JP2021531285A - 高ヒペリシン含有ヒペリシン−pvp複合体 - Google Patents
高ヒペリシン含有ヒペリシン−pvp複合体 Download PDFInfo
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- hypericin
- pvp
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- 229940005608 hypericin Drugs 0.000 title claims abstract description 144
- PHOKTTKFQUYZPI-UHFFFAOYSA-N hypericin Natural products Cc1cc(O)c2c3C(=O)C(=Cc4c(O)c5c(O)cc(O)c6c7C(=O)C(=Cc8c(C)c1c2c(c78)c(c34)c56)O)O PHOKTTKFQUYZPI-UHFFFAOYSA-N 0.000 title claims abstract description 144
- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 title claims abstract description 144
- BTXNYTINYBABQR-UHFFFAOYSA-N hypericin Chemical compound C12=C(O)C=C(O)C(C(C=3C(O)=CC(C)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 BTXNYTINYBABQR-UHFFFAOYSA-N 0.000 title claims abstract 14
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 174
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 103
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 100
- 239000000203 mixture Substances 0.000 claims abstract description 52
- 230000009477 glass transition Effects 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 238000002428 photodynamic therapy Methods 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- 238000001990 intravenous administration Methods 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 230000000249 desinfective effect Effects 0.000 claims description 3
- 230000001954 sterilising effect Effects 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 abstract description 3
- MPGWGYQTRSNGDD-UHFFFAOYSA-N hypericin Chemical compound OC1=CC(O)=C(C2=O)C3=C1C1C(O)=CC(=O)C(C4=O)=C1C1=C3C3=C2C(O)=CC(C)=C3C2=C1C4=C(O)C=C2C MPGWGYQTRSNGDD-UHFFFAOYSA-N 0.000 description 142
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000002253 acid Substances 0.000 description 6
- 239000003504 photosensitizing agent Substances 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 238000011088 calibration curve Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
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- 210000004881 tumor cell Anatomy 0.000 description 4
- -1 2-oxo-1-pyrrolidinyl Chemical group 0.000 description 3
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
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- 150000003839 salts Chemical class 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
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- 239000012153 distilled water Substances 0.000 description 2
- ROFJUMITFMRBRF-UHFFFAOYSA-N fagopyrin Chemical compound CC1=CC(O)=C(C(C2=C3O)=O)C4=C1C1=C(C)C=C(O)C(C(C=5C(O)=C(C6NCCCC6)C(O)=C6C7=5)=O)=C1C7=C4C2=C6C(O)=C3C1CCCCN1 ROFJUMITFMRBRF-UHFFFAOYSA-N 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
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- 239000008363 phosphate buffer Substances 0.000 description 2
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- 159000000001 potassium salts Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 229950003776 protoporphyrin Drugs 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 241000219051 Fagopyrum Species 0.000 description 1
