JP6038132B2 - ニチシノンを含む液体薬学的組成物 - Google Patents
ニチシノンを含む液体薬学的組成物 Download PDFInfo
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- JP6038132B2 JP6038132B2 JP2014516952A JP2014516952A JP6038132B2 JP 6038132 B2 JP6038132 B2 JP 6038132B2 JP 2014516952 A JP2014516952 A JP 2014516952A JP 2014516952 A JP2014516952 A JP 2014516952A JP 6038132 B2 JP6038132 B2 JP 6038132B2
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- OUBCNLGXQFSTLU-UHFFFAOYSA-N nitisinone Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1C(=O)C1C(=O)CCCC1=O OUBCNLGXQFSTLU-UHFFFAOYSA-N 0.000 title claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 239000007788 liquid Substances 0.000 title claims description 5
- 229960001721 nitisinone Drugs 0.000 title description 11
- 239000000203 mixture Substances 0.000 claims description 34
- 238000009472 formulation Methods 0.000 claims description 33
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 16
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 16
- 239000003755 preservative agent Substances 0.000 claims description 14
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 11
- 229920000053 polysorbate 80 Polymers 0.000 claims description 11
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 9
- 229940068968 polysorbate 80 Drugs 0.000 claims description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 8
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 8
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 8
- 229960002216 methylparaben Drugs 0.000 claims description 8
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 8
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 8
- 229960003415 propylparaben Drugs 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 239000000796 flavoring agent Substances 0.000 claims description 7
- 230000002335 preservative effect Effects 0.000 claims description 7
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical group [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 7
- 235000010234 sodium benzoate Nutrition 0.000 claims description 7
- 239000004299 sodium benzoate Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 201000011296 tyrosinemia Diseases 0.000 claims description 6
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- 239000004094 surface-active agent Substances 0.000 claims description 5
- 239000003765 sweetening agent Substances 0.000 claims description 5
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 4
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 235000013355 food flavoring agent Nutrition 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- 239000000375 suspending agent Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
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- 239000007979 citrate buffer Substances 0.000 claims description 3
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- 108010068327 4-hydroxyphenylpyruvate dioxygenase Proteins 0.000 description 7
- 102100028626 4-hydroxyphenylpyruvate dioxygenase Human genes 0.000 description 7
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- QCYUKTBJHGSJBC-UHFFFAOYSA-N 2-nitro-4-(trifluoromethyl)benzoyl chloride Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1C(Cl)=O QCYUKTBJHGSJBC-UHFFFAOYSA-N 0.000 description 2
- 241000220223 Fragaria Species 0.000 description 2
