WO2021256844A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique Download PDF

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Publication number
WO2021256844A1
WO2021256844A1 PCT/KR2021/007518 KR2021007518W WO2021256844A1 WO 2021256844 A1 WO2021256844 A1 WO 2021256844A1 KR 2021007518 W KR2021007518 W KR 2021007518W WO 2021256844 A1 WO2021256844 A1 WO 2021256844A1
Authority
WO
WIPO (PCT)
Prior art keywords
imp
pharmaceutical composition
tablet
escitalopram
lubricant
Prior art date
Application number
PCT/KR2021/007518
Other languages
English (en)
Korean (ko)
Inventor
윤영민
이유훈
홍찬미
신호철
김원
윤소현
Original Assignee
환인제약 주식회사
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 환인제약 주식회사 filed Critical 환인제약 주식회사
Priority to JP2022577091A priority Critical patent/JP2023529499A/ja
Publication of WO2021256844A1 publication Critical patent/WO2021256844A1/fr

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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
    • A61K9/20—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a pharmaceutical composition comprising escitalopram.
  • Escitalopram is a selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs, the structure of which is shown in Formula 1 below:
  • SSRI serotonin reuptake inhibitor
  • escitalopram Unlike other SSRI antidepressants, escitalopram has a wide range of indications, rapid onset of effect, and excellent therapeutic effect and tolerability. It is marketed.
  • USP 42 Escitalopram Tablets
  • citalopram-related compounds A, B, C and E are each defined as follows:
  • Citalopram related compounds A 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxamide);
  • Citalopram related compounds B 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile; 3-hydroxycitalopram;
  • Citalopram related compounds C 3-(3-dimethylaminopropyl)-3-(4-fluorophenyl)-6-cyano-1( 3H )-isobenzofuranone;
  • Citalopram related compound E 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile-N-oxide
  • escitalopram tablets should be stored in a well-closed container, but in reality, most escitalopram tablets are 30 tablets in a plastic container-type tight container. ⁇ 200 tablets are stored and distributed.
  • PTP packaging may be more disadvantageous than storage in plastic containers in terms of stability of medicines before opening.
  • the present inventors have researched to develop escitalopram tablets that can sufficiently ensure stability even in PTP packaging. It was discovered that a tablet capable of minimizing the generation of related substances could be prepared, and the present invention was completed.
  • the present invention is to provide an escitalopram tablet with improved stability.
  • the present invention relates to a pharmaceutical composition containing escitalopram or a pharmaceutically acceptable salt thereof.
  • escitalopram containing at least one of light anhydrous silicic acid or hydrogenated oil as a lubricant is contained. It relates to a pharmaceutical composition.
  • the pharmaceutical composition of the present invention may be in the form of a tablet, and preferably may be coated with a coating layer.
  • the lubricant may include at least one of light anhydrous silicic acid or hardened oil, and preferably includes both light anhydrous silicic acid and hardened oil as the lubricant.
  • light anhydrous silicic acid and hydrogenated oil may be included in an amount of 1 to 10%, preferably 1 to 5%, respectively, based on the total weight of the pharmaceutical composition.
  • the pharmaceutical composition according to the present invention may further include a pharmaceutically acceptable diluent and disintegrant.
  • silicified microcrystalline cellulose lactose, starch, sucrose, sugar alcohol, inorganic salts such as calcium phosphate, crystalline cellulose, etc. may be used, and silicified microcrystalline cellulose is preferably used.
  • crospovidone starch, carboxymethyl cellulose, crystalline cellulose, etc. may be used, and crospovidone is preferably used.
  • the pharmaceutical composition according to the present invention improves stability by inhibiting the production of related substances even during PTP packaging.
  • the present invention it is possible to provide a tablet with improved stability, which can minimize the decrease in the content of the active ingredient or the generation of related substances even during PTP packaging.
  • each tablet was prepared by changing the lubricant.
  • a core tablet was prepared from the mixture by a direct tableting method, and the prepared core tablet was coated with a coating layer to prepare a tablet.
  • RRT 0.43
  • RRT 1.34
  • magnesium stearate as a lubricant is not preferable in terms of stability in the case of PTP packaging of escitalopram tablets.
  • Example 9 a tablet (Example) prepared according to the present invention and a tablet to be used as a control (Comparative Example) were respectively prepared.
  • a core tablet was prepared from the mixture by a direct tableting method, and the prepared core tablet was coated with a coating layer to prepare a tablet.
  • composition of the tablet of each example (content unit mg/1 tablet) ingredient Example 1
  • Example 2 Example 3 core Escitalopram oxalic acid chief ingredient 12.77 12.77 12.77 silicification undecided cellulose excipient 102.63 92.23 85.23 cross povidone disintegrant 7 7 7 light anhydrous silicic acid lubricant 1.3 6.5 10 hydrogenated oil (hydrogenated oil) lubricant 1.3 6.5 10 coating layer Opadry White coating agent 3 3 3 gross weight 128 128 128
  • Comparative Example 8 using glyceryl behenate and stearic acid as lubricants during the manufacturing process of the core tablet, the lubricating power was insufficient, so the sticking phenomenon occurred in which the powder was attached to the lower punch during tableting. Therefore, it was confirmed that the composition of Comparative Example 8 was not suitable in terms of tabletting properties.
  • Comparative Example 7 On the other hand, the purification of Comparative Example 7 using talc and magnesium stearate as lubricants produced as much as 0.48% of impurity C, which was close to the acceptable standard. Therefore, according to the harsh test, Comparative Example 7 is highly likely to exceed the allowable standard value of impurity C in the stability test.
  • Comparative Example 8 using glyceryl behenate and stearic acid as lubricants More impurity C was produced than 1 or 2, and as mentioned above, the tabletting property was poor. In addition, in the tablet of Comparative Example 9, as much as 0.45% of impurity C was generated, it was almost close to the acceptable standard, and also, the tablet became soft during the stability test, resulting in a problem of stability in properties.
  • the escitalopram tablets of Examples 1 and 2 using anhydrous light silicic acid and magnesium stearate as lubricants according to the present invention have the best stability and minimize the generation of related substances even during PTP packaging. there was. In addition, there was no problem in terms of flowability and tabletting properties of the powder even in the tableting process, so it was excellent in terms of the manufacturing process.
  • Control drug A light anhydrous silicic acid and magnesium stearate
  • Control drug B talc and magnesium stearate
  • Control drug C magnesium stearate
  • Control drug D magnesium stearate
  • Example 1 had better stability than the existing commercially available products, thereby minimizing the generation of related substances even during PTP packaging.
  • the present invention provides an escitalopram tablet with improved stability.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique qui contient de l'escitalopram ou un sel pharmaceutiquement acceptable de celui-ci et comprend, en tant que lubrifiant, au moins un type d'acide silicique anhydre léger ou de l'huile hydrogénée, et permet d'obtenir un comprimé qui a une stabilité améliorée et est capable de réduire au minimum les substances associées générées ou les quantités de principes actifs réduites même lors d'un conditionnement dans un emballage PTP.
PCT/KR2021/007518 2020-06-15 2021-06-15 Composition pharmaceutique WO2021256844A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2022577091A JP2023529499A (ja) 2020-06-15 2021-06-15 医薬組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020200072656A KR102441089B1 (ko) 2020-06-15 2020-06-15 의약 조성물
KR10-2020-0072656 2020-06-15

