WO2018216933A1 - Composition pharmaceutique contenant du bazedoxifène ou un sel pharmaceutiquement acceptable de celui-ci - Google Patents

Composition pharmaceutique contenant du bazedoxifène ou un sel pharmaceutiquement acceptable de celui-ci Download PDF

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Publication number
WO2018216933A1
WO2018216933A1 PCT/KR2018/005470 KR2018005470W WO2018216933A1 WO 2018216933 A1 WO2018216933 A1 WO 2018216933A1 KR 2018005470 W KR2018005470 W KR 2018005470W WO 2018216933 A1 WO2018216933 A1 WO 2018216933A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
tablet
sodium
bazedoxifen
composition according
Prior art date
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PCT/KR2018/005470
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English (en)
Korean (ko)
Inventor
박영준
김주은
최숙
임서은
Original Assignee
(주)아이엠디팜
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Publication of WO2018216933A1 publication Critical patent/WO2018216933A1/fr

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Classifications

    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • 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
    • 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
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient apeldoxifen or a pharmaceutically acceptable salt thereof and optionally a vitamin D derivative. More specifically, the present invention relates to a pharmaceutical composition comprising apeledoxifen or a pharmaceutically acceptable salt thereof (and optionally a vitamin D derivative) as an active ingredient and a basic amino acid as a stabilizer and not containing an antioxidant. It is about.
  • Bazedoxifene has the chemical name 1- [4- (2-Azepan-1-yl-ethoxy) -benzyl] -2- (4-hydroxy-phenyl) -3-methyl-1H-indole As -5-ol, it is known as a selective estrogen receptor modulator.
  • Bazedoxifene in the form of an acetate, has been used for the treatment of osteoporosis in postmenopausal women [Viviant Tablet TM (Pfizer).
  • Viviant Tablet TM contains ascorbic acid to ensure the stability of Badoxifene Acetate, but has a short shelf life of 18 months due to its low stability.
  • Korean Patent Registration No. 10-1584674 discloses a non-aqueous pharmaceutical composition and a method for preparing a non-aqueous pharmaceutical composition containing 15% by weight or less of an antioxidant such as ascorbic acid, without including a surfactant. .
  • U.S. Patent Publication No. US2011 / 0165241 discloses that a tablet composition containing apeledoxifen acetate, ascorbic acid, and hydroxypropylmethylcellulose has a problem of deterioration in dissolution stability upon long term storage. It is starting. US 2011/0165241 discloses the use of vitamin E, vitamin E TPGS, propyl gallate, citric acid or butylated hydroxyanisole / butylated hydroxytoluene in place of ascorbic acid. It has been disclosed.
  • Korean Patent Publication No. 10-2007-0018900 discloses a solid dispersion containing apeledoxifen acetate for improving bioavailability.
  • solid preparations containing adoxifen or its pharmaceutically acceptable salts are stored without the use of stabilizers such as antioxidants, they are soluble in only two weeks under severe conditions (60 ° C, 75% RH). The substance will be out of reference.
  • solid preparations containing apeledoxifen or its pharmaceutically acceptable salts together with stabilizers such as antioxidants also have relatively low stability (i.e., a short shelf life of 18 months), allowing for long term storage. There is a need in the art for the development of pharmaceutical compositions having improved stability.
  • the inventors have conducted various studies to develop solid preparations comprising Bazedoxifen or its pharmaceutically acceptable salts with improved stability.
  • the inventors have conducted various studies to develop a formulation that can improve stability by minimizing the generation of a flexible substance derived from apeledoxifen for a long time.
  • a specific stabilizer that is, a basic amino acid is used as a stabilizer
  • antioxidants such as ascorbic acid, vitamin E, and butylated hydroxytoluene
  • a softener derived from apeledoxifen is generated. It was found that can be significantly lowered. It has also been found that even in preparations containing additional vitamin D derivatives for osteoporosis patients with insufficient vitamin D intake, basic amino acids can significantly reduce the generation of analogues derived from apeledoxifen.
