WO2020138791A2 - Préparation à libération prolongée comprenant du tofacitinib ou un sel pharmaceutiquement acceptable associé et son procédé de fabrication - Google Patents

Préparation à libération prolongée comprenant du tofacitinib ou un sel pharmaceutiquement acceptable associé et son procédé de fabrication Download PDF

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WO2020138791A2
WO2020138791A2 PCT/KR2019/017717 KR2019017717W WO2020138791A2 WO 2020138791 A2 WO2020138791 A2 WO 2020138791A2 KR 2019017717 W KR2019017717 W KR 2019017717W WO 2020138791 A2 WO2020138791 A2 WO 2020138791A2
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Prior art keywords
sustained
tofacitinib
release preparation
salt
sustained release
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PCT/KR2019/017717
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English (en)
Korean (ko)
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WO2020138791A3 (fr
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박경희
윤재희
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주식회사 대웅제약
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Publication of WO2020138791A2 publication Critical patent/WO2020138791A2/fr
Publication of WO2020138791A3 publication Critical patent/WO2020138791A3/fr

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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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a sustained release preparation containing tofacitinib or a pharmaceutically acceptable salt thereof and a method for preparing the same. Specifically, it relates to a sustained release preparation comprising a hydrophilic base as tofacitinib or a pharmaceutically acceptable salt and sustained release agent thereof.
  • Such sustained-release preparations can stably and continuously release the drug in vivo, thereby obtaining a desired therapeutic effect by taking only once a day. More specifically, a content lower than that of a commercially available sustained release product, i.e., 10 mg, may have an effect equivalent to that of an immediate release preparation in vivo, and the manufacturing process is also simpler than that of a commercially available sustained release product. It is also characterized by having an advantage.
  • Tofacitinib an active ingredient of the present invention, has a compound name of 3- ⁇ (3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4- 1)-Amino]-piperidin-1-yl ⁇ -3-oxo-propionitrile, and has a structure represented by Formula 1 below.
  • Tofacitinib represented by Chemical Formula 1 is disclosed in International Publication No. WO2001/042246 as having inhibitory activity of protein kinase, such as Janus Kinas3 (JAK3) enzyme, organ transplantation, xenograft, Lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, type I diabetes and diabetes complications, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and immunosuppression It is known to be useful as an immunosuppressant for other diseases.
  • protein kinase such as Janus Kinas3 (JAK3) enzyme
  • organ transplantation such as Janus Kinas3 (JAK3) enzyme
  • organ transplantation such as Janus Kinas3 (JAK3) enzyme
  • organ transplantation such as xenograft, Lupus, multiple sclerosis, rheumatoid arthritis, ps
  • extended release form releases the drug continuously for a certain period of time in the body compared to immediate release form, so it is caused by maintaining the effective blood concentration of the drug for a long time and frequently administering the immediate release agent.
  • a drug requiring a low dosage such as tofacitinib
  • the amount of the additive is greater than that of the active ingredient, it is difficult to secure the uniformity of the content of the active ingredient for each tablet, and thus, the content is contained
  • Sustained-release preparations may also be required in terms of securing content uniformity.
  • sustained-release preparations using tofacitinib as an active ingredient
  • tofacitinib can be formulated as a release-controlling agent
  • matrix systems tablettes or multiples
  • osmotic systems e.g., osmotic systems
  • storage systems e.g., WO2014/147526.
  • OROS formulation of the product that is sold under the trade name of gel janjeu ® XR (XR Xeljanz) in the United States contains a physical dose of 11mg beyond the immediate release formulation daily dosage dose of 10mg.
  • the OROS formulation has a disadvantage in that its manufacturing process is complicated and productivity and economic efficiency are poor.
  • Patent Document 1 International Publication Patent Publication WO2012/100949
  • Patent Document 2 International Publication Patent Publication WO2014/147526
  • the present inventors have studied in order to solve the above problems, and when using a hydrophilic binder in addition to the sustained release agent, the drug is stable and sustained release even with a daily dose of the immediate release preparation, so that the bioequivalent to the immediate release preparation It was confirmed that a sustained release formulation capable of securing a utilization rate could be prepared, and the present invention was completed.
