WO2018216933A1 - Pharmaceutical composition containing bazedoxifene or pharmaceutically acceptable salt - Google Patents

Pharmaceutical composition containing bazedoxifene or pharmaceutically acceptable salt 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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Prior art keywords
pharmaceutical composition
tablet
sodium
bazedoxifen
composition according
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PCT/KR2018/005470
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French (fr)
Korean (ko)
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박영준
김주은
최숙
임서은
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(주)아이엠디팜
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Publication of WO2018216933A1 publication Critical patent/WO2018216933A1/en

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    • 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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Abstract

The present invention provides a pharmaceutical composition not containing an antioxidant, but containing: as an active ingredient, bazedoxifene or a pharmaceutically acceptable salt thereof (and selectively, a vitamin D derivative); and a basic amino acid as a stabilizing agent. The pharmaceutical composition of the present invention has excellent stability by remarkably lowering the generation of an associated substance derived from bazedoxifene, thereby being useful for a long period of time.

Description

바제독시펜 또는 이의 약학적으로 허용가능한 염을 포함하는 약학 조성물Pharmaceutical composition comprising bazedoxifen or a pharmaceutically acceptable salt thereof
본 발명은 활성성분으로서 바제독시펜 또는 이의 약학적으로 허용가능한 염 및 선택적으로 비타민 D 유도체를 포함하는 약학 조성물에 관한 것이다. 더욱 상세하게는, 본 발명은 활성성분으로서 바제독시펜 또는 이의 약학적으로 허용가능한 염(및 선택적으로 비타민 D 유도체) 및 안정화제로서 염기성 아미노산을 포함하고, 항산화제를 포함하지 않는 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition comprising as active ingredient bazedoxifen or a pharmaceutically acceptable salt thereof and optionally a vitamin D derivative. More specifically, the present invention relates to a pharmaceutical composition comprising bazedoxifen 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.
바제독시펜(bazedoxifene)은 화학명이 1-[4-(2-아제판-1-일-에톡시)-벤질]-2-(4-하이드록시-페닐)-3-메틸-1H-인돌-5-올로서, 선택적 에스트로겐 수용체 조절제로 알려져 있다. 바제독시펜은 아세트산염의 형태로, 폐경 후 여성의 골다공증 치료를 위해 사용되고 있다[비비안트정TM (한국화이자제약)]. 비비안트정TM은 바제독시펜 아세트산염의 안정성 확보를 위해 아스코르브산을 함유하고 있으나, 낮은 안정성으로 인해 18개월의 다소 짧은 사용기간을 지니고 있다. 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.
대한민국 특허등록 제10-1584674호(WO 2007/024961)는 계면활성제는 포함하지 않고, 아스코르브산 등의 항산화제를 15 중량% 이하로 함유하는 비-수성 약제학적 조성물 및 제조방법을 개시한 바 있다. Korean Patent Registration No. 10-1584674 (WO 2007/024961) 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. .
또한, 미국 특허공개 제US2011/0165241호는 바제독시펜 아세트산염, 아스코르브산, 및 히드록시프로필메틸셀룰로오스를 함유하는 정제 조성물이 장기간 저장시 용출 안정성(dissolution stability)의 저하를 나타내는 문제가 있음을 개시하고 있다. 미국 특허공개 제US2011/0165241호는 상기 문제를 해결하기 위한 수단으로서, 아스코르브산 대신에 비타민 E, 비타민 E TPGS, 프로필갈레이트, 구연산 또는 부틸화히드록시아니솔/부틸화히드록시톨루엔의 사용을 개시한 바 있다. In addition, U.S. Patent Publication No. US2011 / 0165241 discloses that a tablet composition containing bazedoxifen 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.
기타, 대한민국 특허공개 제10-2007-0018900호(국제특허공개 제WO 2005/099677호)는 생체이용률 개선을 위한 바제독시펜 아세트산염을 함유하는 고체분산체를 개시한 바 있다.In addition, Korean Patent Publication No. 10-2007-0018900 (WO 2005/099677) discloses a solid dispersion containing bazedoxifen acetate for improving bioavailability.
그러나, 바제독시펜 또는 이의 약학적으로 허용가능한 염을 함유하는 고형 제제를 항산화제 등의 안정화제를 사용하지 않고 보관할 경우, 가혹조건(60℃, 75%RH)에서 단 2주간만에 유연물질이 기준치를 벗어나게 된다. 또한, 항산화제 등의 안정화제와 함께 바제독시펜 또는 이의 약학적으로 허용가능한 염을 함유하는 고형 제제 또한 상대적으로 낮은 안정성(즉, 18개월의 짧은 사용기간)을 가지므로, 장기간 보관을 가능하도록 하는 개선된 안정성을 갖는 약학 조성물의 개발이 당업계에 요구된다.However, when solid preparations containing bazedoxifen 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. In addition, solid preparations containing bazedoxifen 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.
본 발명자들은 안정성이 개선된 바제독시펜 또는 이의 약학적으로 허용가능한 염을 포함하는 고형 제제를 개발하기 위하여 다양한 연구를 수행하였다. 특히, 본 발명자들은 장기간 동안 바제독시펜 유래의 유연물질 발생을 최소화함으로써 안정성을 개선할 수 있는 제제를 개발하기 위하여 다양한 연구를 수행하였다. 그 결과, 안정화제로서 종래에 사용된 아스코르브산, 비타민 E, 부틸화히드록시톨루엔 등의 항산화제 대신에, 특정 안정화제 즉, 염기성 아미노산을 안정화제로서 사용할 경우 바제독시펜 유래의 유연물질 발생을 현저하게 낮출 수 있음을 발견하였다. 또한, 비타민 D 섭취가 불충분한 골다공증 환자를 위해 비타민 D 유도체를 추가로 함유하는 제제에 있어서도, 염기성 아미노산이 바제독시펜 유래의 유연물질 발생을 현저하게 낮출 수 있음을 발견하였다.The inventors have conducted various studies to develop solid preparations comprising Bazedoxifen or its pharmaceutically acceptable salts with improved stability. In particular, the inventors have conducted various studies to develop a formulation that can improve stability by minimizing the generation of a flexible substance derived from bazedoxifen for a long time. As a result, when a specific stabilizer, that is, a basic amino acid is used as a stabilizer, in place of conventionally used antioxidants such as ascorbic acid, vitamin E, and butylated hydroxytoluene, a softener derived from bazedoxifen 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 bazedoxifen.
따라서, 본 발명은 바제독시펜 또는 이의 약학적으로 허용가능한 염(및 선택적으로 비타민 D 유도체) 및 안정화제로서 염기성 아미노산을 포함하고, 항산화제를 포함하지 않는 약학 조성물을 제공하는 것을 목적으로 한다.Accordingly, it is an object of the present invention to provide a pharmaceutical composition comprising bazedoxifen or a pharmaceutically acceptable salt thereof (and optionally a vitamin D derivative) and a basic amino acid as a stabilizer and without an antioxidant. .
