained were not completely released.
  • the release of controlled-release tablets is mild and long-lasting, and the release in 20 hours is greater than 90%, and the release is basically complete.
  • the different polymorphs of ticagrelor in Example 6 have no effect on the release curve, indicating that the single-chamber osmotic pump controlled release tablet can eliminate the influence of different solid forms on solubility and achieve an effective controlled release effect.
  • Example 6-Form II The samples in Example 6-Form II were placed under accelerated conditions (40°C/relative humidity RH75%) and long-term conditions (25°C/relative humidity RH65%) for one month, and evaluated according to the release degree in Example 5. Methods, the change trend of the in vitro release rate was investigated, and the release situation is shown in Table 7.
  • the release situation of the ticagrelor controlled-release tablet of Example 6 of the present invention under accelerated conditions and long-term conditions is the same as the release trend of the ticagrelor controlled-release tablet under the condition of 0 months. There is no obvious change. From this, it can be seen that the ticagrelor controlled-release tablet of Example 6 of the present invention has good stability, and does not change significantly under accelerated conditions and long-term storage conditions.

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Abstract

L'invention concerne un comprimé de ticagrélor à libération contrôlée et son procédé de préparation, le comprimé à libération contrôlée comprenant un noyau de comprimé et un système d'enrobage commandé par film, le noyau de comprimé comprenant du ticagrélor représentant 30 à 60 % en poids du poids total du noyau de comprimé, et le comprimé à libération contrôlée comportant au moins deux trous de libération de médicament. Le comprimé de ticagrélor à libération contrôlée a une libération douce et durable, peut être libéré presque complètement en 20 h, peut avoir un bon effet de libération sur le ticagrélor de différentes formes cristallines, et est également stable en termes de performances, peut être stocké pendant une longue période, et a un processus de préparation simple et est approprié pour la production industrielle.
PCT/CN2021/075842 2020-05-07 2021-02-07 Comprimé de ticagrélor à libération contrôlée et son procédé de préparation Ceased WO2021223480A1 (fr)

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Cited By (1)

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KR20230118434A (ko) * 2022-02-04 2023-08-11 주식회사 포스테라헬스사이언스 티카그렐러 또는 이의 약학적으로 허용 가능한 염을 유효 성분으로 포함하는 서방성 다층정제 및 이의 제조 방법

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CN111450072B (zh) * 2020-05-07 2022-07-15 江苏艾立康医药科技有限公司 一种替格瑞洛控释片及其制备方法
CN113368700B (zh) * 2021-06-08 2022-04-12 中南大学湘雅医院 一种血液净化改性膜及其制备方法
WO2022271167A1 (fr) * 2021-06-23 2022-12-29 Elite Pharmaceutical Solution Inc. Forme posologique orale de ticagrelor et son procédé de préparation
US11723873B2 (en) * 2021-06-23 2023-08-15 Elite Pharmaceutical Solution Inc. Oral dosage form of ticagrelor and preparation method thereof

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