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WO2018182205A1 - Composition pharmaceutique stabilisée contenant de l'acétate de bazedoxifène - Google Patents

Composition pharmaceutique stabilisée contenant de l'acétate de bazedoxifène Download PDF

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Publication number
WO2018182205A1
WO2018182205A1 PCT/KR2018/002889 KR2018002889W WO2018182205A1 WO 2018182205 A1 WO2018182205 A1 WO 2018182205A1 KR 2018002889 W KR2018002889 W KR 2018002889W WO 2018182205 A1 WO2018182205 A1 WO 2018182205A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
bazedoxifen
pharmaceutical composition
pharmaceutically acceptable
sodium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2018/002889
Other languages
English (en)
Korean (ko)
Inventor
박봉현
조정현
김영훈
김용일
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Original Assignee
Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from KR1020170169991A external-priority patent/KR20180111469A/ko
Application filed by Hanmi Pharmaceutical Co Ltd, Hanmi Pharmaceutical Industries Co Ltd filed Critical Hanmi Pharmaceutical Co Ltd
Publication of WO2018182205A1 publication Critical patent/WO2018182205A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • 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

Definitions

  • the present invention relates to a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.
  • a stabilized pharmaceutical formulation comprising Bazedoxifene acetate as an active ingredient, by containing an antioxidant, coating with a coating base, or packaged in a packaging material, Bazedoxifene acetate flexible material
  • the production of is significantly inhibited to provide a pharmaceutical formulation with improved stability.
  • Bazedoxifene acetate is (1-4- [2- (hexahydro-1H-azin-1-yl) ethoxy] benzyl-2- (4-hydroxyphenyl) -3-methyl-1H-indole- 5-ol monoacetate), having the formula:
  • Bazedoxifene acetate is one of the selective estrogen receptor modulators (SERM), and Pfizer Pharmaceuticals Co., Ltd. is licensed in Korea under the name of "Biviant Tablet” as a product containing bazedoxifene acetate as an active ingredient. It is commercially available. It is a product of tablet formulations that are administered once daily for the purpose of treating or preventing osteoporosis in postmenopausal women.
  • SERM selective estrogen receptor modulators
  • Bazedoxifen According to the related art known to Bazedoxifen, such as International Application Publication No. 2009/012734, it is difficult to purify Bazedoxifen, and tends to be easily broken down.
  • Representative impurities are degradation products (bazedoxifene N-oxides) or synthetic unreacted products produced during the synthesis or degradation of apeledoxifen.
  • sodium ascorbate or ascorbyl palmitate is used as an antioxidant to inhibit N-oxide production in raw materials as well as pharmaceutical formulations.
  • the present inventors conducted a forced degradation study in order to confirm the degradation product (flexible material) of apeledoxifen acetate and to confirm the degree of degradation according to the exposure conditions. As a result of the test, it was confirmed that apeledoxifen acetate was very unstable under oxidizing conditions.
  • the present inventors have attempted to develop breakthrough compositions and formulations that can suppress the problems of increased softeners and discoloration during long-term storage while suppressing the softeners that increase significantly under oxidizing conditions.
  • Vasedoxifen acetate despite its good osteoporosis therapeutic effect, is not easy to manufacture into tablets and has the disadvantage of being prone to degradation. Therefore, although an antioxidant such as ascorbic acid was used to suppress the production of decomposition products such as N-oxide, the inventors conducted a forced decomposition test, and as a result, the Bazedoxifene acetate increased in unknown conditions in acidic conditions. It was confirmed that the degree exceeded 0.2% which is an unknown flexible substance standard recommended by ICH.
  • the present inventors have been seeking various solutions to solve this problem, while using a stable drug that can be stored for a long time without causing the storage problems such as discoloration while suppressing the formation of the flexible material without using acidic conditions such as ascorbic acid
  • the development of the pharmaceutical composition has led to the completion of the present invention.
  • the present inventors have completed the present invention by developing a pharmaceutical formulation with improved stability by inhibiting the formation of a flexible material by coating with a specific coating base.
  • the present inventors have provided a method for confirming the correlation between the moisture permeability of the packaging material and the generation of the apeledoxifen flexible material, and using the packaging material having a low moisture permeability to provide a method for long-term storage of the pharmaceutical formulation.
  • the present invention relates to a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising apeledoxifen or a pharmaceutically acceptable salt thereof, and an antioxidant.