본 발명의 일 태양에 따라, 활성성분으로서 바제독시펜 또는 이의 약학적으로 허용가능한 염; 및 안정화제로서 염기성 아미노산을 포함하고, 항산화제를 포함하지 않는 약학 조성물이 제공된다.According to one aspect of the invention, as active ingredient bazedoxifen or a pharmaceutically acceptable salt thereof; And a basic amino acid as a stabilizer and no antioxidant.
본 발명의 약학 조성물은 활성성분으로서 콜레칼시페롤(colecalciferol), 칼시트리올(calcitriol), 칼시포트리올(calcipotriol), 타칼시톨(tacalcitol), 막사칼시톨(maxacalcitol), 파리칼시톨(paricalcitol), 및 세오칼시톨(seocalcitol)로 이루어진 군으로부터 1종 이상 선택된 비타민 D 유도체를 추가로 포함할 수 있다.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.
본 발명의 약학 조성물에 있어서, 상기 바제독시펜의 약학적으로 허용가능한 염은 바제독시펜 아세트산염일 수 있으며, 상기 비타민 D 유도체는 콜레칼시페롤일 수 있다.In the pharmaceutical composition of the present invention, the pharmaceutically acceptable salt of bazedoxifen may be bazedoxifen acetate, and the vitamin D derivative may be cholecalciferol.
본 발명의 약학 조성물에 있어서, 상기 염기성 아미노산은 히스티딘, 아르기닌, 및 라이신으로 이루어진 군으로부터 1종 이상 선택될 수 있으며, 바람직하게는 히스티딘일 수 있다. 상기 염기성 아미노산은 조성물 총 중량에 대하여 0.1 ∼ 20.0 중량%의 범위, 바람직하게는 0.5 ∼ 5 중량%의 범위로 존재할 수 있다.In the pharmaceutical composition of the present invention, 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.
본 발명의 약학 조성물은 유당, 만니톨, 이소말트, 미결정 셀룰로오스, 덱스트란, 말토덱스트린, 솔비톨, 포도당, 전호화전분, 감자전분, 옥수수전분, 경질무수규산, 콜로이드성 이산화규소, 결정 셀룰로오스, 무수인산칼슘, 카복시메틸 셀룰로오스, 카복시에틸 셀룰로오스, 하이드록시에틸 셀룰로오스, 및 마그네슘 알루미늄 실리케이트로 이루어진 군으로부터 1종 이상 선택된 희석제; 전분, 전호화 전분, 전분글리콜산나트륨, 크로스카멜로스 나트륨, 크로스포비돈, 카르복시메틸셀룰로오스 칼슘, 카르복시메틸셀룰로오스 나트륨, 알긴산, 및 알긴산나트륨으로 이루어진 군으로부터 1종 이상 선택된 붕해제; 및 푸마르산스테아릴나트륨, 콜로이드성 이산화규소, 실리카, 스테아린산 또는 이의 염, 탈크, 마그네슘/알루미늄실리케이트, 글리세릴 비헤네이트, 경질 피마자유, 식물성 피마자유, 폴리에틸렌글리콜, 글리세릴 모노스테아레이트, 및 자당 스테아린산 에스테르로 이루어진 군으로부터 1종 이상 선택된 활택제를 추가로 포함할 수 있다. 예를 들어, 본 발명의 약학 조성물은 정제의 형태를 가질 수 있으며, 상기 정제는 추가로 필름코팅될 수 있다.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, polyethylene glycol, glyceryl monostearate, and sucrose stearic acid It may further comprise a glidant selected from the group consisting of esters. For example, the pharmaceutical composition of the present invention may have the form of a tablet, which tablet may be further film coated.
일 구현예에서, 본 발명의 약학 조성물은 1정당 바제독시펜 아세트산염 22.6 mg, 전호화 전분 10.0 내지 90.0 mg, 미결정 셀룰로오스 26.4 내지 199.4 mg, 콜로이드성 이산화규소 1.0 내지 15.0 mg, 유당 수화물 15.0 내지 131.1 mg, 히스티딘 0.5 내지 20.0 mg, 전분글리콜산나트륨 3.0 내지 26.0 mg, 및 푸마르산스테아릴나트륨 2.0 내지 15.0 mg을 포함하는, 정제 형태의 약학 조성물일 수 있으며, 바람직하게는 폴리비닐알코올을 함유하는 필름코팅층이 상기 정제 상에 형성된, 제피-정제 형태의 약학 조성물일 수 있다.In one embodiment, the pharmaceutical composition of the present invention is 22.6 mg of bazedoxifen 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.
다른 구현예에서, 본 발명의 약학 조성물은 1정당 바제독시펜 아세트산염 22.6 mg, 콜레칼시페롤 800 내지 5600 IU, 전호화 전분 10.0 내지 90.0 mg, 미결정 셀룰로오스 26.38 내지 199.38 mg, 콜로이드성 이산화규소 1.0 내지 15.0 mg, 유당 수화물 15.0 내지 118.0 mg, 히스티딘 0.5 내지 20.0 mg, 전분글리콜산나트륨 3.0 내지 26.0 mg, 푸마르산스테아릴나트륨 2.0 내지 15.0 mg을 포함하는, 정제 형태의 약학 조성물일 수 있으며, 바람직하게는 폴리비닐알코올을 함유하는 필름코팅층이 상기 정제 상에 형성된, 제피-정제 형태의 약학 조성물일 수 있다.In another embodiment, the pharmaceutical composition of the present invention contains 22.6 mg of bazedoxifen 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.
안정화제로서 종래에 사용된 아스코르브산, 비타민 E, 부틸화히드록시톨루엔 등의 항산화제 대신에, 특정 안정화제 즉, 염기성 아미노산을 안정화제로서 사용할 경우 바제독시펜 유래의 유연물질 발생을 현저하게 낮출 수 있다는 것이 본 발명에 의해 밝혀졌다. 또한, 비타민 D 유도체를 추가로 함유하는 제제에 있어서도, 염기성 아미노산이 바제독시펜 유래의 유연물질 발생을 현저하게 낮출 수 있다는 것이 본 발명에 의해 밝혀졌다. 따라서, 본 발명에 따른 바제독시펜 또는 이의 약학적으로 허용가능한 염을 활성성분으로서 포함하는 단일제제 및 본 발명에 따른 바제독시펜 또는 이의 약학적으로 허용가능한 염 및 비타민 D 유도체를 활성성분으로서 포함하는 복합제제는 우수한 안정성을 가짐으로써, 장기간 동안 유용하게 사용될 수 있다.Instead of antioxidants such as ascorbic acid, vitamin E, and butylated hydroxytoluene, which are conventionally used as stabilizers, the use of certain stabilizers, i.e., basic amino acids, as stabilizers significantly reduces the generation of analogues derived from bazedoxifen. It has been found by the present invention that it can lower. In addition, it has been found by the present invention that even in preparations containing additional vitamin D derivatives, basic amino acids can significantly lower the generation of analogues derived from bazedoxifen. Therefore, a single agent comprising bazedoxifen or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient and bazedoxifen 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.
본 발명은 활성성분으로서 바제독시펜 또는 이의 약학적으로 허용가능한 염; 및 안정화제로서 염기성 아미노산을 포함하고, 항산화제를 포함하지 않는 약학 조성물을 제공한다. The present invention provides an active ingredient as bazedoxifen or a pharmaceutically acceptable salt thereof; And a basic amino acid as a stabilizer and no antioxidant.
