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WO2019139313A1 - Formulation pharmaceutique stabilisée comprenant de l'évérolimus - Google Patents

Formulation pharmaceutique stabilisée comprenant de l'évérolimus Download PDF

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Publication number
WO2019139313A1
WO2019139313A1 PCT/KR2019/000204 KR2019000204W WO2019139313A1 WO 2019139313 A1 WO2019139313 A1 WO 2019139313A1 KR 2019000204 W KR2019000204 W KR 2019000204W WO 2019139313 A1 WO2019139313 A1 WO 2019139313A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
everolimus
granules
butylhydroxytoluene
formulation according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2019/000204
Other languages
English (en)
Inventor
Kyung Hee Han
Min Soo Kim
Shin Jung Park
Jong Lae Lim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chong Kun Dang Corp
Original Assignee
Chong Kun Dang Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chong Kun Dang Corp filed Critical Chong Kun Dang Corp
Priority to JP2020538112A priority Critical patent/JP7218372B2/ja
Priority to MX2020007434A priority patent/MX391867B/es
Priority to EA202091455A priority patent/EA202091455A1/ru
Priority to CN201980007209.1A priority patent/CN111565714B/zh
Priority to BR112020014292-1A priority patent/BR112020014292B1/pt
Publication of WO2019139313A1 publication Critical patent/WO2019139313A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F41—WEAPONS
    • F41A—FUNCTIONAL FEATURES OR DETAILS COMMON TO BOTH SMALLARMS AND ORDNANCE, e.g. CANNONS; MOUNTINGS FOR SMALLARMS OR ORDNANCE
    • F41A17/00—Safety arrangements, e.g. safeties
    • F41A17/42—Safeties for locking the breech-block or bolt in a safety position
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to a stabilized pharmaceutical formulation comprising everolimus. Specifically, the present invention relates to a pharmaceutical formulation comprising granules comprising everolimus as an active ingredient and butylhydroxytoluene as an antioxidant.
  • Immunosuppressants are pharmaceutical compounds that reduce the activity of the immune system. They are commonly used in the therapy of autoimmune diseases. It is autoimmune diseases which are believed to involve some types of hypersensitivity of the immune system, which is, for example, known for Crohn's disease, multiple sclerosis, rheumatoid arthritis, ulcerative colitis, Addison's disease, and numerous other diseases. The immunosuppressants are also used for the prevention and treatment of organ transplant rejection due to differences in human leukocyte antigen haplotypes between the donor and recipient after an organ transplantation.
  • Immunosuppressants that have been developed for therapeutic use may be classified according to their chemical structure and their mechanism of action.
  • Immunosuppressive compounds comprise pimecrolimus, sirolimus, deforolimus, temsirolimus, and zotarolimus.
  • Everolimus is a derivative of sirolimus wherein a hydroxyethyl group is added to the 40-O group of sirolimus, and is marketed by Novartis under the trade names of Zortress ® in the US and Certican ® in Republic of Korea and Europe for preventing organ transplant rejection.
  • this drug inhibits mTOR pathway to inhibit the expression of vascular endothelial growth factor (VEGF), thereby exhibiting an anticancer activity.
  • VEGF vascular endothelial growth factor
  • Afinitor ® for the purpose of treating advanced renal cell carcinoma after failure of VEGF-targeted therapy with sunitinib or sorafenib.
  • Many clinical trials have also been under way on breast cancer, gastric cancer, liver cancer, pancreatic cancer, and the like.
  • Everolimus is defined as dihydroxy-12- ⁇ (2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl ⁇ -19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0(4,9)] hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone having Formula I below:
  • US 5,665,772 specifies a rapamycin compound and derivatives derived therefrom and discloses a step and method for synthesizing everolimus.
  • sirolimus derivatives such as everolimus has very low water solubility and high molecular weight such that they have difficulties in permeating membranes of the gastrointestinal tract. Further, it is not easy that they are absorbed into the blood stream in an effective amount, since they serve as a substrate of the efflux pump such as P-glycoprotein.
  • Sirolimus derivatives such as everolimus are thus known as having drawbacks including unpredictable dissolution rate, non-uniform bioavailability, and instability.
  • Korean Patent No. 0695834 discloses a pharmaceutical composition having improved stability by preparing a mixture of a sirolimus derivative that is sensitive to an oxidation reaction, and an antioxidant.
  • the Korean patent states that the stability can be improved by preparing a mixed precipitate of a sirolimus derivative with an antioxidant.
  • it is disadvantageous in that complicated procedures should be involved in an actual manufacturing process.