  • the present invention relates to a stabilized pharmaceutical composition
  • a stabilized pharmaceutical composition comprising a stabilized pharmaceutical composition
  • comprising a stabilized pharmaceutical composition
  • an antioxidant an antioxidant
  • the present invention examines substances other than acids such as ascorbic acid and citric acid which exhibit acidic conditions among antioxidants (antioxidants), and has found an antioxidant that can significantly reduce the amount of analogues produced ascorbic acid.
  • one of the known analogs of apeledoxifen acetate is 2- (4-Hydroxy-phenyl) -3-methyl-1- ⁇ 4- [2- (1-oxy It was found to completely inhibit N-Oxide analogues having the structure -azepan-1-yl) -ethoxy] -benzyl ⁇ -iH-Indole-5-ol.
  • the pharmaceutical composition containing can be used as an agent for treating and preventing osteoporosis in postmenopausal women by securing significantly superior stability compared to existing commercially available formulations.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof as an active ingredient and having excellent stability by coating with a specific coating base.
  • the present invention provides a stable pharmaceutical composition containing a bicarbonate, which significantly increases the formation of a flexible substance under oxidizing conditions, while suppressing the formation of the flexible substance and preventing discoloration during long-term storage.
  • the present invention provides as active ingredient apeldoxifen or a pharmaceutically acceptable salt thereof, and
  • antioxidants sodium sulfite, sodium bisulfite, sodium metabisulfite, butyl hydroxyl toluene, propyl gallate, cysteine and tocopherol ( Tocopherol) relates to a pharmaceutical composition comprising at least one antioxidant selected from the group consisting of.
  • the antioxidant of the present invention may preferably be sodium sulfite, sodium hydrogen sulfite or sodium metabisulfite, and most preferably sodium hydrogen sulfite, but is not limited thereto.
  • the present invention may include 0.02 to 0.5% by weight of sodium bisulfite with respect to apeledoxifen acetate, preferably 0.04 to 0.25% by weight.
  • the apeledoxifen of the present invention or a pharmaceutically acceptable salt thereof may preferably be apeledoxifen acetate.
  • composition of the present invention may be formulated as a pharmaceutical preparation for oral administration.
  • the formulation may be a pellet, a powder, a granule, a dry syrup, a tablet or a capsule, but is not limited thereto.
  • the present invention includes apeldoxifen or a pharmaceutically acceptable salt thereof as an active ingredient,
  • HPMC hydroxypropylmethyl cellulose
  • PVA polyvinyl alcohol
  • EC ethyl cellulose
  • the coating base may be most preferably hydroxypropyl methyl cellulose (HPMC), but is not limited thereto.
  • HPMC hydroxypropyl methyl cellulose
  • the pharmaceutical formulation of the present invention may be packaged in a blister or a bottle, but is not limited thereto.
  • the water vapor transmission rate (WVTR) of the packaging material is 2.0 g / m 2 / day or less, and more preferably 1.0 g / m 2 / day or less.
  • WVTR Water Vapor Transmission Rate
  • Metal, aluminum, or blister packaging plastic or polymer materials in blister packaging such as polyvinylchloride (PVC), polyvinylidene chloride (PVDC), polychlorotrifluoroethylene (PCTFE) and aluminum, It is not limited to this.
  • PVC polyvinylchloride
  • PVDC polyvinylidene chloride
  • PCTFE polychlorotrifluoroethylene
  • aluminum It is not limited to this.
  • the blister is an aluminum blister, but is not limited thereto.
  • the bottle is a high density polyethylene (HDPE) bottle, but is not limited thereto.
  • HDPE high density polyethylene
  • UV absorbance photometer (wavelength: 220nm)
  • Decomposition Product Content (%) Relative hold time (RRT) contrast Oxidation base mountain Heat Content of Bazedoxifen 1.00 99.90 4.67 57.75 98.65 99.90 Content of Degradation Product 1 0.13 N / D 50.56 26.91 1.45 N / D Content of Degradation Product 2 0.29 N / D 15.14 1.40 0.21 N / D Content of Degradation Product 3 0.35 N / D 20.44 0.15 N / D N / D Content of Degradation Product 4 1.12 0.10 2.07 0.25 0.09 0.10 Content of Degradation Product 5 1.28 N / D N / D 6.45 0.02 N / D
  • Decomposition product 4 2- (4-Hyroxy-phenyl) -3-methyl-1- ⁇ 4- [2- (1-oxy-azepan-1-yl) -ethoxy] -benzyl ⁇ -iH-Indole-5 N-Oxide flexible material with -ol structure
  • barzedoxifene acetate 22.6 mg were mixed with 90.4 mg of microcrystalline cellulose, 158.5 mg of lactose, 15.0 mg of sodium starch glycolate, and 3.0 mg of the antioxidants described in Table 2 below. This was combined with 0.05 mL of purified water dissolved in povidone 9.0 mg as a binding solution (association condition: Agitator speed (150 rpm), Agitator pressure (1.6A), Chopper speed (3000 rpm)), dried and sieved with about 20 mesh sieve. Wet granules of phen acetate were prepared. Thereafter, the wet granules were mixed with 4.5 mg of magnesium stearate to prepare final granules, which were then prepared into tablets using a tablet press.