  • the present invention is to solve the problem of providing a sustained release preparation for the prevention or treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, contains tofacitinib as an active ingredient, and is effective by using a hydrophilic binder in addition to a sustained release agent.
  • a specific solution is to provide a sustained release formulation that is stable and continuously released in a form in which the powder is dispersed in a hydrophilic matrix.
  • the present invention uses two or more hydrophilic bases and exhibits an equivalent effect to a rapid release preparation in vivo despite the lower content of tofacitinib or a pharmaceutically acceptable salt thereof than a commercially available sustained release product. It is a special problem of the present invention to provide a sustained release preparation of a hydrophilic matrix formulation that is excellent in productivity and economic efficiency due to a simple manufacturing process.
  • the present invention discloses the following means.
  • the present invention discloses a sustained release formulation comprising tofacitinib or a pharmaceutically acceptable salt, sustained release agent and hydrophilic binder.
  • the tofacitinib or a pharmaceutically acceptable salt thereof is a citrate salt, aspartate, succinate, orotate, palmitate, stearate, benzoate, ascorbate, and oleate.
  • the sustained release agent in the sustained release preparation, can be used as long as it is a pharmaceutically acceptable sustained release base, preferably polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), hydroxypropyl Methyl cellulose phthalate, methyl cellulose (MC), sodium carboxymethyl cellulose (CMC-Na), hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), pectin, cyclodextrins, galactomannan, polyethylene glycol (PEG), ethyl It may be one or more selected from the group consisting of cellulose (EC) and gelatin. More preferably, HPMC can be used.
  • PVP polyvinylpyrrolidone
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropyl Methyl cellulose phthalate
  • MC methyl cellulose
  • CMC-Na sodium carboxymethyl cellulose
  • HPC hydroxyethyl cellulose
  • pectin
  • the hydrophilic binder may be used as long as it is a pharmaceutically acceptable hydrophilic binder, preferably microcrystalline cellulose, sucrose, titanium oxide, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), corn starch. And it may be one or two or more selected from the group consisting of lactose hydrate. Preferably it may be HPC, PVP or a combination thereof.
  • the mixing ratio of the two selected types may be 1:4 to 4:1.
  • tofacitinib may be included 10mg.
  • the hydrophilic binder may be included in an amount of 5.0 to 20.0 wt% based on the total weight of the formulation.
  • the tofacitinib may be in a form dispersed in a hydrophilic matrix.
  • the invention provides tofacitinib or a pharmaceutically acceptable salt thereof; Hydroxypropyl methylcellulose (HPMC) as a sustained release agent; Hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone (PVP) as hydrophilic binders; Lactose monohydrate as a diluent; And a sustained release preparation comprising magnesium stearate as a lubricant.
  • HPMC Hydroxypropyl methylcellulose
  • HPC Hydroxypropyl cellulose
  • HPC Hydroxypropyl cellulose
  • PVP polyvinylpyrrolidone
  • Lactose monohydrate as a diluent
  • a sustained release preparation comprising magnesium stearate as a lubricant.
  • the present invention comprises the steps of preparing a mixture by mixing the main component tofacitinib or a pharmaceutically acceptable salt and other additives thereof; Compressing and sizing the mixture to granulate; Tableting the granules; And it discloses a method for producing a sustained release preparation comprising the step of coating the tablet.
  • the sustained-release preparations according to the present invention show the prevention or treatment effect of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. More specifically, by using a hydrophilic binder in addition to a sustained release agent, the active ingredient exhibits a stable and sustained release, and thus, an equivalent bioavailability can be exhibited only with the same amount as the daily dosage of the immediate release preparation. In particular, compared to a commercially available OROS product, the manufacturing process is relatively simple, thereby providing a sustained release preparation excellent in productivity and economic efficiency.
  • 1 is a graph comparing the dissolution rate of the sustained-release preparation of the present invention, a sustained-release preparation containing only one hydrophilic binder, and a commercial sustained-release product.
  • Figure 2 is a graph comparing the PK profile of the sustained-release preparations and commercially-released products of the present invention.
  • Figure 3 is a graph comparing the PK profile before and after meals of the sustained release formulation of the present invention.
  • the content of the immediate-release preparation exceeds the daily dosage, and the manufacturing process is a complicated OROS formulation, whereas the hydrophilic matrix is added using a hydrophilic binder in addition to the sustained release agent.