Publications (1)

Publication Number Publication Date
WO2021256844A1 true WO2021256844A1 (fr) 2021-12-23

Family

ID=79175960

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/007518 WO2021256844A1 (fr) 2020-06-15 2021-06-15 Composition pharmaceutique

Country Status (3)

Country Link
JP (1) JP2023529499A (fr)
KR (1) KR102441089B1 (fr)
WO (1) WO2021256844A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007015270A2 (fr) * 2005-08-02 2007-02-08 Lupin Limited Nouvelles compositions a liberation controlee a base d'inhibiteurs selectifs de la recapture de la serotonine
WO2009135646A2 (fr) * 2008-05-05 2009-11-12 Farmaprojects, Sa Compositions pharmaceutiques stables et procédés de préparation desdites compositions adaptés à l’échelle industrielle
US20100215740A1 (en) * 2007-10-10 2010-08-26 Rubicon Research Private Limited Taste-masked orally disintegrating tablets of memantine hydrochloride
US20110196032A1 (en) * 2005-05-20 2011-08-11 Ashish Gogia Pharmaceutical Dosage Form of an Antidepressant
US20160008375A1 (en) * 2013-03-01 2016-01-14 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical formulations comprising quetiapine and escitalopram

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8814057D0 (en) 1988-06-14 1988-07-20 Lundbeck & Co As H New enantiomers & their isolation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110196032A1 (en) * 2005-05-20 2011-08-11 Ashish Gogia Pharmaceutical Dosage Form of an Antidepressant
WO2007015270A2 (fr) * 2005-08-02 2007-02-08 Lupin Limited Nouvelles compositions a liberation controlee a base d'inhibiteurs selectifs de la recapture de la serotonine
US20100215740A1 (en) * 2007-10-10 2010-08-26 Rubicon Research Private Limited Taste-masked orally disintegrating tablets of memantine hydrochloride
WO2009135646A2 (fr) * 2008-05-05 2009-11-12 Farmaprojects, Sa Compositions pharmaceutiques stables et procédés de préparation desdites compositions adaptés à l’échelle industrielle
US20160008375A1 (en) * 2013-03-01 2016-01-14 Sanovel Ilac Sanayi Ve Ticaret A.S. Pharmaceutical formulations comprising quetiapine and escitalopram

Also Published As

Publication number Publication date
JP2023529499A (ja) 2023-07-10
KR102441089B1 (ko) 2022-09-07
KR20210155447A (ko) 2021-12-23

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