  • the present invention is to provide a pharmaceutical formulation comprising everolimus as an active ingredient and having pharmaceutically improved properties. Specifically, while screening an antioxidant exerting improved antioxidant effect in a pharmaceutical formulation comprising everolimus as an active ingredient, it has surprisingly been found that butylhydroxytoluene exhibits superior antioxidant effect, based on which the present invention has been achieved.
  • a formulation having more improved stability can be provided when preparing granules comprising everolimus as an active ingredient and butylhydroxytoluene as an antioxidant wherein each ingredient is comprised in a specific weight ratio in the granules.
  • the present invention provides granules comprising everolimus as an active ingredient and butylhydroxytoluene as an antioxidant.
  • the granules may be prepared by wet granulation, dry granulation, and the like. Preferably, they are prepared by wet granulation.
  • any known process in the art can be used for the wet granulation in view of the purpose of the present invention.
  • the granules may comprise, based on the total weight of the granules, preferably, 0.5 to 20 wt% of everolimus, more preferably, 1 to 10 wt% of everolimus.
  • the granules may comprise, based on the total weight of the granules, preferably, 0.05 to 10 wt% of butylhydroxytoluene as an antioxidant, more preferably, 0.1 to 5 wt%.
  • the granules may further comprise a binder, a disintegrating agent, and other excipients.
  • the granules may further comprise hypromellose as a binder.
  • the pharmaceutical formulation according to the present invention may be prepared by (i) a step of dissolving everolimus, butylhydroxytoluene and binder(s), and preparing a mixture; (ii) a step of preparing granules from the mixture; and (iii) a step of adding a lubricant into the granules to prepare a granule mixture.
  • the final granule mixture may be tableted by using a tableting machine to provide a stable tablet comprising everolimus as an active ingredient and butylhydroxytoluene as an antioxidant.
  • the pharmaceutical formulation according to the present invention may further comprise a lubricant.
  • the lubricant may be, but is not limited to, at least one selected from the group consisting of glyceryl behenate, magnesium stearate, sodium stearyl fumarate, and colloidal silicon dioxide. Most preferably, the lubricant of the present invention may be glyceryl behenate.
  • the present invention which is directed to a pharmaceutical formulation comprising everolimus as an active ingredient, exerts superior stability and has simple manufacturing process, whereby mass production is allowed.
  • the present invention provides a pharmaceutical formulation comprising granules comprising everolimus as an active ingredient and butylhydroxytoluene as an antioxidant.
  • the granules have more improved stability when comprising 0.5 to 20 wt% of everolimus and 0.05 to 10 wt% of butylhydroxytoluene based on the total weight of the granules.
  • the granules have most improved stability when comprising 1 to 10 wt% of everolimus and 0.1 to 5 wt% of butylhydroxytoluene based on the total weight of the granules.
  • the granules may be prepared by a conventional method for preparing a granule comprising dry granulation or wet granulation. Preferably, they may be prepared by wet granulation.
  • the granules according to the present invention may further comprise a binder.
  • binder refers to a substance to provide elasticity and adhesion so that a hardness of a formulation as formed, especially, a hardness of a tablet as formed, is increased.
  • the binder according to the present invention may be a binder conventionally used, preferably, hypromellose.
  • the pharmaceutical formulation according to the present invention may further comprise a lubricant.
  • lubricant refers to a substance with which improved flowability is provided to a formulation.
  • the lubricant may be, but is not limited to, at least one selected from the group consisting of glyceryl behenate, magnesium stearate, sodium stearyl fumarate, and colloidal silicon dioxide.
  • glyceryl behenate may be used as a lubricant.
  • the pharmaceutical formulation according to the present invention may further comprise a diluent.
  • a diluent refers to an inactive substance used as a filter to provide a desired bulk, flowability, and compressibility when preparing a solid dosage form.
  • the diluent may be, but is not limited to, lactose hydrate, anhydrous lactose, sucrose, corn starch, or dibasic calcium phosphate in the form of an anhydride or a hydrate.
  • the pharmaceutical formulation according to the present invention may further comprise a disintegrating agent.
  • a disintegrating agent refers to a substance used to accelerate the disintegration of a solid form so that an active ingredient exerting the medicinal effect is released from the form within a short time.