  • Example 6 According to the content of sodium hydrogen sulfite in Table 3, to prepare a tablet in the same manner as in Examples 1 to 5. However, in the case of Example 6, wet granules were prepared of Bazedoxifen acetate and sodium hydrogen sulfite was mixed for 5 minutes. Thereafter, 4.5 mg of magnesium stearate was mixed to prepare a final granule, which was then tableted using a tablet press.
  • a coated tablet was prepared by using the coating solution prepared according to the composition of each example of Table 4 in the tablet prepared by the above method.
  • the types and amounts of plasticizers, colorants, and anti-sticking agents used at various frequencies for each coating base were selected, and the concentration of the coating base was 10% w using purified water as a solvent. It was prepared to be / w.
  • Example Coating base Plasticizer coloring agent Adhesion inhibitor One - - - - - 10 HPMC (70%) PEG 400 (10%) TiO 2 (5%) Talc (15%) 11 PVA (45%) PEG 3350 (15%) TiO 2 (20%) Talc (20%) 12 EC (35%) PEG 6000 (10%) TiO 2 (20%) Talc (35%) 13 HEC (40%) PEG 4000 (15%) TiO 2 (10%) Talc (35%)
  • HPMC hydroxypropylmethylcellulose, molecular weight 400,000,
  • PVA polyvinyl alcohol, molecular weight 20,000,
  • EC ethyl cellulose, molecular weight 160,000,
  • HEC hydroxyethyl cellulose, molecular weight 300,000
  • PEG polyethylene glycol
  • Coated tablets were prepared using the coating solution prepared according to the composition of Example 10 in Table 4 with the tablets prepared by the above-described method.
  • the coated tablets thus prepared were packaged using the respective packaging materials shown in Table 5 below.
  • PVC, PVDC, PCTFE and aluminum were used for the top plate of the blister package, respectively, and the bottom plate was all used for aluminum, and the top plate and the bottom plate were bonded and packed with Blister.
  • Example Packing material type Package form * WVTR (g / m 2 / day) 10 Bottle: HDPE, Lid: PP Bottle 0.75 14 No packaging - - 15 PVC (250um) **-Alu Blister 3.10 16 PVDC (150um) -Alu Blister 0.65 17 PCTFE (15um) -Alu Blister 0.39 18 PVC (250um) -Alu + Alu bag *** Blister 0.005 19 Alu-alu Blister 0.005
  • WVTR Water Vapor Transmission Rate
  • PVDC Polyvinylidene Chloride
  • PCTFE Polychlorotrifluoroethylene
  • HDPE HDPE
  • Example 1-9 The tablets prepared in Example 1-9 were placed in an HDPE bottle, closed with a lid, and stored in a chamber maintained at 60 ° C. for 4 weeks. Thereafter, samples were taken at 1, 2, and 4 weeks, and a flexible material test was conducted under the following analysis conditions.
  • UV absorbance photometer (wavelength: 220nm)
  • N-oxide production amount (%) Exposure period Early 60 ° C 1 week exposure 60 ° C 2 weeks exposure 60 °C 4 weeks exposure Example 1 0.14 0.51 1.10 2.18 Example 2 0.39 0.59 0.85 1.12 Example 3 0.19 0.16 0.35 0.76 Example 4 * ⁇ LOQ ⁇ LOQ ⁇ LOQ ⁇ LOQ Example 5 0.08 0.18 0.21 0.25
  • butylhydroxytoluene, sodium bisulfite, and propylgallate were used as antioxidants over time as compared to those without antioxidants and ascorbic acid as antioxidants. It was found that the amount of formation of the analog and the amount of N-oxide produced were significantly less.
  • N-oxide production amount (%) Exposure period Early 60 ° C 1 week exposure 60 ° C 2 weeks exposure 60 °C 4 weeks exposure Example 6 ⁇ LOQ ⁇ LOQ ⁇ LOQ ⁇ LOQ Example 7 ⁇ LOQ ⁇ LOQ ⁇ LOQ ⁇ LOQ Example 8 ⁇ LOQ ⁇ LOQ ⁇ LOQ ⁇ LOQ Example 9 ⁇ LOQ ⁇ LOQ ⁇ LOQ ⁇ LOQ ⁇ LOQ
  • Example 1 Example 2
  • Example 3 Example 4
  • Example 5 Initial - - - - - - 60 ° C 1 week exposure (HDPE bottle) One 3 0 0 0 40 °C / 75% RH, 1 week exposure (Petri dish) One 5 0 0 0
  • the coated tablets prepared in Examples 10 to 13 were placed in HDPE bottles, and the lids were well closed and then stored in a chamber maintained at 60 ° C. for 4 weeks. Thereafter, samples were taken at 1, 2, and 4 weeks, and a flexible material test was conducted under the following analysis conditions.
  • UV absorbance photometer (wavelength: 220nm)
  • N-oxide production amount (%) Exposure period Early 60 ° C 1 week exposure 60 ° C 2 weeks exposure 60 °C 4 weeks exposure Example 1 0.14 0.51 1.10 2.18 Example 10 0.09 0.14 0.23 0.48 Example 11 0.15 0.25 0.41 0.72 Example 12 0.16 0.48 1.12 1.82 Example 13 0.19 0.94 1.91 3.65
  • Example 13 As shown in Tables 11 and 12, the coating tablets of the other examples except for Example 13 using HEC as the coating base are significantly less than the amount of the flexible material produced compared to Example 1, which is an uncoated tablet without coating. .
  • UV absorbance photometer (wavelength: 220nm)
  • Trihydroxy indole analogue content (%) Exposure period Early 60 ° C 1 week exposure 60 ° C 2 weeks exposure 60 °C 4 weeks exposure Example 10 0.11 0.16 0.24 0.43 Example 14 0.08 0.54 1.62 2.15 Example 15 0.09 0.21 0.48 0.93 Example 16 0.11 0.16 0.22 0.47 Example 17 0.11 0.14 0.21 0.40 Example 18 0.10 0.12 0.15 0.29 Example 19 0.13 0.14 0.16 0.31
  • Example 14 without the packaging material and Example 15 having a WVTR value of 3.10 g / m 2 / day it was confirmed that shows a higher increase in the flexible material than the other examples. It was confirmed that this is related to the WVTR value in view of the increase of trihydroxy indole analogues increased under moisture conditions.