또한, 본 발명의 약학 조성물은 활성성분으로서 콜레칼시페롤(colecalciferol), 칼시트리올(calcitriol), 칼시포트리올(calcipotriol), 타칼시톨(tacalcitol), 막사칼시톨(maxacalcitol), 파리칼시톨(paricalcitol), 및 세오칼시톨(seocalcitol)로 이루어진 군으로부터 1종 이상 선택된 비타민 D 유도체를 추가로 포함할 수 있다.In addition, 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.
본 발명의 약학 조성물에 있어서, 바제독시펜의 약학적으로 허용가능한 염은 바제독시펜 아세트산염일 수 있으나, 이에 제한되는 것은 아니다. 바제독시펜 또는 이의 약학적으로 허용가능한 염은 치료학적으로 유효한 양으로 사용될 수 있으며, 예를 들어 단위 제제당 바제독시펜으로서 1∼100 mg의 범위, 바람직하게는 10∼30 mg의 범위, 더욱 바람직하게는 약 20 mg (바제독시펜 아세트산염으로서 약 22.6 mg)으로 사용될 수 있다. 또한, 상기 비타민 D 유도체는 바람직하게는 콜레칼시페롤일 수 있다. 콜레칼시페롤 등의 비타민 D 유도체는 치료학적으로 유효한 양으로 사용될 수 있으며, 예를 들어 단위 제제당 50∼5,600 IU의 범위, 바람직하게는 400∼2,000 IU의 범위로 사용될 수 있다. 약 800 IU의 콜레칼시페롤은 콜레칼시페롤의 단위 그램당 역가(40,000,000IU/g ∼ 100,000IU/g)에 따라 약 0.02∼8 mg의 질량을 갖는다.  In the pharmaceutical composition of the present invention, the pharmaceutically acceptable salt of bazedoxifen may be, but is not limited to, bazedoxifen acetate. Bazedoxifen or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount, for example as bazedoxifen 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 bazedoxifen acetate). In addition, 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.
본 발명의 약학 조성물은, 종래에 사용된 항산화제[예를 들어, 아스코르브산 또는 이의 염(예를 들어, 소듐염, 팔미트산염), 비타민 E, 프로필갈레이트, 부틸화하이드록시톨루엔(BHT), 부틸화하이드록시아니솔(BHA) 등] 대신에, 염기성 아미노산을 안정화제를 포함함으로써, 바제독시펜 유래의 유연물질 발생을 현저하게 낮출 수 있다. 하기 시험예에서 밝힌 바와 같이, 안정화제로서 히스티딘 등의 염기성 아미노산을 함유하는 제제는 가혹조건(60℃, 75%RH)에서도 장기간(예를 들어, 약 4주) 동안 유연물질의 발생을 최소화시킬 수 있으며, 따라서 우수한 안정성을 나타낸다. 상기 염기성 아미노산은 히스티딘, 아르기닌, 및 라이신으로 이루어진 군으로부터 1종 이상 선택될 수 있으며, 바람직하게는 히스티딘일 수 있다. 상기 염기성 아미노산은 조성물 총 중량에 대하여 0.1 ∼ 20.0 중량%의 범위, 바람직하게는 0.5 ∼ 5 중량%의 범위로 존재할 수 있다.The pharmaceutical 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 bazedoxifen. 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. 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.
본 발명의 약학 조성물은 제제학 분야에서 통상적으로 사용되는 희석제, 붕해제, 활택제 등의 첨가제를 포함할 수 있다. 상기 희석제의 예는 유당(유당 수화물과 같은 수화물을 포함), 만니톨, 이소말트, 미결정 셀룰로오스, 덱스트란, 말토덱스트린, 솔비톨, 포도당, 전호화전분, 감자전분, 옥수수전분, 경질무수규산, 콜로이드성 이산화규소, 결정 셀룰로오스, 무수인산칼슘, 카복시메틸 셀룰로오스, 카복시에틸 셀룰로오스, 하이드록시에틸 셀룰로오스, 및 마그네슘 알루미늄 실리케이트 등을 포함한다. 상기 붕해제의 예는 전분, 전호화 전분, 전분글리콜산나트륨, 크로스카멜로스 나트륨, 크로스포비돈, 카르복시메틸셀룰로오스 칼슘, 카르복시메틸셀룰로오스 나트륨, 알긴산, 알긴산나트륨 등을 포함한다. 상기 활택제의 예는 푸마르산스테아릴나트륨, 콜로이드성 이산화규소, 실리카, 스테아린산 또는 이의 염, 탈크, 마그네슘/알루미늄실리케이트, 글리세릴 비헤네이트, 경질 피마자유, 식물성 피마자유, 폴리에틸렌글리콜, 글리세릴 모노스테아레이트, 자당 스테아린산 에스테르(sucrose stearic acid ester) 등을 포함한다. 예를 들어, 본 발명의 약학 조성물은 희석제로서 유당 및 미결정 셀룰로오스의 조합; 붕해제로서 전호화 전분 및 전분글리콜산나트륨의 조합; 활택제로서 푸마르산스테아릴나트륨 및 콜로이드성 이산화규소의 조합을 바람직하게 포함할 수 있다. 상기 희석제, 붕해제, 활택제 등의 첨가제의 사용량은 특별히 제한되는 것은 아니며, 본 기술분야의 당업자에 의해 적절히 선택될 수 있다. 예를 들어, 희석제는 조성물 총 중량에 대하여 30 ∼ 90 중량%의 범위, 붕해제는 조성물 총 중량에 대하여 1 ∼ 20 중량%의 범위, 활택제는 조성물 총 중량에 대하여 0.5 ∼ 5 중량%의 범위로 사용될 수 있으나, 이에 제한되는 것은 아니다.The pharmaceutical composition of the present invention may include additives such as diluents, disintegrants, glidants and the like commonly used in the pharmaceutical field. Examples of such 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. Examples of such disintegrants 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. For example, 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. For example, 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, and 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.
본 발명의 약학 조성물은 산제, 과립제, 캡슐제, 정제 등의 고형 제형(solid dosage form)일 수 있으며, 바람직하게는 캡슐제 또는 정제의 형태이고, 더욱 바람직하게는 정제의 형태이다. 또한, 본 발명의 약학 조성물은 제피-정제 형태일 수 있으며, 예를 들어 폴리비닐알코올을 함유하는 필름코팅용 기제[예를 들어, 오파드라이TM 85F42129(칼라콘사) 등]로 필름코팅층이 형성된 제피-정제의 형태일 수 있다.The pharmaceutical 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. In addition, the 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.