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof (and optionally a vitamin D derivative) and a basic amino acid as a stabilizer and without an antioxidant.
  • the pharmaceutical composition of the present invention is the active ingredient colecalciferol (colecalciferol), calcitriol (calcitriol), calcipotriol (calcipotriol), tacalcitol (maxacalcitol), maxacalcitol (paricalcitol), paricalcitol ), And at least one vitamin D derivative selected from the group consisting of seocalcitol.
  • the pharmaceutically acceptable salt of apeledoxifen may be apeledoxifen acetate, and the vitamin D derivative may be cholecalciferol.
  • the basic amino acid may be at least one selected from the group consisting of histidine, arginine, and lysine, preferably histidine.
  • the basic amino acid may be present in the range of 0.1 to 20.0% by weight, preferably 0.5 to 5% by weight, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention is lactose, mannitol, isomalt, microcrystalline cellulose, dextran, maltodextrin, sorbitol, glucose, pregelatinized starch, potato starch, corn starch, hard silicic anhydride, colloidal silicon dioxide, crystalline cellulose, phosphoric anhydride Diluents selected from the group consisting of calcium, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, and magnesium aluminum silicate; Disintegrating agents selected from the group consisting of starch, pregelatinized starch, sodium starch glycolate, sodium croscarmellose sodium, crospovidone, calcium carboxymethylcellulose, sodium carboxymethylcellulose, alginic acid, and sodium alginate; And sodium stearyl fumarate, colloidal silicon dioxide, silica, stearic acid or salts thereof, talc, magnesium / aluminum silicate, glyceryl bihenate, hard castor oil, vegetable castor oil
  • the pharmaceutical composition of the present invention is 22.6 mg of apeldoxifen acetate per tablet, 10.0 to 90.0 mg pregelatinized starch, 26.4 to 199.4 mg microcrystalline cellulose, 1.0 to 15.0 mg colloidal silicon dioxide, 15.0 to lactose hydrate
  • a pharmaceutical composition in the form of a tablet comprising 131.1 mg, histidine 0.5-20.0 mg, sodium starch glycolate 3.0-26.0 mg, and 2.0-15.0 mg sodium stearyl fumarate, preferably a film containing polyvinyl alcohol
  • the coating layer may be a pharmaceutical composition in a coating-tablet form, formed on the tablet.
  • the pharmaceutical composition of the present invention contains 22.6 mg of apeldoxifen acetate per tablet, 800-5600 IU cholecalciferol, 10.0-90.0 mg pregelatinized starch, 26.38-199.38 mg microcrystalline cellulose, colloidal silicon dioxide It may be a pharmaceutical composition in the form of a tablet, comprising 1.0 to 15.0 mg, lactose hydrate 15.0 to 118.0 mg, histidine 0.5 to 20.0 mg, sodium starch glycolate 3.0 to 26.0 mg, sodium stearyl fumarate 2.0 to 15.0 mg, preferably May be a pharmaceutical composition in the form of a tablet- tablet, wherein a film coating layer containing polyvinyl alcohol is formed on the tablet.
  • antioxidants such as ascorbic acid, vitamin E, and butylated hydroxytoluene
  • certain stabilizers i.e., basic amino acids
  • it can lower.
  • basic amino acids can significantly lower the generation of analogues derived from apeledoxifen.
  • a single agent comprising apeldoxifen or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient and apeledoxifen or a pharmaceutically acceptable salt thereof and a vitamin D derivative thereof according to the present invention are active ingredients Co-formulations, including as having excellent stability, can be usefully used for a long time.
  • the present invention provides an active ingredient as apeldoxifen or a pharmaceutically acceptable salt thereof; And a basic amino acid as a stabilizer and no antioxidant.
  • the pharmaceutical composition of the present invention is the active ingredient colecalciferol (colecalciferol), calcitriol (calcitriol), calcipotriol (calcipotriol), tacalcitol (tacalcitol), maxacalcitol (paracalcitol), paricalcitol (paricalcitol), and at least one vitamin D derivative selected from the group consisting of seocalcitol.