  • the viscosity of the immediate-release preparation is made on the basis that the sustained-release preparation that can exhibit the same effect with only the same amount as the daily dosage is produced through a simple manufacturing process.
  • hydrophilic binder when only one type of hydrophilic binder is used, the elution is too late or the initial elution proceeds too quickly, whereas a combination of two or more hydrophilic binders such as hydroxypropylcellulose (HPC) and polyvinylpyrrolidone (PVP) When combined, it is based on the fact that the active ingredient tofacitinib from the hydrophilic matrix is stable and can continuously elute.
  • HPC hydroxypropylcellulose
  • PVP polyvinylpyrrolidone
  • sustained-release preparations for the prevention or treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis include tofacitinib or a pharmaceutically acceptable salt thereof, a sustained release agent and a hydrophilic binder.
  • the sustained release formulation of the present invention has a drug dissolution rate from the formulation at 2 hours of 45% or less, and a drug dissolution rate from the formulation at 3 hours of 55% or more and 80% or less.
  • the tofacitinib usable in the present invention is tofacitinib free base or a pharmaceutically acceptable acid addition salt (hereinafter, unless indicated otherwise, in the specification, tofacitinib or a pharmaceutically acceptable salt thereof is referred to as'topa Cytinib'), for example, citrate salt, aspartate, Succinate, orotate, palmitate, stearate, benzoate, ascorbate, oleate, sulfonate, sulfate, dodecyl sulfate, cyclamate, edisylate, nitrate, maleate, phosphate Citrate salt is the most preferred.
  • a pharmaceutically acceptable acid addition salt for example, citrate salt, aspartate, Succinate, orotate, palmitate, stearate, benzoate, ascorbate, oleate, sulfonate, sulfate, dodecyl sulfate, cyclamate,
  • the sustained-release agent used in the sustained-release preparation of the present invention can be used as long as it is a pharmaceutically acceptable sustained-release agent, preferably polyvinylpyrrolidone (PVP), a cellulose polymer, for example, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate, methylcellulose (MC), sodium carboxymethylcellulose (CMC-Na), hydroxyethylcellulose or hydroxypropylcellulose (HPC), pectin, cyclodextrins, galactomannan, It may be one or more selected from the group consisting of polyethylene glycol (PEG), ethyl cellulose (EC) and gelatin. More preferably, HPMC can be used.
  • PVP polyvinylpyrrolidone
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • MC methylcellulose
  • CMC-Na sodium carboxymethylcellulose
  • HPC hydroxyethylcellulose or hydroxypropylcellulose
  • the hydrophilic binder may be used as long as it is a pharmaceutically acceptable hydrophilic binder, preferably microcrystalline cellulose, sucrose, titanium oxide, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), corn starch. And it may be one or two or more selected from the group consisting of lactose hydrate. Preferably it is HPC, PVP, and the like, and most preferably, it may be a combination of HPC and PVP. Particularly, when a low viscosity HPC is used, a more preferable sustained effect can be obtained, and the viscosity measured by using a 2% aqueous solution at 20°C using a Brookfield viscometer is 6.0-10.0 mPa*s.
  • the sustained release preparation of the present invention is a form in which tofacitinib is dispersed in a hydrophilic matrix, and a hydrophilic matrix reacts with a water-soluble medium in the digestive tract in vivo to form a gel layer film from the outer outer layer of the tablet, and through this gel layer film, tofacitinib It is released slowly over a period of time.
  • the sustained-release preparation of the present invention is capable of releasing topacitinib as an active ingredient at a stable and constant rate by using a hydrophilic binder in addition to a sustained release agent.
  • the hydrophilic binder may be included in 5.0 to 20.0% by weight based on the total weight of the formulation, preferably 10.0 to 17.5% by weight.
  • the hydrophilic binder is less than 5.0% by weight, it is insufficient to adjust the viscosity of the hydrophilic matrix to enable continuous elution, and when it exceeds 20.0% by weight, it is uneconomical, and excessive amounts of the hydrophilic binder may cause problems in the manufacturing process of granules. This is because the total weight of the unit dosage form increases, causing inconvenience to taking.
  • the mixing ratio is preferably 1-4:4-1. In particular, the mixing ratio is most preferably 2:3.
  • sustained release preparations of the present invention may additionally include pharmaceutically acceptable additives, such as diluents, colorants, sweeteners, surfactants, lubricants, stabilizers, and the like.
  • pharmaceutically acceptable additives such as diluents, colorants, sweeteners, surfactants, lubricants, stabilizers, and the like.
  • the diluent may include lactose, microcrystalline cellulose, starch, etc.
  • lactose includes lactose monohydrate, lactose anhydride, spray-dried lactose monohydrate, etc.
  • microcrystalline celluloses include microcrystalline cellulose and silicate. Microcrystalline cellulose, and the like, but is not limited to corn starch, pregelatinized starch, and the like.