일 구현예에서, 본 발명의 약학 조성물은 1정당 바제독시펜 아세트산염 22.6 mg, 전호화 전분 10.0 내지 90.0 mg, 미결정 셀룰로오스 26.4 내지 199.4 mg, 콜로이드성 이산화규소 1.0 내지 15.0 mg, 유당 수화물 15.0 내지 131.1 mg, 히스티딘 0.5 내지 20.0 mg, 전분글리콜산나트륨 3.0 내지 26.0 mg, 및 푸마르산스테아릴나트륨 2.0 내지 15.0 mg을 포함하는, 정제 형태의 약학 조성물 일 수 있으며, 바람직하게는 폴리비닐알코올을 함유하는 필름코팅층이 상기 정제 상에 형성된, 제피-정제 형태의 약학 조성물일 수 있다.In one embodiment, the pharmaceutical composition of the present invention is 22.6 mg of bazedoxifen 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.
다른 구현예에서, 본 발명의 약학 조성물은 1정당 바제독시펜 아세트산염 22.6 mg, 콜레칼시페롤 800 내지 5600 IU, 전호화 전분 10.0 내지 90.0 mg, 미결정 셀룰로오스 26.38 내지 199.38 mg, 콜로이드성 이산화규소 1.0 내지 15.0 mg, 유당 수화물 15.0 내지 118.0 mg, 히스티딘 0.5 내지 20.0 mg, 전분글리콜산나트륨 3.0 내지 26.0 mg, 푸마르산스테아릴나트륨 2.0 내지 15.0 mg을 포함하는, 정제 형태의 약학 조성물 일 수 있으며, 바람직하게는 폴리비닐알코올을 함유하는 필름코팅층이 상기 정제 상에 형성된, 제피-정제 형태의 약학 조성물일 수 있다.In another embodiment, the pharmaceutical composition of the present invention contains 22.6 mg of bazedoxifen 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.
본 발명의 약학 조성물의 제조방법은 바제독시펜 또는 이의 약학적으로 허용가능한 염(및 선택적으로 비타민 D 유도체), 염기성 아미노산, 및 약학적으로 허용가능한 첨가제를 혼합하는 단계; 및 얻어진 혼합물을 캡슐에 충진하여 캡슐제를 얻거나 혹은 얻어진 혼합물을 타정하여 정제를 얻는 단계를 포함할 수 있다. 또한, 상기한 바와 같이, 필요에 따라 폴리비닐알코올을 함유하는 필름코팅용 기제[예를 들어, 오파드라이TM 85F42129(칼라콘사) 등]로 필름코팅층을 형성시키는 단계를 추가로 포함할 수 있다. 상기 혼합은 모든 성분들을 1회의 혼합 공정을 통하여 수행되거나 혹은 일부의 성분들을 혼합한 후 나머지 성분들을 혼합하는 복수의 혼합 공정을 통하여 수행될 수 있다. 상기 혼합 공정, 캡슐 충진 공정, 타정 공정, 필름코팅 공정 등은 제제학 분야에 공지된 통상의 방법에 따라 수행될 수 있다.The method for preparing a pharmaceutical composition of the present invention comprises the steps of mixing the bazedoxifen 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. In addition, as described above, 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.
이하, 본 발명을 실시예 및 시험예를 통하여 더욱 상세히 설명한다. 그러나, 하기 실시예 및 시험예는 본 발명을 예시하기 위한 것으로, 본 발명이 이들에 의해 제한되는 것은 아니다.Hereinafter, the present invention will be described in more detail through Examples and Test Examples. However, the following examples and test examples are for illustrating the present invention, but the present invention is not limited thereto.
실시예 1. 바제독시펜 아세트산염을 함유하는 정제의 제조Example 1 Preparation of Tablets Containing Bazedoxifen Acetate
하기 표 1의 함량 및 조성에 따라 바제독시펜 아세트산염을 함유하는 정제를 제조하였다. 표 1의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 바제독시펜 아세트산염(정제당 22.6 mg, 바제독시펜으로서 20 mg), 콜로이드성 이산화규소 및 히스티딘을 혼합한 후, 미결정 셀룰로오스, 전호화 전분, 전분글리콜산나트륨을 추가로 넣고 혼합하였다. 얻어진 혼합물을 30 mesh 체로 정립한 다음, 유당 수화물을 추가로 넣고 혼합하였다. 얻어진 혼합물에 푸마르산스테아릴나트륨을 혼합하였다. 얻어진 혼합물을 타정하여 290 mg의 정제를 제조하였다. 얻어진 정제를 오파드라이TM 85F42129(칼라콘 사)로 코팅하여 필름코팅정을 제조하였다.According to the content and composition of Table 1 below, a tablet containing bazedoxifen 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 bazedoxifen), 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 ™ 85F42129 (Kalcon Co.) to prepare film coated tablets.
성분ingredient 실시예 (mg/정제)Example (mg / tablet)
1-11-1 1-21-2 1-31-3 1-41-4 1-51-5
바제독시펜 아세트산염Vasedoxifen Acetate 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6
전호화 전분Pregelatinized starch 45.045.0 45.045.0 10.010.0 90.090.0 90.090.0
미결정 셀룰로오스Microcrystalline cellulose 89.489.4 73.473.4 199.4199.4 26.426.4 26.426.4
콜로이드성 이산화규소Colloidal silicon dioxide 9.09.0 9.09.0 1.01.0 1.01.0 15.015.0
유당 수화물Lactose carb 90.090.0 90.090.0 15.015.0 122.5122.5 131.1131.1
히스티딘Histidine 5.05.0 20.020.0 5.05.0 0.50.5 0.50.5
전분글리콜산나트륨Sodium starch glycolate 21.021.0 21.021.0 26.026.0 3.03.0 3.03.0
푸마르산스테아릴나트륨Sodium stearyl fumarate 9.09.0 9.09.0 2.02.0 15.015.0 15.015.0
오파드라이TM 85F42129Opadry TM 85F42129 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
실시예Example 2.  2. 바제독시펜Bazedoksifen 아세트산염 및  Acetates and 콜레칼시페롤(40,000,000 IU/g)을Cholecalciferol (40,000,000 IU / g) 함유하는 정제의 제조 Preparation of containing tablet
하기 표 2의 함량 및 조성에 따라 바제독시펜 아세트산염과 콜레칼시페롤 분말(40,000,000 IU/g)을 함유하는 정제를 제조하였다. 표 2의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 콜레칼시페롤과 미결정 셀룰로오스(총 사용량의 약 9.0 중량%)를 혼합한 후, 바제독시펜 아세트산염(정제당 22.6 mg, 바제독시펜으로서 20 mg), 콜로이드성 이산화규소 및 히스티딘을 추가로 넣고 혼합한 다음, 미결정 셀룰로오스(총 사용량의 약 91.0 중량%), 전호화 전분, 전분글리콜산나트륨을 추가로 넣고 혼합하였다. 얻어진 혼합물을 30 mesh 체로 정립한 다음, 유당 수화물을 넣고 혼합하였다. 얻어진 혼합물에 푸마르산스테아릴나트륨을 혼합하였다. 얻어진 혼합물을 타정하여 290 mg의 정제를 제조하였다. 얻어진 정제를 오파드라이TM 85F42129(칼라콘 사)로 코팅하여 필름코팅정을 제조하였다.Tablets containing Bazedoxifen acetate and cholecalciferol powder (40,000,000 IU / g) 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). After mixing cholecalciferol and microcrystalline cellulose (approximately 9.0% by weight of total usage), additionally added bazedoxifen acetate (22.6 mg per tablet, 20 mg as bazedoxifen), colloidal silicon dioxide and histidine After adding and mixing, 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 ™ 85F42129 (Kalcon) to prepare a film coated tablet.