  • the pharmaceutically acceptable salt of apeledoxifen may be, but is not limited to, apeledoxifen acetate.
  • Bazedoxifen or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount, for example as apeledoxifen per unit formulation, in the range of 1-100 mg, preferably in the range of 10-30 mg More preferably about 20 mg (about 22.6 mg as apeledoxifen acetate).
  • the vitamin D derivative may be preferably cholecalciferol.
  • Vitamin D derivatives such as cholecalciferol may be used in therapeutically effective amounts, for example in the range of 50-5,600 IU, preferably 400-2,000 IU per unit preparation.
  • About 800 IU of cholecalciferol has a mass of about 0.02 to 8 mg depending on the titer (40,000,000 IU / g to 100,000 IU / g) per gram of cholecalciferol.
  • compositions of the present invention may be prepared by the antioxidants used in the prior art [eg, ascorbic acid or salts thereof (eg, sodium salt, palmitate), vitamin E, propylgallate, butylated hydroxytoluene (BHT ), Butylated hydroxyanisole (BHA) and the like, instead of the basic amino acid containing a stabilizer, it is possible to significantly reduce the generation of a flexible substance derived from apeledoxifen. As shown in the following test examples, preparations containing basic amino acids such as histidine as stabilizers can minimize the generation of analogues for long periods (eg, about 4 weeks) even under harsh conditions (60 ° C., 75% RH). And thus shows excellent stability.
  • antioxidants used in the prior art eg, ascorbic acid or salts thereof (eg, sodium salt, palmitate), vitamin E, propylgallate, butylated hydroxytoluene (BHT ), Butylated hydroxyanisole (BHA) and the like,
  • the basic amino acid may be at least one selected from the group consisting of histidine, arginine, and lysine, preferably histidine.
  • the basic amino acid may be present in the range of 0.1 to 20.0% by weight, preferably 0.5 to 5% by weight, based on the total weight of the composition.
  • the pharmaceutical composition of the present invention may include additives such as diluents, disintegrants, glidants and the like commonly used in the pharmaceutical field.
  • diluents include lactose (including hydrates such as lactose hydrate), mannitol, isomalt, microcrystalline cellulose, dextran, maltodextrin, sorbitol, glucose, pregelatinized starch, potato starch, corn starch, hard silicic anhydride, colloidal Silicon dioxide, crystalline cellulose, anhydrous calcium phosphate, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl cellulose, magnesium aluminum silicate and the like.
  • disintegrants examples include starch, pregelatinized starch, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, alginic acid, sodium alginate and the like.
  • examples of such lubricants include sodium stearyl fumarate, colloidal silicon dioxide, silica, stearic acid or salts thereof, talc, magnesium / aluminum silicate, glyceryl bihenate, hard castor oil, vegetable castor oil, polyethylene glycol, glyceryl monostea Latex, sucrose stearic acid ester, and the like.
  • the pharmaceutical composition of the present invention may be a combination of lactose and microcrystalline cellulose as a diluent; Combination of pregelatinized starch and sodium starch glycolate as disintegrant;
  • the lubricant may preferably include a combination of sodium stearyl fumarate and colloidal silicon dioxide.
  • the amount of the additives such as diluents, disintegrants, lubricants, and the like is not particularly limited and may be appropriately selected by those skilled in the art.
  • the diluent is in the range of 30 to 90% by weight relative to the total weight of the composition
  • the disintegrant is in the range of 1 to 20% by weight relative to the total weight of the composition
  • the lubricant is in the range of 0.5 to 5% by weight relative to the total weight of the composition. It may be used as, but is not limited thereto.
  • compositions of the present invention may be in solid dosage forms such as powders, granules, capsules, tablets, etc., preferably in the form of capsules or tablets, more preferably in the form of tablets.
  • pharmaceutical composition of the present invention may be in a film-refining form, for example, a film coating layer formed of a film coating base containing polyvinyl alcohol (for example, Opadry TM 85F42129 (Colorcon)). It may be in the form of a tablet.