  • the disintegrating agent may be, but is not limited to, carboxymethyl cellulose calcium (CMC-Ca), Crospovidone, sodium starch glycolate, croscarmellose sodium, or low-substituted hydroxypropyl cellulose.
  • the pharmaceutical formulation of the present invention may be formulated in an oral dosage form.
  • the oral dosage form may be, but is not limited to, a tablet.
  • the pharmaceutical formulation of the present invention may be used for the prevention or treatment of organ transplant rejection.
  • the present invention provides a method for preparing a pharmaceutical formulation comprising everolimus as an active ingredient and butylhydroxytoluene as an antioxidant, comprising the steps of: dissolving everolimus, butylhydroxytoluene and binder(s), and preparing a mixture; preparing first granules from the mixture; and adding a lubricant into the granules to prepare a granule mixture.
  • Hypromellose, butylhydroxytoluene, and everolimus were added into an organic solvent to obtain a binding solution.
  • the binding solution was added into a mixture of lactose hydrate, Crospovidone, and hypromellose, followed by granulating, drying, and sieving by a sieving machine.
  • the granules after sieving were mixed with lactose hydrate, anhydrous lactose, and Crospovidone, followed by adding glyceryl behenate and finally mixing to prepare a granule mixture of everolimus.
  • the final mixture was tableted by a tableting machine to prepare a tablet.
  • the prepared tablet comprises 1.0 mg of everolimus.
  • Examples 1 to 5 were prepared according to the preparation method above, provided that the weight percent (wt%) of everolimus and butylhydroxytoluene based on the total weight of the intra-part (granules) is different in each example in accordance with Table 1 below.
  • Example 1 2 3 4 5 Intra-part (granules) Everolimus (mg) 1.00 1.00 1.00 1.00 1.00 wt% of everolimus based on the total weight of the intra-part 8.2 5.0 2.7 1.1 1.1 Hypromellose (mg) 4.00 4.00 15.00 20.00 50.00 Lactose hydrate (mg) 1.00 9.00 15.00 64.80 34.80 Crospovidone (mg) 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 6.00 Butylhydroxytoluene (mg) 0.20 0.20 0.20 0.20 0.20 wt% of butylhydroxytoluene based on the total weight of the intra-part 1.6 1.0 0.5 0.2 0.2 Total weight of the intra-part (mg) 12.2 20.2 37.2 92.0 92.0 Extra-part Crospovidone (mg) 6.00 6.00 6.00 6.00 6.00 Lactose hydrate (mg) 63.80 55.80 37.80 - -
  • the stability was evaluated through the impurity test on the tablets of Examples 1 to 5 using the impurity test condition below.
  • Each formulation was stored at a stress condition (60°C of temperature) for four weeks to evaluate the amount of impurities by liquid chromatography.
  • the total amount of impurities in Examples 2 and 3 was no more than 1%, from which high stability was confirmed. It was confirmed that the total amount of impurities in Examples 1, 4, and 5 are two or three times more than in Examples 2 and 3.
  • a lubricant refers to a substance with which improved flowability is provided to a formulation.
  • the stability of a formulation according to the type of lubricant was evaluated where the lubricant is glyceryl behenate, magnesium stearate, sodium stearyl fumarate, or colloidal silicon dioxide.
  • Example 3 had the most superior stability.
  • the amount of impurities produced in Examples 7 and 8 are two times more than in Example 3, while that in Example 6 are seven times more than in Example 3.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique stabilisée comprenant de l'évérolimus. La présente invention concerne spécifiquement une formulation pharmaceutique comprenant des granules comprenant de l'évérolimus en tant que principe actif et du butylhydroxytoluène en tant qu'antioxydant. En outre, la présente invention concerne un procédé de préparation d'une formulation pharmaceutique comprenant de l'évérolimus en tant que principe actif et du butylhydroxytoluène en tant qu'antioxydant, comprenant les étapes consistant à : dissoudre l'évérolimus, le butylhydroxytoluène et un ou plusieurs liants, et préparer un mélange ; préparer des granules à partir du mélange ; et ajouter un lubrifiant dans les granules pour préparer un mélange de granules.
PCT/KR2019/000204 2018-01-12 2019-01-07 Formulation pharmaceutique stabilisée comprenant de l'évérolimus Ceased WO2019139313A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2020538112A JP7218372B2 (ja) 2018-01-12 2019-01-07 エベロリムスを含む安定化した薬剤学的製剤
MX2020007434A MX391867B (es) 2018-01-12 2019-01-07 Formulación farmacéutica estabilizada que comprende everolimus.
EA202091455A EA202091455A1 (ru) 2018-01-12 2019-01-07 Стабилизированный фармацевтический состав, содержащий эверолимус
CN201980007209.1A CN111565714B (zh) 2018-01-12 2019-01-07 包含依维莫司的实现稳定化的药剂学制剂
BR112020014292-1A BR112020014292B1 (pt) 2018-01-12 2019-01-07 Formulação farmacêutica tendo grânulos de everolimo, método de produção e uso