성분ingredient 실시예 (mg/정제)Example (mg / tablet)
2-12-1 2-22-2 2-32-3 2-42-4 2-52-5 2-62-6 2-72-7 2-82-8 2-92-9
바제독시펜 아세트산염Vasedoxifen Acetate 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6
콜레칼시페롤Cholecalciferol 0.020.02 0.020.02 0.020.02 0.040.04 0.080.08 0.140.14 8.08.0 0.020.02 0.020.02
전호화 전분Pregelatinized starch 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0 10.010.0 90.090.0
미결정 셀룰로오스Microcrystalline cellulose 89.3889.38 74.3874.38 88.3888.38 89.3689.36 89.3289.32 89.2689.26 88.488.4 199.38199.38 26.3826.38
콜로이드성 이산화규소Colloidal silicon dioxide 15.015.0 15.015.0 9.09.0 15.015.0 15.015.0 15.015.0 9.09.0 1.01.0 1.01.0
유당 수화물Lactose carb 85.085.0 85.085.0 90.090.0 85.085.0 85.085.0 85.085.0 82.082.0 15.015.0 118.0118.0
히스티딘Histidine 5.05.0 20.020.0 5.05.0 5.05.0 5.05.0 5.05.0 5.05.0 5.05.0 5.05.0
전분글리콜산나트륨Sodium starch glycolate 20.020.0 20.020.0 21.021.0 20.020.0 20.020.0 20.020.0 21.021.0 26.026.0 3.03.0
푸마르산스테아릴나트륨Sodium stearyl fumarate 8.08.0 8.08.0 9.09.0 8.08.0 8.08.0 8.08.0 9.09.0 2.02.0 15.015.0
오파드라이TM 85F42129Opadry TM 85F42129 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
실시예Example 3.  3. 바제독시펜Bazedoksifen 아세트산염 및  Acetates and 콜레칼시페롤(100,000 IU/g)을Cholecalciferol (100,000 IU / g) 함유하는 정제의 제조 Preparation of containing tablet
하기 표 3의 함량 및 조성에 따라 바제독시펜 아세트산염과 콜레칼시페롤 분말(100,000 IU/g)을 함유하는 정제를 제조하였다. 표 3의 각 성분의 함량은 정제당 함량(mg)을 나타낸다. 바제독시펜 아세트산염(정제당 22.6 mg, 바제독시펜으로서 20 mg), 콜로이드성 이산화규소 및 히스티딘을 넣고 혼합한 다음, 농축 콜레칼시페롤(정제당 8.0 mg, 비타민 D3로서 800IU)과 혼합한 후, 미결정 셀룰로오스, 전호화 전분, 전분글리콜산나트륨을 추가로 넣고 혼합하였다. 얻어진 혼합물을 30 mesh 체로 정립한 다음, 유당 수화물을 넣고 혼합하였다. 얻어진 혼합물에 푸마르산스테아릴나트륨을 혼합하였다. 얻어진 혼합물을 타정하여 290 mg의 정제를 제조하였다. 얻어진 정제를 오파드라이TM 85F42129(칼라콘 사)로 코팅하여 필름코팅정을 제조하였다.Tablets containing Bazedoxifen acetate and cholecalciferol powder (100,000 IU / g) 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 bazedoxifene), 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 ™ 85F42129 (Kalcon Co.) to prepare film coated tablets.
성분ingredient 실시예 (mg/정제)Example (mg / tablet)
3-13-1 3-23-2 3-33-3 3-43-4 3-53-5 3-63-6 3-73-7 3-83-8 3-93-9
바제독시펜 아세트산염Vasedoxifen Acetate 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6
콜레칼시페롤Cholecalciferol 8.08.0 8.08.0 16.016.0 32.032.0 40.040.0 50.050.0 56.056.0 0.50.5 4.04.0
전호화 전분Pregelatinized starch 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0
미결정 셀룰로오스Microcrystalline cellulose 88.488.4 73.473.4 80.480.4 64.464.4 56.456.4 46.446.4 40.440.4 88.488.4 88.488.4
콜로이드성 이산화규소Colloidal silicon dioxide 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
유당 수화물Lactose carb 82.082.0 82.082.0 82.082.0 82.082.0 82.082.0 82.082.0 82.082.0 89.589.5 86.086.0
히스티딘Histidine 5.05.0 20.020.0 5.05.0 5.05.0 5.05.0 5.05.0 5.05.0 5.05.0 5.05.0
전분글리콜산나트륨Sodium starch glycolate 21.021.0 21.021.0 21.021.0 21.021.0 21.021.0 21.021.0 21.021.0 21.021.0 21.021.0
푸마르산스테아릴나트륨Sodium stearyl fumarate 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
오파드라이TM 85F42129Opadry TM 85F42129 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
비교예Comparative example 1.  One. 바제독시펜Bazedoksifen 아세트산염을 함유하는 정제의 제조 Preparation of Tablets Containing Acetate
히스티딘 대신 아미노 알코올인 메글루민(비교예 1-1), 무기염인 탄산칼슘(비교예 1-2), 항산화제인 아스코르브산(비교예 1-3) 또는 부틸화히드록시톨루엔(비교예 1-4)을 사용한 것을 제외하고는, 실시예 1-1과 동일한 방법으로 바제독시펜 아세트산염을 함유하는 정제를 제조하였다. 또한, 비교를 위하여 히스티딘을 사용하지 않은 것을 제외하고는 실시예 1-1과 동일한 방법으로 바제독시펜 아세트산염을 함유하는 정제(비교예 1-5)를 제조하였다. 비교예 1-1 내지 1-5의 조성은 하기 표 4와 같다. 표 4의 각 성분의 함량은 정제당 함량(mg)을 나타낸다.Instead of histidine, amino alcohol meglumine (Comparative Example 1-1), inorganic salt calcium carbonate (Comparative Example 1-2), antioxidant ascorbic acid (Comparative Example 1-3) or butylated hydroxytoluene (Comparative Example 1 Except for using -4), a tablet containing bazedoxifen acetate was prepared in the same manner as in Example 1-1. In addition, except that histidine was not used for comparison, a tablet containing Bazedoxifen acetate was prepared in the same manner as in Example 1-1 (Comparative Example 1-5). The compositions of Comparative Examples 1-1 to 1-5 are shown in Table 4 below. The content of each component in Table 4 represents the content of refined sugar (mg).