- 235000009419 Fagopyrum esculentum Nutrition 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000546188 Hypericum Species 0.000 description 1
- 235000017309 Hypericum perforatum Nutrition 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920001609 Poly(3,4-ethylenedioxythiophene) Polymers 0.000 description 1
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 230000002209 hydrophobic effect Effects 0.000 description 1
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- 150000002576 ketones Chemical class 0.000 description 1
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- 230000008018 melting Effects 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000000258 photobiological effect Effects 0.000 description 1
- 230000000886 photobiology Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920002627 poly(phosphazenes) Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
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Abstract
Description
本発明によるヒペリシン−PVP複合体を含有する薬学的に許容される製剤を提供すること、及び
癌を患っている対象者にこの組成物の有効量を投与すること
を含む。
30mgのポリビニルピロリドン(PVP 25kD)を15mgのヒペリシン(99%、HPLC)と乾式混合した。200μL(200マイクロリットル=0.2mL)のエタノールと100μL(100マイクロリットル=0.1mL)の水を混合物に加えた。次に、混合物を撹拌し、20分間放置した。この後、混合物を乾燥キャビネット内でゆっくりと180℃に加熱した。温度は、室温から180℃まで約20分間かけて上昇するようにプログラムした。混合物を180℃の温度で約8分間維持した。この後、混合物を室温まで冷却した。次に、約3〜6mLの水を加え、1時間撹拌した。これにより、可溶性成分であるヒペリシン−PVP複合体が溶液に取り込まれた。不溶性成分及び複合体を形成していないヒペリシンをろ過した(細孔径0.2〜0.4μm)。濾液を乾燥させ、さらに使用するために乾燥状態で保存した。
ヒペリシンの代わりにナトリウム塩を使用したことを除いて(ヒペリシン酸ナトリウム)、実施例1と同様にした。ヒペリシン酸ナトリウムは、Kapinusら(Monatshefte fur Chemie130(1999)436−441)によって与えられた指示に従って生成した。
従来のヒペリシン−PVP複合体を、Kubinらの「ヒペリシンを水溶性にする方法(How to make hypericin water−soluble)」、Die Pharmazie 63(2008)263−269に記載されているように製造した。これに関して、超音波を使用して10mgのヒペリシンを2.5mLのエタノールに溶解し、その後、1000mgのPVP 25kD及び8mLの蒸留水を加えた。混合物を約5分間70℃に加熱した。その後、5mLの水を加え、混合物をさらに10分間撹拌した。次に、溶液をロータリーエバポレーターで乾燥させ、得られたヒペリシン−PVP複合体をさらに使用するために乾燥状態で保存した。
ヒペリシン−PVP複合体を、実施例1から3に記載の方法に従って製造した。
ヒペリシン−PVP複合体中のヒペリシンの重量割合は、HPLCを使用して、またヒペリシンによる適切なキャリブレーションを使用して決定した。HPLC法は、実質的に、Freytag W.E.(Deutsche Apothekerzeitung 124 No.46(1984)2383−2386)によって記載されているように行った。
溶離液:568.0gのメタノール、157.8gの酢酸エチル、185.5gのバッファー(1000mLの蒸留水中の13.8gのNaH2PO4H2O、85%オルトリン酸(pH2.1))
カラム:Nucleosil 120 3C18(長さ120mm、内径4mm)
流量:0.6mL/分
検出:588nmでのUV−vis
<付記>
本開示の態様は以下を含む。
<項1>
複合体全体に対するヒペリシン又はヒペリシン塩の平均重量割合が6重量%を超えることを特徴とする、ヒペリシン又はヒペリシン塩と、ポリビニルピロリドン(PVP)とから形成された複合体。
<項2>
前記複合体中のPVPに対するヒペリシンの平均モル比が2.5を超えることを特徴とする、項1に記載の複合体。
<項3>
前記PVPが10〜40kD、好ましくは12〜25kDの平均モル質量を有することを特徴とする、項1又は項2に記載の複合体。
<項4>
項1〜項3のいずれか一項に記載の複合体を含有する医薬組成物。
<項5>
前記組成物が静脈内投与用に提供され、前記組成物が少なくとも25mg/Lの濃度でヒペリシンを含有することを特徴とする、項4に記載の医薬組成物。
<項6>
ヒペリシンとPVPとの混合物が、使用されるPVPのガラス転移温度よりも高い温度に加熱されることを特徴とする、項1〜項3のいずれか一項に記載の複合体の製造方法。
<項7>
ヒペリシンとPVPとの前記混合物に、溶媒又は溶媒の混合物、好ましくは水、エタノール、メタノール、ピリジン、アセトン、エチルメチルケトン及び/又は酢酸エチル、より好ましくは水、エタノール、メタノール及び/又はピリジン、より好ましくは水及び/又はエタノールが加えられることを特徴とする、項6に記載の方法。
<項8>
前記混合物が、使用されるPVPのガラス転移温度よりも高い温度に少なくとも5分間維持されることを特徴とする、項6又は項7に記載の方法。
<項9>
治療方法に使用するための、好ましくは腫瘍疾患を治療するための光線力学療法(PDT)に適用するための、項4又は項5に記載の医薬組成物。
<項10>
表面又は液体を滅菌及び/又は消毒するための、項1〜項3のいずれか一項に記載の複合体の使用。
Claims (10)