  • the colorant may include one or more selected from titanium oxide, iron sulfate, or pigments recommended by FD&C.
  • the sweetener may include one or more selected from sucralose, sucrose, dextrose, fructose, glucose, liquid glucose or maltose.
  • talc stearyl fumarate, magnesium stearate, or hydrogenated castor oil may be used.
  • the sustained release formulation of the present invention may include a pharmaceutically usable film coating.
  • the film coating is one or more of the additives commonly used in the coating of oral preparations such as hypromellose, titanium dioxide, PEG, iron oxide, and talc. You can choose and use.
  • sustained release preparations of the present invention can be prepared in various dosage forms. For example, it may be formulated into tablets, powders, granules or capsules, such as tablets, coated tablets, multilayer tablets or nucleated tablets, and preferably tablets.
  • the sustained release preparations of the present invention may include about 5 to 15 mg of tofacitinib, preferably 10 mg of tofacitinib, and the route of administration may be appropriately controlled, but may preferably be administered orally.
  • the present invention also provides a method for preparing a sustained release preparation.
  • the method of preparing the sustained release formulation of the present invention is a method for preparing a sustained release preparation. In one embodiment, the method of preparing the sustained release formulation of the present invention
  • (4) may include the step of coating the tablet.
  • composition of Table 1 the main components of tofacitinib aspartate, diluent lactose monohydrate, sustained release agent HPMC (Methocel K100LV CR ® ) and two hydrophilic binders (HPC-L and PVP K30) were mixed and then lubricated Jane magnesium stearate was further added and mixed. This mixture was compressed and granulated in a dry granulator to prepare a dry granulated product, and then compressed and compressed into 1 tablet portions in a rotary tableting machine.
  • HPMC Metalhocel K100LV CR ®
  • HPC-L and PVP K30 two hydrophilic binders
  • Example 1 Example 2
  • Example 3 Example 4 Tofacitinib aspartate 14.26mg 14.26mg 14.26mg 14.26mg Lactose monohydrate 63.85% 63.85% 63.85% 63.85% Methocel K100LV CR 15% 15% 15% 15% HPC-L 10% 7.5% 5% 2.5% PVP K30 2.5% 5% 7.5% 10% Magnesium stearate 2% 2% 2% 2% Sum 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%
  • composition of Table 2 the main component of tofacitinib aspartate, diluent lactose monohydrate, sustained release agent HPMC (Methocel K100LV CR ® ) and one hydrophilic binder (HPC-L or PVP K30) are mixed and then lubricated Jane magnesium stearate was further added and mixed. This mixture was compressed and granulated in a dry granulator to prepare a dry granulated product, and then compressed and compressed into 1 tablet portions in a rotary tableting machine.
  • HPMC Metalhocel K100LV CR ®
  • HPC-L or PVP K30 hydrophilic binder
  • the sustained-release preparations prepared in Examples 1 to 4 and Comparative Examples 1 and 2 and the currently available gelzand XR tablets (control, 11 mg as tofacitinib) were tested for dissolution in the United States Pharmacopoeia (USP). It was performed on the device. Specifically, the speed of the paddle is rotated at 50 rpm, 900 mL of pH 6.8 potassium phosphate buffer is used as a dissolution medium, and the temperature of the buffer is maintained at 37° C., while the eluent obtained at an appropriate time during the test is subjected to a filter and high performance liquid chromatography Analysis of tofacitinib released by (HPLC) investigated the dissolution properties and the results are shown in Table 3 and FIG. 1.
  • Tofacitinib is a drug of BCS Class 3, and since the drug has high solubility and low biomembrane permeability, absorption of the drug in vivo is determined by the rate of permeation of the drug itself.
  • the additives that may affect the biomembrane permeability such as the sustained-release preparation, are not included, in vivo permeation is dependent on the physicochemical properties of tofacitinib, so the degree of in vivo release can be predicted according to the results of in vitro dissolution. .
  • the Tmax of the currently available Gelzanz XR tablets is 3 to 4 h, and in order to be released in vivo at an equivalent level, it is important to dissolve at a time of 2 to 4 h in an in vitro dissolution experiment, suitably 20 to 42% at 2 h, 2.5 h Elution of 33-56%, 46-65% at 3h, 55-70% at 3.5h, and 72-76% at 4h.
  • the pre-prediction vs post-prandial AUC value of the sustained-release preparation of the present invention exhibited an equivalent level, and the sustained-release preparation was not affected by the diet in the case of the sustained-release preparation of the present invention. It means that you have secured the standards you must have.
  • the sustained-release preparation according to the present invention exhibits a preventive or therapeutic effect on rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, and thus can be used as a pharmaceutical in the pharmaceutical industry and the medical field.