성분ingredient 비교예 (mg/정제)Comparative Example (mg / Tablet)
1-11-1 1-21-2 1-31-3 1-41-4 1-51-5
바제독시펜 아세트산염Vasedoxifen Acetate 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6
전호화 전분Pregelatinized starch 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0
미결정 셀룰로오스Microcrystalline cellulose 89.489.4 89.489.4 89.489.4 89.489.4 94.494.4
콜로이드성 이산화규소Colloidal silicon dioxide 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
유당 수화물Lactose carb 90.090.0 90.090.0 90.090.0 90.090.0 90.090.0
메글루민Meglumine 5.05.0 -- -- -- --
탄산칼슘Calcium carbonate -- 5.05.0 -- -- --
아스코르브산Ascorbic acid -- -- 5.05.0 -- --
부틸화하이드록시톨루엔Butylated hydroxytoluene -- -- -- 5.05.0 --
전분글리콜산나트륨Sodium starch glycolate 21.021.0 21.021.0 21.021.0 21.021.0 21.021.0
푸마르산스테아릴나트륨Sodium stearyl fumarate 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
오파드라이TM 85F42129Opadry TM 85F42129 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
비교예Comparative example 2.  2. 바제독시펜Bazedoksifen 아세트산염 및  Acetates and 콜레칼시페롤을Cholecalciferol 함유하는 정제의 제조 Preparation of containing tablet
히스티딘 대신 아미노 알코올인 메글루민(비교예 2-1), 무기염인 탄산칼슘(비교예 2-2), 항산화제인 아스코르브산(비교예 2-3) 또는 부틸화히드록시톨루엔(비교예 2-4)을 사용한 것을 제외하고는, 실시예 2-1과 동일한 방법으로 바제독시펜 아세트산염과 콜레칼시페롤을 함유하는 정제를 제조하였다. 또한, 비교를 위하여 히스티딘을 사용하지 않은 것을 제외하고는 실시예 2-1과 동일한 방법으로 바제독시펜 아세트산염과 콜레칼시페롤을 함유하는 정제(비교예 2-5)를 제조하였다. 비교예 2-1 내지 2-5의 조성은 하기 표 5와 같다. 표 5의 각 성분의 함량은 정제당 함량(mg)을 나타낸다.Instead of histidine, amino alcohol meglumine (Comparative Example 2-1), inorganic salt calcium carbonate (Comparative Example 2-2), antioxidant ascorbic acid (Comparative Example 2-3) or butylated hydroxytoluene (Comparative Example 2 Except for using -4), a tablet containing bazedoxifen acetate and cholecalciferol was prepared in the same manner as in Example 2-1. In addition, except that histidine was not used for comparison, tablets containing Bazedoxifen acetate and cholecalciferol (Comparative Example 2-5) were prepared in the same manner as in Example 2-1. The compositions of Comparative Examples 2-1 to 2-5 are shown in Table 5 below. The content of each component in Table 5 represents the content of refined sugar (mg).
성분ingredient 비교예 (mg/정제)Comparative Example (mg / Tablet)
2-12-1 2-22-2 2-32-3 2-42-4 2-52-5
바제독시펜 아세트산염Vasedoxifen Acetate 22.622.6 22.622.6 22.622.6 22.622.6 22.622.6
콜레칼시페롤Cholecalciferol 0.020.02 0.020.02 0.020.02 0.020.02 0.020.02
전호화 전분Pregelatinized starch 45.045.0 45.045.0 45.045.0 45.045.0 45.045.0
미결정 셀룰로오스Microcrystalline cellulose 89.3889.38 89.3889.38 89.3889.38 89.3889.38 93.493.4
콜로이드성 이산화규소Colloidal silicon dioxide 15.015.0 15.015.0 15.015.0 15.015.0 15.015.0
유당 수화물Lactose carb 85.085.0 85.085.0 85.085.0 85.085.0 85.085.0
메글루민Meglumine 5.05.0 -- -- -- --
탄산칼슘Calcium carbonate -- 5.05.0 -- -- --
아스코르브산Ascorbic acid -- -- 5.05.0 -- --
부틸화하이드록시톨루엔Butylated hydroxytoluene -- -- -- 5.05.0 --
전분글리콜산나트륨Sodium starch glycolate 20.020.0 20.020.0 20.020.0 20.020.0 20.020.0
푸마르산스테아릴나트륨Sodium stearyl fumarate 8.08.0 8.08.0 8.08.0 8.08.0 8.08.0
오파드라이TM 85F42129Opadry TM 85F42129 9.09.0 9.09.0 9.09.0 9.09.0 9.09.0
시험예Test Example 1.  One. 바제독시펜Bazedoksifen 아세트산염을 함유하는 정제의 안정성 평가 Evaluation of stability of tablets containing acetate
실시예 1-1의 정제 및 비교예 1-1 내지 1-6의 정제에 대한 초기 유연물질을 측정한 다음, 가혹조건(60℃, 75%RH)에서 개방(Open) 및 밀폐(Close) 조건하에서 4주 동안 보관하면서, 바제독시펜으로부터 유래되는 유연물질의 함량을 측정하였다. 상기 유연물질의 함량 측정은 표준액과 검액을 제조하여 HPLC로 측정하였다. 상기 표준액은 바제독시펜 아세트산염 표준품을 취해 최종농도가 바제독시펜으로서 20 ug/mL이 되도록 검체 용매[25mM 인산완충액 + 4.5mM 핵산술폰산 (pH 3.0±0.1) / 아세토니트릴 (50:50) (v:v)]를 사용하여 제조하였다. 검액은 10정씩 취하여 상기한 검체 용매를 사용하여 제조하였다. HPLC 조건은 다음과 같다.Initial softening materials for the tablets of Example 1-1 and the tablets of Comparative Examples 1-1 to 1-6 were measured and then opened and closed under severe conditions (60 ° C., 75% RH). Under 4 weeks of storage, the amount of analogue derived from bazedoxifen was measured. The content of the flexible substance was measured by HPLC using a standard solution and a sample solution. The standard solution was taken from the Bazedoxifene acetate standard, so that the final concentration was 20 ug / mL as bazedoxifen. ) (v: v)]. 10 tablets were prepared by using the sample solvent described above. HPLC conditions are as follows.
<HPLC 분석조건><HPLC Analysis Conditions>
- 검출기: 자외부흡광광도계 (측정파장: 220nm)-Detector: ultraviolet absorbance photometer (wavelength: 220nm)
Photodiode array (측정파장: 200 ~ 350 nm)Photodiode array (wavelength: 200 ~ 350 nm)
- 컬럼: C18, 5um, 150 X 4.6 mm 컬럼Column: C18, 5um, 150 X 4.6 mm column
- 컬럼 온도: 30 ℃Column temperature: 30 ° C.
- 이동상: 25 mM 인산완충액(pH 3.0)/아세토니트릴 (68:32) (v/v)Mobile phase: 25 mM phosphate buffer (pH 3.0) / acetonitrile (68:32) (v / v)
- 유속: 약 1.5 mL/분Flow rate: about 1.5 mL / min
상기와 같이 가혹조건에서 유연물질의 함량을 측정한 결과는 하기 표 6과 같다.As a result of measuring the content of the flexible material in the harsh conditions as shown in Table 6 below.