  • the pharmaceutical composition of the present invention is 22.6 mg of apeldoxifen acetate per tablet, 10.0 to 90.0 mg pregelatinized starch, 26.4 to 199.4 mg microcrystalline cellulose, 1.0 to 15.0 mg colloidal silicon dioxide, 15.0 to lactose hydrate
  • a pharmaceutical composition in the form of a tablet comprising 131.1 mg, histidine 0.5-20.0 mg, sodium starch glycolate 3.0-26.0 mg, and 2.0-15.0 mg sodium stearyl fumarate, preferably a film containing polyvinyl alcohol
  • the coating layer may be a pharmaceutical composition in a coating-tablet form, formed on the tablet.
  • the pharmaceutical composition of the present invention contains 22.6 mg of apeldoxifen acetate per tablet, 800-5600 IU cholecalciferol, 10.0-90.0 mg pregelatinized starch, 26.38-199.38 mg microcrystalline cellulose, colloidal silicon dioxide It may be a pharmaceutical composition in the form of a tablet, comprising 1.0 to 15.0 mg, lactose hydrate 15.0 to 118.0 mg, histidine 0.5 to 20.0 mg, sodium starch glycolate 3.0 to 26.0 mg, sodium stearyl fumarate 2.0 to 15.0 mg, preferably May be a pharmaceutical composition in the form of a tablet- tablet, wherein a film coating layer containing polyvinyl alcohol is formed on the tablet.
  • the method for preparing a pharmaceutical composition of the present invention comprises the steps of mixing the apeledoxifen or pharmaceutically acceptable salts (and optionally vitamin D derivatives), basic amino acids, and pharmaceutically acceptable additives thereof; And filling the obtained mixture into capsules to obtain capsules or tableting the obtained mixture to obtain tablets.
  • the method may further include forming a film coating layer with a film coating base (eg, Opadry TM 85F42129 (Kalcon Co.), etc.) containing polyvinyl alcohol as necessary.
  • the mixing may be performed through a single mixing process of all the components or through a plurality of mixing processes of mixing some components and then mixing the remaining components.
  • the mixing process, capsule filling process, tableting process, film coating process and the like can be carried out according to conventional methods known in the field of formulations.
  • a tablet containing acetate was prepared.
  • the content of each component in Table 1 represents the content of refined sugar (mg).
  • Bazedoxifen acetate (22.6 mg per tablet, 20 mg as apeldoxifen), colloidal silicon dioxide and histidine were mixed, followed by addition of microcrystalline cellulose, pregelatinized starch, sodium starch glycolate and mixed.
  • the resulting mixture was sized in a 30 mesh sieve, and then further added lactose hydrate and mixed.
  • Sodium stearyl fumarate was mixed with the obtained mixture.
  • the resulting mixture was compressed to prepare 290 mg of tablet.
  • the tablets thus obtained were coated with Opadry TM 85F42129 (Kalcon Co.) to prepare film coated tablets.
  • Tablets containing Bazedoxifen acetate and cholecalciferol powder were prepared according to the contents and compositions of Table 2 below.
  • the content of each component in Table 2 represents the content of refined sugar (mg).
  • cholecalciferol and microcrystalline cellulose approximately 9.0% by weight of total usage
  • additional added cholecalciferol and microcrystalline cellulose (approximately 9.0% by weight of total usage)
  • cholecalciferol and microcrystalline cellulose approximately 9.0% by weight of total usage
  • microcrystalline cellulose about 91.0% by weight of the total amount used
  • pregelatinized starch and sodium starch glycolate were further added and mixed.
  • the resulting mixture was sized in a 30 mesh sieve and then mixed with lactose hydrate.
  • Sodium stearyl fumarate was mixed with the obtained mixture.
  • the resulting mixture was compressed to prepare 290 mg of tablet.
  • the tablets thus obtained were coated with Opadry TM 85F42129 (Kalcon) to prepare
  • Tablets containing Bazedoxifen acetate and cholecalciferol powder were prepared according to the content and composition of Table 3 below.