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Abstract

La présente invention concerne une préparation à libération prolongée comprenant du tofacitinib ou un sel pharmaceutiquement acceptable associé, un agent de prolongement de libération et un liant hydrophile. L'invention concerne une préparation à libération prolongée dans une forme de formulation de matrice hydrophile qui présente des effets in vivo aussi bons que ceux d'une préparation à libération immédiate à une dose inférieure à celle des produits à libération prolongée actuellement commercialisés, à savoir, à une dose de 10 mg, et qui est relativement simple dans son procédé de fabrication et présente ainsi une excellente productivité et un avantage économique.
PCT/KR2019/017717 2018-12-28 2019-12-13 Préparation à libération prolongée comprenant du tofacitinib ou un sel pharmaceutiquement acceptable associé et son procédé de fabrication WO2020138791A2 (fr)

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KR1020180172103A KR20200082006A (ko) 2018-12-28 2018-12-28 토파시티닙 또는 그의 약제학적으로 허용되는 염을 함유한 서방성 제제 및 그의 제조방법
KR10-2018-0172103 2018-12-28

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114588158A (zh) * 2022-03-14 2022-06-07 武汉工程大学 吲哚哌啶嘧啶类衍生物在制备新型冠状病毒抑制剂中的应用
CN115006361A (zh) * 2022-06-10 2022-09-06 北京诺康达医药科技股份有限公司 一种托法替布缓释包芯片及其制备方法
CN115887408A (zh) * 2022-11-29 2023-04-04 江苏慧聚药业股份有限公司 包含托法替布的药物组合物和药物制剂
WO2024042218A1 (fr) * 2022-08-26 2024-02-29 Synthon B.V. Compositions de tofacitinib à libération prolongée sans enrobage fonctionnel
CN115887408B (zh) * 2022-11-29 2024-05-24 江苏慧聚药业股份有限公司 包含托法替布的药物组合物和药物制剂

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0613310D0 (en) * 2006-07-05 2006-08-16 Merck Sharp & Dohme The use of pvp to control the release profile of an active ingredient from a hydrophilic polymer matrix tablet
EP2481411A1 (fr) 2011-01-27 2012-08-01 Ratiopharm GmbH Formes galéniques orales pour libération modifiée comportant l'inhibiteur de JAK3 tasocitinib
JP6041823B2 (ja) 2013-03-16 2016-12-14 ファイザー・インク トファシチニブの経口持続放出剤形
WO2014174073A1 (fr) * 2013-04-26 2014-10-30 Sandoz Ag Formulations de tofacitinib à libération prolongée
KR20160117596A (ko) * 2014-02-07 2016-10-10 오스펙스 파마슈티칼스, 인코포레이티드 신규 제약 제제
WO2017029587A1 (fr) * 2015-08-19 2017-02-23 Sun Pharmaceutical Industries Limited Compositions pharmaceutiques orales à libération prolongée de tofacitinib

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114588158A (zh) * 2022-03-14 2022-06-07 武汉工程大学 吲哚哌啶嘧啶类衍生物在制备新型冠状病毒抑制剂中的应用
CN114588158B (zh) * 2022-03-14 2023-09-05 武汉工程大学 吲哚哌啶嘧啶类衍生物在制备新型冠状病毒抑制剂中的应用
CN115006361A (zh) * 2022-06-10 2022-09-06 北京诺康达医药科技股份有限公司 一种托法替布缓释包芯片及其制备方法
WO2024042218A1 (fr) * 2022-08-26 2024-02-29 Synthon B.V. Compositions de tofacitinib à libération prolongée sans enrobage fonctionnel
CN115887408A (zh) * 2022-11-29 2023-04-04 江苏慧聚药业股份有限公司 包含托法替布的药物组合物和药物制剂
CN115887408B (zh) * 2022-11-29 2024-05-24 江苏慧聚药业股份有限公司 包含托法替布的药物组合物和药物制剂

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