- 複合体全体に対するヒペリシン又はヒペリシン塩の平均重量割合が6重量%を超えることを特徴とする、ヒペリシン又はヒペリシン塩と、ポリビニルピロリドン(PVP)とから形成された複合体。
- 前記複合体中のPVPに対するヒペリシンの平均モル比が2.5を超えることを特徴とする、請求項1に記載の複合体。
- 前記PVPが10〜40kD、好ましくは12〜25kDの平均モル質量を有することを特徴とする、請求項1又は請求項2に記載の複合体。
- 請求項1〜請求項3のいずれか一項に記載の複合体を含有する医薬組成物。
- 前記組成物が静脈内投与用に提供され、前記組成物が少なくとも25mg/Lの濃度でヒペリシンを含有することを特徴とする、請求項4に記載の医薬組成物。
- ヒペリシンとPVPとの混合物が、使用されるPVPのガラス転移温度よりも高い温度に加熱されることを特徴とする、請求項1〜請求項3のいずれか一項に記載の複合体の製造方法。
- ヒペリシンとPVPとの前記混合物に、溶媒又は溶媒の混合物、好ましくは水、エタノール、メタノール、ピリジン、アセトン、エチルメチルケトン及び/又は酢酸エチル、より好ましくは水、エタノール、メタノール及び/又はピリジン、より好ましくは水及び/又はエタノールが加えられることを特徴とする、請求項6に記載の方法。
- 前記混合物が、使用されるPVPのガラス転移温度よりも高い温度に少なくとも5分間維持されることを特徴とする、請求項6又は請求項7に記載の方法。
- 治療方法に使用するための、好ましくは腫瘍疾患を治療するための光線力学療法(PDT)に適用するための、請求項4又は請求項5に記載の医薬組成物。
- 表面又は液体を滅菌及び/又は消毒するための、請求項1〜請求項3のいずれか一項に記載の複合体の使用。
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EP18183435.9 | 2018-07-13 | ||
EP18183435.9A EP3593815A1 (de) | 2018-07-13 | 2018-07-13 | Hypericin-pvp komplex mit hohem hypericinanteil |
PCT/EP2019/068775 WO2020011960A1 (de) | 2018-07-13 | 2019-07-12 | Hypericin-pvp komplex mit hohem hypericinanteil |
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US20060127349A1 (en) * | 2000-05-23 | 2006-06-15 | Andreas Kubin | Novel of preparation hypericin bonded with poly-n-vinylamides |
JP2013035819A (ja) * | 2011-08-09 | 2013-02-21 | Norimichi Kawashima | 薬剤およびその使用方法 |
US20180055935A1 (en) * | 2015-09-28 | 2018-03-01 | Sanochemia Pharmazeutika Ag | Method for the production of a formulation of a hypericin salt |
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US9629932B2 (en) | 2015-09-28 | 2017-04-25 | Sanochemia Pharmazeutika Ag | Photodynamic diagnosis, formulations usable as photosensitizers for this purpose, method for the production and use thereof |
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US20060127349A1 (en) * | 2000-05-23 | 2006-06-15 | Andreas Kubin | Novel of preparation hypericin bonded with poly-n-vinylamides |
JP2013035819A (ja) * | 2011-08-09 | 2013-02-21 | Norimichi Kawashima | 薬剤およびその使用方法 |
US20180055935A1 (en) * | 2015-09-28 | 2018-03-01 | Sanochemia Pharmazeutika Ag | Method for the production of a formulation of a hypericin salt |
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PHARMAZIE, vol. 63, JPN6022017532, 2008, pages 263 - 269, ISSN: 0005064372 * |
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EP3820524A1 (de) | 2021-05-19 |
US20210260192A1 (en) | 2021-08-26 |
ES2964390T3 (es) | 2024-04-05 |
WO2020011960A1 (de) | 2020-01-16 |
ZA202007995B (en) | 2022-06-29 |
CN112533634B (zh) | 2023-02-24 |
JP7323259B2 (ja) | 2023-08-08 |
EP3820524B1 (de) | 2023-09-06 |
KR20210031897A (ko) | 2021-03-23 |
SG11202012794VA (en) | 2021-01-28 |
EP3593815A1 (de) | 2020-01-15 |
BR112021000404A2 (pt) | 2021-04-06 |
MX2020013925A (es) | 2021-03-29 |
EP3820524C0 (de) | 2023-09-06 |
CN112533634A (zh) | 2021-03-19 |
AU2019300351B2 (en) | 2024-05-02 |
IL279753A (en) | 2021-03-01 |
PL3820524T3 (pl) | 2024-02-26 |
PE20210925A1 (es) | 2021-05-19 |
AU2019300351A1 (en) | 2021-01-21 |
CA3104404A1 (en) | 2020-01-16 |
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