가혹조건(60℃, 75%RH)에서의 유연물질 함량Lead content in harsh conditions (60 ℃, 75% RH)
조건Condition 유연물질Leading substance 실시예 (mg)Example (mg) 비교예(mg)Comparative Example (mg)
1-11-1 1-11-1 1-21-2 1-31-3 1-41-4 1-51-5
Open 조건Open condition 초기 유연물질Early lead material 0.0000.000 0.0000.000 0.0000.000 0.0000.000 0.0000.000 0.0000.000
가혹1주 유연물질1 week 0.2350.235 0.3640.364 0.3330.333 0.4230.423 0.2870.287 0.3300.330
가혹2주 유연물질2 week harsh substance 0.3300.330 0.7810.781 0.4790.479 0.9240.924 0.8120.812 0.4800.480
가혹4주 유연물질4-week flexible material 0.8110.811 1.2131.213 1.2581.258 1.8841.884 1.1661.166 1.1231.123
Close 조건Close condition 초기 유연물질Early lead material 0.0000.000 0.0000.000 0.0000.000 0.0000.000 0.0000.000 0.0000.000
가혹1주 유연물질1 week 0.0910.091 0.2110.211 0.1510.151 0.2110.211 0.1870.187 0.2270.227
가혹2주 유연물질2 week harsh substance 0.1050.105 0.2900.290 0.2720.272 0.4400.440 0.2430.243 0.2700.270
가혹4주 유연물질4-week flexible material 0.1940.194 0.3760.376 0.3200.320 0.7720.772 0.2910.291 0.3100.310
상기 표 6의 결과로부터 알 수 있는 바와 같이, 실시예 1-1의 정제는 현저하게 낮은 유연물질의 생성을 나타냄에 반하여, 아미노 알코올, 무기염, 또는 항산화제를 함유하거나 안정화제를 함유하고 있지 않은 비교예의 정제는 모두 높은 유연물질의 생성을 나타내었다. 따라서, 본 발명에 따라 얻어진 정제는 유연물질 생성이 최소화됨으로써, 우수한 안정성을 나타냄을 확인할 수 있다.As can be seen from the results in Table 6, the tablets of 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.
시험예Test Example 2.  2. 바제독시펜Bazedoksifen 아세트산염 및  Acetates and 콜레칼시페롤을Cholecalciferol 함유하는 정제의 안정성 평가 Evaluation of stability of containing tablet
실시예 2-1의 정제 및 비교예 2-1 내지 2-6의 정제에 대한 초기 유연물질을 측정한 다음, 가혹조건(60℃, 75%RH)에서 개방(Open) 및 밀폐(Close) 조건하에서 4주 동안 보관하면서, 바제독시펜으로부터 유래되는 유연물질의 함량을 측정하였다. 상기 유연물질의 함량 측정은 시험예 1과 동일한 방법으로 수행하였으며, 그 결과는 하기 표 7과 같다.Initial softening materials for the tablets of Example 2-1 and the tablets of Comparative Examples 2-1 to 2-6 were measured and then opened and closed under severe conditions (60 ° C., 75% RH). Under 4 weeks of storage, the amount of analogue derived from bazedoxifen was measured. The content of the flexible material was measured in the same manner as in Test Example 1, and the results are shown in Table 7 below.
가혹조건(60℃, 75%RH)에서의 유연물질 함량Lead content in harsh conditions (60 ℃, 75% RH)
조건Condition 유연물질Leading substance 실시예 (mg)Example (mg) 비교예(mg)Comparative Example (mg)
2-12-1 2-12-1 2-22-2 2-32-3 2-42-4 2-52-5
Open 조건Open condition 초기 유연물질Early lead material 0.0000.000 0.0000.000 0.0000.000 0.0000.000 0.0000.000 0.0000.000
가혹1주 유연물질1 week 0.2410.241 0.3640.364 0.3090.309 0.4020.402 0.2650.265 0.3210.321
가혹2주 유연물질2 week harsh substance 0.3700.370 0.7750.775 0.4290.429 0.8640.864 0.7940.794 0.4650.465
가혹4주 유연물질4-week flexible material 0.7670.767 1.1231.123 1.1111.111 1.7781.778 1.1551.155 1.1431.143
Close 조건Close condition 초기 유연물질Early lead material 0.0000.000 0.0000.000 0.0000.000 0.0000.000 0.0000.000 0.0000.000
가혹1주 유연물질1 week 0.0840.084 0.2020.202 0.1400.140 0.1990.199 0.1730.173 0.2100.210
가혹2주 유연물질2 week harsh substance 0.0990.099 0.2840.284 0.2850.285 0.3970.397 0.2350.235 0.2530.253
가혹4주 유연물질4-week flexible material 0.1900.190 0.3560.356 0.3130.313 0.7550.755 0.2850.285 0.3160.316
상기 표 7의 결과로부터 알 수 있는 바와 같이, 실시예 1-1의 정제와 동일하게 실시예 2-1의 정제도 현저하게 낮은 유연물질의 생성을 나타냄에 반하여, 아미노 알코올, 무기염, 또는 항산화제를 함유하거나 안정화제를 함유하고 있지 않은 비교예의 정제는 모두 높은 유연물질의 생성을 나타내었다. 따라서, 본 발명에 따라 얻어진 정제는 유연물질 생성이 최소화됨으로써, 우수한 안정성을 나타냄을 확인할 수 있다.As can be seen from the results of Table 7, 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. The tablets of the comparative examples, which contained no agents or stabilizers, all showed the production of high analogs. Therefore, it can be seen that the tablets obtained according to the present invention exhibit excellent stability by minimizing the formation of analogues.

Claims (14)

  1. 활성성분으로서 바제독시펜 또는 이의 약학적으로 허용가능한 염; 및 안정화제로서 염기성 아미노산을 포함하고, 항산화제를 포함하지 않는 약학 조성물.Bazedoxifen or a pharmaceutically acceptable salt thereof as the active ingredient; And a basic amino acid as a stabilizer and no antioxidant.
  2. 제1항에 있어서, 활성성분으로서 콜레칼시페롤, 칼시트리올, 칼시포트리올, 타칼시톨, 막사칼시톨, 파리칼시톨, 및 세오칼시톨로 이루어진 군으로부터 1종 이상 선택된 비타민 D 유도체를 추가로 포함하는 약학 조성물.The vitamin D derivative according to claim 1, wherein the active ingredient is at least one selected from the group consisting of cholecalciferol, calcitriol, calcipotriol, tacalcitol, maxacalcitol, paricalcitol, and ceocalcitol Pharmaceutical composition further comprising.
  3. 제1항 또는 제2항에 있어서, 상기 바제독시펜의 약학적으로 허용가능한 염이 바제독시펜 아세트산염인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of bazedoxifen is bazedoxifen acetate.
  4. 제2항에 있어서, 상기 비타민 D 유도체가 콜레칼시페롤인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 2, wherein the vitamin D derivative is cholecalciferol.
  5. 제1항 또는 제2항에 있어서, 상기 염기성 아미노산이 히스티딘, 아르기닌, 및 라이신으로 이루어진 군으로부터 1종 이상 선택되는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 1 or 2, wherein the basic amino acid is selected from the group consisting of histidine, arginine, and lysine.
  6. 제5항에 있어서, 상기 염기성 아미노산이 히스티딘인 것을 특징으로 하는 약학 조성물.6. A pharmaceutical composition according to claim 5 wherein the basic amino acid is histidine.