  • the content of each component in Table 3 represents the content of refined sugar (mg).
  • Bazedoxifene acetate (22.6 mg per tablet, 20 mg as chili, tartarate), colloidal silicon dioxide and histidine were added and mixed, followed by mixing with concentrated cholecalciferol (8.0 mg per tablet, 800 IU as vitamin D3). Thereafter, microcrystalline cellulose, pregelatinized starch and sodium starch glycolate were further added and mixed. The resulting mixture was sized in a 30 mesh sieve and then mixed with lactose hydrate. Sodium stearyl fumarate was mixed with the obtained mixture. The resulting mixture was compressed to prepare 290 mg of tablet.
  • the tablets thus obtained were coated with Opadry TM 85F42129 (Kalcon Co.) to prepare film coated tablets.
  • Photodiode array (wavelength: 200 ⁇ 350 nm)
  • Example 1-1 exhibited significantly lower formation of analogues, whereas they did not contain amino alcohols, inorganic salts, or antioxidants or contained stabilizers. All of the tablets of the Comparative Examples which did not show the production of high analog. Therefore, it can be seen that the tablets obtained according to the present invention exhibit excellent stability by minimizing the formation of analogues.
  • the tablets of Example 2-1 like the tablets of Example 1-1, showed a significantly lower amount of analogues, whereas amino alcohols, inorganic salts, or antioxidants.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique ne contenant pas d'antioxydant mais contenant : comme principe actif, du bazedoxifène ou un sel pharmaceutiquement acceptable de celui-ci (et de façon sélective, un dérivé de vitamine D); et un acide aminé basique comme agent stabilisant. La composition pharmaceutique selon l'invention présente une excellente stabilité par l'abaissement remarquable de la production d'une substance associée issue du bazedoxifène, ce qui rend la composition utile pendant une longue durée.
PCT/KR2018/005470 2017-05-24 2018-05-14 Composition pharmaceutique contenant du bazedoxifène ou un sel pharmaceutiquement acceptable de celui-ci WO2018216933A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2017-0063942 2017-05-24
KR1020170063942A KR101940569B1 (ko) 2017-05-24 2017-05-24 바제독시펜 또는 이의 약학적으로 허용가능한 염을 포함하는 약학 조성물

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WO2018216933A1 true WO2018216933A1 (fr) 2018-11-29

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050010886A (ko) * 2002-06-13 2005-01-28 와이어쓰 바제독시펜 치료 방식
KR20100113627A (ko) * 2008-02-11 2010-10-21 와이어쓰 엘엘씨 바제독시펜 아세테이트의 다형체 형태 ａ의 제조방법
KR20140088917A (ko) * 2005-08-24 2014-07-11 와이어쓰 엘엘씨 바제독시펜 아세테이트 제형 및 이의 제조방법
CN104013630A (zh) * 2014-05-23 2014-09-03 合肥九研医药科技开发有限公司 一种复方醋酸巴多昔芬雌激素组合物
KR20170029141A (ko) * 2015-09-07 2017-03-15 주식회사 경보제약 고순도 바제독시펜 아세테이트의 제조방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050010886A (ko) * 2002-06-13 2005-01-28 와이어쓰 바제독시펜 치료 방식
KR20140088917A (ko) * 2005-08-24 2014-07-11 와이어쓰 엘엘씨 바제독시펜 아세테이트 제형 및 이의 제조방법
KR20100113627A (ko) * 2008-02-11 2010-10-21 와이어쓰 엘엘씨 바제독시펜 아세테이트의 다형체 형태 ａ의 제조방법
CN104013630A (zh) * 2014-05-23 2014-09-03 合肥九研医药科技开发有限公司 一种复方醋酸巴多昔芬雌激素组合物
KR20170029141A (ko) * 2015-09-07 2017-03-15 주식회사 경보제약 고순도 바제독시펜 아세테이트의 제조방법

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KR20180128612A (ko) 2018-12-04

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