- 235000016623 Fragaria vesca Nutrition 0.000 description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 2
- 102100029115 Fumarylacetoacetase Human genes 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 108010022687 fumarylacetoacetase Proteins 0.000 description 2
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- SURCGQGDUADKBL-UHFFFAOYSA-N 2-(2-hydroxyethylamino)-5-nitrobenzo[de]isoquinoline-1,3-dione Chemical compound [O-][N+](=O)C1=CC(C(N(NCCO)C2=O)=O)=C3C2=CC=CC3=C1 SURCGQGDUADKBL-UHFFFAOYSA-N 0.000 description 1
- XMLFPUBZFSJWCN-UHFFFAOYSA-N 2-Hydroxy-4-trifluoromethyl benzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1O XMLFPUBZFSJWCN-UHFFFAOYSA-N 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- MYSAXQPTXWKDPQ-UHFFFAOYSA-N 2-nitro-4-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1[N+]([O-])=O MYSAXQPTXWKDPQ-UHFFFAOYSA-N 0.000 description 1
- OMFWHSRZHVVVAL-UHFFFAOYSA-N 3,5-dioxooctanedioic acid Chemical compound OC(=O)CCC(=O)CC(=O)CC(O)=O OMFWHSRZHVVVAL-UHFFFAOYSA-N 0.000 description 1
- WYEPBHZLDUPIOD-UHFFFAOYSA-N 4,6-dioxoheptanoic acid Chemical compound CC(=O)CC(=O)CCC(O)=O WYEPBHZLDUPIOD-UHFFFAOYSA-N 0.000 description 1
- GACSIVHAIFQKTC-OWOJBTEDSA-N 4-fumarylacetoacetic acid Chemical compound OC(=O)CC(=O)CC(=O)\C=C\C(O)=O GACSIVHAIFQKTC-OWOJBTEDSA-N 0.000 description 1
- GACSIVHAIFQKTC-UPHRSURJSA-N 4-maleylacetoacetic acid Chemical compound OC(=O)CC(=O)CC(=O)\C=C/C(O)=O GACSIVHAIFQKTC-UPHRSURJSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
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- 150000001413 amino acids Chemical class 0.000 description 1
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- 235000010233 benzoic acid Nutrition 0.000 description 1
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- 230000006652 catabolic pathway Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
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- 230000002068 genetic effect Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
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- 230000002363 herbicidal effect Effects 0.000 description 1
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- 208000015181 infectious disease Diseases 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
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- 208000007903 liver failure Diseases 0.000 description 1
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- -1 polyoxyethylene Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
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- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Classifications
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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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
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- Veterinary Medicine (AREA)
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pain & Pain Management (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
本発明によれば、微粒子化されたニチシノンの懸濁液を含み、pHが約3の液体薬学的製剤が、安定性の増加のような、驚くべき有利な性質を持つことが示された。したがって、本発明は、以下:
(a) 微粒子化された有効量の2-(2-ニトロ-4-トリフルオロメチルベンゾイル)-1,3-シクロヘキサンジオン(ニチシノン)の懸濁液;及び
(b)pH2.5〜3.5、好ましくはpH3.0のクエン酸緩衝液
を含む、経口投与に好適な液体薬学的製剤に関連する。
(a)ニチシノン(4mg/ml);
(b)クエン酸一水和物(9mg/ml);
(c)無水クエン酸三ナトリウム(2.1mg/ml);
(d)ヒドロキシプロピルメチルセルロース(5mg/ml);
(e)グリセロール(500mg/ml);
(f)メチルパラベン(1.4mg/ml);
(g)プロピルパラベン(0.14mg/ml);及び
(h)ポリソルベート80(0.14mg/ml)。
(a)ニチシノン(4mg/ml);