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020180004458A KR102051806B1 (ko) 2018-01-12 2018-01-12 에베로리무스를 포함하는 안정화된 약제학적 제제
KR10-2018-0004458 2018-01-12

Publications (1)

Publication Number Publication Date
WO2019139313A1 true WO2019139313A1 (fr) 2019-07-18

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ID=67219083

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2019/000204 Ceased WO2019139313A1 (fr) 2018-01-12 2019-01-07 Formulation pharmaceutique stabilisée comprenant de l'évérolimus

Country Status (6)

Country Link
JP (1) JP7218372B2 (fr)
KR (1) KR102051806B1 (fr)
CN (1) CN111565714B (fr)
EA (1) EA202091455A1 (fr)
MX (1) MX391867B (fr)
WO (1) WO2019139313A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111388455A (zh) * 2020-04-09 2020-07-10 沈阳药科大学 一种依维莫司口腔膜剂及其制备方法

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WO2008016633A2 (fr) * 2006-08-02 2008-02-07 Ariad Gene Therapeutics, Inc. Thérapie par combinaison
WO2010056754A2 (fr) * 2008-11-11 2010-05-20 The Board Regents Of The University Of Texas System Inhibition de cible mammalienne de rapamycine
KR20140032586A (ko) * 2012-09-06 2014-03-17 한국원자력의학원 Ｐｔｅｎ 기능저하에 의한 ｅｇｆｒ-ｔｋｉ 저해제-내성 폐암의 방사선 치료용 약학 조성물
KR20140058670A (ko) * 2011-10-06 2014-05-14 노파르티스 아게 40-o-(2-히드록시)에틸-라파마이신을 포함하는 제약 조성물
US20160045441A1 (en) * 2013-03-19 2016-02-18 Novartis Ag Pharmaceutical Compositions Comprising Everolimus

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GB9826882D0 (en) 1998-12-07 1999-01-27 Novartis Ag Organic compounds
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MX367121B (es) 2013-08-02 2019-08-06 Laboratorio Raam De Sahuayo S A De C V Composición sólida estable de inmunosupresores.
KR20150138104A (ko) * 2014-05-30 2015-12-09 동아에스티 주식회사 베포타스틴과 글리세릴베헤네이트를 포함하는 약제학적 제제
CN104398483B (zh) 2014-11-05 2018-01-26 上海医药集团青岛国风药业股份有限公司 一种奥美沙坦酯片及其制备工艺
CN105106145A (zh) * 2015-08-27 2015-12-02 济川药业集团有限公司 一种依维莫司片剂及其制备方法
JP6793652B2 (ja) 2015-09-03 2020-12-02 日本化薬株式会社 ラパマイシン又はその誘導体を含有する医薬組成物
JP2018111662A (ja) 2017-01-12 2018-07-19 ニプロ株式会社 エベロリムス製剤

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008016633A2 (fr) * 2006-08-02 2008-02-07 Ariad Gene Therapeutics, Inc. Thérapie par combinaison
WO2010056754A2 (fr) * 2008-11-11 2010-05-20 The Board Regents Of The University Of Texas System Inhibition de cible mammalienne de rapamycine
KR20140058670A (ko) * 2011-10-06 2014-05-14 노파르티스 아게 40-o-(2-히드록시)에틸-라파마이신을 포함하는 제약 조성물
KR20140032586A (ko) * 2012-09-06 2014-03-17 한국원자력의학원 Ｐｔｅｎ 기능저하에 의한 ｅｇｆｒ-ｔｋｉ 저해제-내성 폐암의 방사선 치료용 약학 조성물
US20160045441A1 (en) * 2013-03-19 2016-02-18 Novartis Ag Pharmaceutical Compositions Comprising Everolimus

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111388455A (zh) * 2020-04-09 2020-07-10 沈阳药科大学 一种依维莫司口腔膜剂及其制备方法
CN111388455B (zh) * 2020-04-09 2022-09-02 沈阳药科大学 一种依维莫司口腔膜剂及其制备方法

Also Published As

Publication number Publication date
CN111565714A (zh) 2020-08-21
JP7218372B2 (ja) 2023-02-06
BR112020014292A2 (pt) 2020-12-08
JP2021510374A (ja) 2021-04-22
CN111565714B (zh) 2022-05-17
KR20190086212A (ko) 2019-07-22
MX391867B (es) 2025-03-21
KR102051806B1 (ko) 2019-12-04
MX2020007434A (es) 2022-04-27
EA202091455A1 (ru) 2020-10-05

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