  7. 제1항 또는 제2항에 있어서, 상기 염기성 아미노산이 조성물 총 중량에 대하여 0.1 ∼ 20.0 중량%의 범위로 존재하는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 1 or 2, wherein the basic amino acid is present in the range of 0.1 to 20.0% by weight based on the total weight of the composition.
  8. 제7항에 있어서, 상기 염기성 아미노산이 조성물 총 중량에 대하여 0.5 ∼ 5 중량%의 범위로 존재하는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 7, wherein the basic amino acid is present in the range of 0.5 to 5% by weight based on the total weight of the composition.
  9. 제1항 또는 제2항에 있어서, 유당, 만니톨, 이소말트, 미결정 셀룰로오스, 덱스트란, 말토덱스트린, 솔비톨, 포도당, 전호화전분, 감자전분, 옥수수전분, 경질무수규산, 콜로이드성 이산화규소, 결정 셀룰로오스, 무수인산칼슘, 카복시메틸 셀룰로오스, 카복시에틸 셀룰로오스, 하이드록시에틸 셀룰로오스, 및 마그네슘 알루미늄 실리케이트로 이루어진 군으로부터 1종 이상 선택된 희석제; 전분, 전호화 전분, 전분글리콜산나트륨, 크로스카멜로스 나트륨, 크로스포비돈, 카르복시메틸셀룰로오스 칼슘, 카르복시메틸셀룰로오스 나트륨, 알긴산, 및 알긴산나트륨으로 이루어진 군으로부터 1종 이상 선택된 붕해제; 및 푸마르산스테아릴나트륨, 콜로이드성 이산화규소, 실리카, 스테아린산 또는 이의 염, 탈크, 마그네슘/알루미늄실리케이트, 글리세릴 비헤네이트, 경질 피마자유, 식물성 피마자유, 폴리에틸렌글리콜, 글리세릴 모노스테아레이트, 및 자당 스테아린산 에스테르로 이루어진 군으로부터 1종 이상 선택된 활택제를 추가로 포함하는 것을 특징으로 하는 약학 조성물.3. Lactose, mannitol, isomalt, microcrystalline cellulose, dextran, maltodextrin, sorbitol, glucose, pregelatinized starch, potato starch, corn starch, hard silicic acid, colloidal silicon dioxide, crystals according to claim 1 or 2 Diluents selected from the group consisting of cellulose, anhydrous calcium phosphate, 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, polyethylene glycol, glyceryl monostearate, and sucrose stearic acid Pharmaceutical composition, characterized in that it further comprises at least one lubricant selected from the group consisting of esters.
  10. 제1항 또는 제2항에 있어서, 정제의 형태를 갖는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition according to claim 1 or 2, which is in the form of a tablet.
  11. 제9항에 있어서, 상기 정제가 추가로 필름코팅되는 것을 특징으로 하는 약학 조성물.The pharmaceutical composition of claim 9, wherein the tablet is further film coated.
  12. 제1항에 있어서, 1정당 바제독시펜 아세트산염 22.6 mg, 전호화 전분 10.0 내지 90.0 mg, 미결정 셀룰로오스 26.4 내지 199.4 mg, 콜로이드성 이산화규소 1.0 내지 15.0 mg, 유당 수화물 15.0 내지 131.1 mg, 히스티딘 0.5 내지 20.0 mg, 전분글리콜산나트륨 3.0 내지 26.0 mg, 및 푸마르산스테아릴나트륨 2.0 내지 15.0 mg을 포함하는, 정제 형태의 약학 조성물.The method of claim 1, wherein 22.6 mg of bazedoxifen acetate per tablet, 10.0 to 90.0 mg of pregelatinized starch, 26.4 to 199.4 mg of microcrystalline cellulose, 1.0 to 15.0 mg of colloidal silicon dioxide, 15.0 to 131.1 mg of lactose hydrate, 0.5 histidine 0.5 To 20.0 mg, sodium starch glycolate 3.0 to 26.0 mg, and sodium stearyl fumarate 2.0 to 15.0 mg.
  13. 제2항에 있어서, 1정당 바제독시펜 아세트산염 22.6 mg, 콜레칼시페롤 800 내지 5600 IU, 전호화 전분 10.0 내지 90.0 mg, 미결정 셀룰로오스 26.38 내지 199.38 mg, 콜로이드성 이산화규소 1.0 내지 15.0 mg, 유당 수화물 15.0 내지 118.0 mg, 히스티딘 0.5 내지 20.0 mg, 전분글리콜산나트륨 3.0 내지 26.0 mg, 푸마르산스테아릴나트륨 2.0 내지 15.0 mg을 포함하는, 정제 형태의 약학 조성물.The method of claim 2, wherein 22.6 mg of bazedoxifen acetate per tablet, 800-5600 IU cholecalciferol, 10.0-90.0 mg pregelatinized starch, 26.38-199.38 mg microcrystalline cellulose, 1.0-15.0 mg colloidal silicon dioxide, A pharmaceutical composition in the form of a tablet, comprising 15.0 to 118.0 mg of lactose hydrate, 0.5 to 20.0 mg of histidine, 3.0 to 26.0 mg of sodium starch glycolate, and 2.0 to 15.0 mg of sodium stearyl fumarate.
  14. 제12항 또는 제13항에 있어서, 폴리비닐알코올을 함유하는 필름코팅층이 상기 정제 상에 형성된, 제피-정제 형태의 약학 조성물.The pharmaceutical composition according to claim 12 or 13, wherein a film coating layer containing polyvinyl alcohol is formed on the tablet.
PCT/KR2018/005470 2017-05-24 2018-05-14 Pharmaceutical composition containing bazedoxifene or pharmaceutically acceptable salt WO2018216933A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
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KR20050010886A (en) * 2002-06-13 2005-01-28 와이어쓰 Bazedoxifene treatment regimens
KR20100113627A (en) * 2008-02-11 2010-10-21 와이어쓰 엘엘씨 Methods of preparing polymorphic form a of bazedoxifene acetate
KR20140088917A (en) * 2005-08-24 2014-07-11 와이어쓰 엘엘씨 Bazedoxifene acetate formulations and manufacturing process thereof
CN104013630A (en) * 2014-05-23 2014-09-03 合肥九研医药科技开发有限公司 Compound bazedoxifene acetate estrogen composition
KR20170029141A (en) * 2015-09-07 2017-03-15 주식회사 경보제약 Method for the preparation of high purity Bazedoxifene Acetate

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050010886A (en) * 2002-06-13 2005-01-28 와이어쓰 Bazedoxifene treatment regimens
KR20140088917A (en) * 2005-08-24 2014-07-11 와이어쓰 엘엘씨 Bazedoxifene acetate formulations and manufacturing process thereof
KR20100113627A (en) * 2008-02-11 2010-10-21 와이어쓰 엘엘씨 Methods of preparing polymorphic form a of bazedoxifene acetate
CN104013630A (en) * 2014-05-23 2014-09-03 合肥九研医药科技开发有限公司 Compound bazedoxifene acetate estrogen composition
KR20170029141A (en) * 2015-09-07 2017-03-15 주식회사 경보제약 Method for the preparation of high purity Bazedoxifene Acetate

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