(b)クエン酸一水和物(9mg/ml);
(c)無水クエン酸三ナトリウム(2.1mg/ml);
(d)ヒドロキシプロピルメチルセルロース(5mg/ml);
(e)グリセロール(500mg/ml);
(f)安息香酸ナトリウム(1.0mg/ml);及び
(g)ポリソルベート80(0.14mg/ml)。
(h)イチゴフレーバー(0.7mg/ml)。
実験室規模のエアジェットミル、2インチ認定モデル、Sturtevant Inc.を、スイスのBachem社から得たニチシノンを微粒子化するのに使用した。ミルは、並行流(すなわち、空気と薬物がミルチェンバーの中で同じ方向に送られる)で操作した。粉砕されていない薬剤は、送給される材料をミルチェンバーに引き入れるために空気を用いる、Venturi送給システムであるSyncron(登録商標)Magnet Feeder model F-TO-Cを用いてミルに送られた。製品フィルターバッグをミルの出口に取り付け、排気と粉砕された薬物を集めた。ミル粉砕の条件は、下記のように設定した。
・摩砕エア:乾燥窒素ガス
・摩砕圧力:90psi
・送給圧力:85psi
・室内条件:室温
表IIに示すように、本発明の製剤を、標準的な製法に従って調製した。
表IIIに示すように、本発明の製剤を、標準的な製法に従って調製した。
表IVに示すニチシノン溶液を、標準的な製法に従って調製した。
異なる量の保存料の結果を、下記表V及び表VIに示す。
実施例2に従って調製された微粒子化されたニチシノン経口懸濁液のサンプル、及び実施例4に従って調製されたニチシノンを、12か月間、+5℃、+25℃、及び+40℃それぞれで、安定性のために置いた。ニチシノンと分解生成物である6-(トリフルオロメチル)-3,4-ジヒドロ-1H-キサンテネン(xanthenene)-1,9(2H)-ジオン(オキソテトラヒドロキサンテノン)の濃度を、紫外線検出付HPLCで追跡した。結果は表VII〜表Xに示され、ニチシノンの、表示濃度に対するパーセントとして表されている(表示量に対する割合(%))。
実施例6の主な分解生成物である、オキソテトラヒドロキサンテノンの安定性研究を、実施例6に記載の条件と類似の条件で行う。クエン酸緩衝液pH3.0中またはリン酸緩衝液pH6.8中のオキソテトラヒドロキサンテノン(OTHX)81μg/mlの試料を、6か月間、+5℃、+25℃、及び+37℃それぞれで、安定性のために置いた。OTHXの濃度及び、二次的分解生成物である1,3-シクロヘキサンジオン(CHD)及び4-(トリフルオロメチル)サリチル酸(TSA)を、LC-MSによって分析した。結果は下記表XIに示され、OTHXの初期濃度に対する割合(%)として表されている。OTHXの初期濃度と比較したCHD+OTHX+TSAの総回収率として表される物質収支は、μg/mlで表されたMmOTHX/(MmCHD+MmTSA)×(CHDconc+TSAconc)+OTHXconcから計算され、ここで、MmOTHX、MmCHD及びMmTSAはそれぞれ、282g/mol、202g/mol及び206g/molに相当する分子量である。物質収支の結果は、OTHXの初期濃度に対する%として表され、表XIIに示されている。
Claims (18)
- (a)有効量の微粒子化された2-(2-ニトロ-4-トリフルオロメチルベンゾイル)-1,3-シクロヘキサンジオン(ニチシノン)の懸濁液;及び
(b)pH2.5〜3.5、好ましくはpH3.0のクエン酸緩衝液
を含む、経口投与に適した液体薬学的製剤。 - ニチシノンの量が、1〜10mg/ml、好ましくは4mg/mlである、請求項1記載の製剤。
- 懸濁剤、甘味料、保存料、界面活性剤、及び香味料からなる群から選択された、一つ以上の薬学的に許容される成分をさらに含む、請求項1記載の製剤。
- 懸濁剤が、ヒドロキシプロピルメチルセルロースである、請求項3記載の製剤。
- 懸濁剤が、1〜20mg/ml、好ましくは5mg/mlの量のヒドロキシプロピルメチルセルロースである、請求項4記載の製剤。
- 甘味料がグリセロールである、請求項3記載の製剤。
- 甘味料が、100〜500mg/ml、好ましくは500mg/mlの量のグリセロールである、請求項6記載の製剤。
- 保存料が、メチルパラベン及び/またはプロピルパラベンである、請求項3記載の製剤。
- 保存料が、1〜2mg/ml、好ましくは1.4mg/mlの量のメチルパラベン、及び0.1〜0.2mg/ml、好ましくは0.14mg/mlの量のプロピルパラベンである、請求項8記載の製剤。
- 保存料が、0.2〜5mg/ml、好ましくは1mg/mlの量の安息香酸ナトリウムである、請求項3記載の製剤。
- 界面活性剤が、ポリソルベート80である、請求項3記載の製剤。
- 界面活性剤が、0.1〜20mg/ml、好ましくは0.10〜0.15mg/mlの量のポリソルベート80である、請求項11記載の製剤。
- (a)ニチシノン(4mg/ml);
(b)クエン酸一水和物(9mg/ml);
(c)無水クエン酸三ナトリウム(2.1mg/ml);
(d)ヒドロキシプロピルメチルセルロース(5mg/ml);
(e)グリセロール(500mg/ml);
(f)メチルパラベン(1.4mg/ml);
(g)プロピルパラベン(0.14mg/ml);及び
(h)ポリソルベート80(0.14mg/ml)
を含む、請求項1〜9、11、または12のいずれか一項記載の製剤。 - (a)ニチシノン(4mg/ml);
(b)クエン酸一水和物(9mg/ml);
(c)無水クエン酸三ナトリウム(2.1mg/ml);
(d)ヒドロキシプロピルメチルセルロース(5mg/ml);
(e)グリセロール(500mg/ml);
(f)安息香酸ナトリウム(1.0mg/ml);及び
(g)ポリソルベート80(0.14mg/ml)
を含む、請求項1〜7または10〜12のいずれか一項記載の製剤。 - 香味料をさらに含む、請求項13または14記載の製剤。
- チロシン血症、パーキンソン病、うつ病、下肢静止不能症候群、及びアルカプトン尿症から選択される医学的状態の処置に使用するための、請求項1〜15のいずれか一項記載の製剤。
- 遺伝性チロシン血症I型(HT-1)の処置に使用するための、請求項16記載の製剤。
- 小児患者の遺伝性チロシン血症I型(HT-1)の処置に使用するための、請求項17記載の製剤。
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WO2013181292A1 (en) * | 2012-05-29 | 2013-12-05 | Biotie Therapies, Inc. | Nitisinone formulations |
MA39918A (fr) | 2014-04-30 | 2017-03-08 | Swedish Orphan Biovitrum Int Ab | Régimes posologiques de la nitisinone pour le traitement de l'alcaptonurie |
CN104623428A (zh) * | 2015-03-13 | 2015-05-20 | 庄彩梅 | 一种缓解遗传性酪氨酸血症的中药制剂及其制备方法 |
ITUB20160650A1 (it) | 2016-02-11 | 2017-08-11 | Dipharma S A | Formulazioni farmaceutiche solide stabili contenenti 2-(2-nitro-4-trifluorometilbenzoil)-1,3-cicloesandione |
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