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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)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique stabilisée contenant de l'acétate de bazedoxifène en tant que principe actif et un antioxydant. De façon spécifique, la présente invention concerne une composition pharmaceutique, qui supprime la production de substances apparentées et a une stabilité de stockage à long terme améliorée en comprenant un antioxydant ou une base de revêtement en plus de l'acétate de bazedoxifène, ce qui augmente remarquablement la production de substances apparentées dans des conditions oxydatives.
PCT/KR2018/002889 2017-03-30 2018-03-12 Composition pharmaceutique stabilisée contenant de l'acétate de bazedoxifène Ceased WO2018182205A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2017-0040446 2017-03-30
KR20170040446 2017-03-30
KR1020170169991A KR20180111469A (ko) 2017-03-30 2017-12-12 바제독시펜 아세테이트를 함유하는 안정화된 약제학적 조성물
KR10-2017-0169991 2017-12-12

Publications (1)

Publication Number Publication Date
WO2018182205A1 true WO2018182205A1 (fr) 2018-10-04

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Application Number Title Priority Date Filing Date
PCT/KR2018/002889 Ceased WO2018182205A1 (fr) 2017-03-30 2018-03-12 Composition pharmaceutique stabilisée contenant de l'acétate de bazedoxifène

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080031037A (ko) * 2005-06-29 2008-04-07 와이어쓰 결합형 에스트로겐과 바제독시펜의 제형
KR20080043853A (ko) * 2005-08-24 2008-05-19 와이어쓰 바제독시펜 아세테이트 제형
US20110165241A1 (en) * 2009-10-27 2011-07-07 Wyeth Llc Bazedoxifene formulations with antioxidants
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
KR20080031037A (ko) * 2005-06-29 2008-04-07 와이어쓰 결합형 에스트로겐과 바제독시펜의 제형
KR20080043853A (ko) * 2005-08-24 2008-05-19 와이어쓰 바제독시펜 아세테이트 제형
US20110165241A1 (en) * 2009-10-27 2011-07-07 Wyeth Llc Bazedoxifene formulations with antioxidants
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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