JP2015057407A - ネビボロールおよび医薬的に許容しうる塩、ネビボロールの製造方法、および医薬組成物 - Google Patents
ネビボロールおよび医薬的に許容しうる塩、ネビボロールの製造方法、および医薬組成物 Download PDFInfo
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- JP2015057407A JP2015057407A JP2014218548A JP2014218548A JP2015057407A JP 2015057407 A JP2015057407 A JP 2015057407A JP 2014218548 A JP2014218548 A JP 2014218548A JP 2014218548 A JP2014218548 A JP 2014218548A JP 2015057407 A JP2015057407 A JP 2015057407A
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- Prior art keywords
- nebivolol
- hydrochloride
- methanol
- formula
- benzopyran
- Prior art date
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- 229960000619 nebivolol Drugs 0.000 title claims abstract description 98
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 114
- JWEXHQAEWHKGCW-VCVZPGOSSA-N (S,R,R,R)-nebivolol hydrochloride Chemical compound [Cl-].C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)C[NH2+]C[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 JWEXHQAEWHKGCW-VCVZPGOSSA-N 0.000 claims description 100
- 229940068174 nebivolol hydrochloride Drugs 0.000 claims description 91
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
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- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 8
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- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract description 8
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 abstract description 6
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 22
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 18
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- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940098462 oral drops Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000003901 oxalic acid esters Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical class CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical class [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229920003124 powdered cellulose Chemical class 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229940023144 sodium glycolate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Chemical class 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical class [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229960005137 succinic acid Drugs 0.000 description 1
- 239000005720 sucrose Chemical class 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
- JEJAMASKDTUEBZ-UHFFFAOYSA-N tris(1,1,3-tribromo-2,2-dimethylpropyl) phosphate Chemical compound BrCC(C)(C)C(Br)(Br)OP(=O)(OC(Br)(Br)C(C)(C)CBr)OC(Br)(Br)C(C)(C)CBr JEJAMASKDTUEBZ-UHFFFAOYSA-N 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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Abstract
【解決手段】ネビボロールの改良合成方法は、不要な異性体不純物を減少、所望の高純度のジアステレオマー混合物を合成する方法を発展させ、有害な水素化ナトリウムを用いず、同時にネビボロール合成の処理工程を減らした方法。即ち、6−フルオロ−3,4−ジヒドロベンゾピラン−2−アルデヒドをカリウムtert−ブトキシドの存在下、アルデヒド基をオキシラン基に変換した後、該化合物のベンジル化体と該化合物とを反応させ、ベンジル化ネビボロール塩基を経由する上記式(I)で表される塩を製造する方法。ネビボロールを有効成分として使用し、且つ湿潤剤不使用で調製された医薬組成物は、優れた溶解性を示す。更に、フォームT1と称するネビボロール及び医薬的に許容しうる塩の新しい非晶形についても記載する。
【選択図】なし
Description
− 6−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−2−カルボキシアルデヒド(VI)は、塩基としてのカリウムtert−ブトキシドの存在下、式(VII)で表されるオキシラン異性体混合物に変換され、
− (VII)のベンジル化A−異性体(すなわち、中間体I)とB−異性体(VII−B)との反応、および反応生成物の単離は有機溶媒の存在下、時間および温度条件を管理して行い、フリーベンジル化ネビボロール塩基(IX)の生成に至る。
(i)カラムクロマトグラフィーの使用を回避し、
(ii)シュウ酸塩調製およびその再結晶化工程を回避し、および
(iii)続くシュウ酸塩のアルカリ処理によるフリーベンジル化ネビボロール塩基への変換を回避する。
5.4330±0.2、11.1544±0.2および19.7730±0.2(度2−シータ)に顕著なピークがある。
b. ネビボロールまたは医薬的に許容しうる塩、およびヒドロキシプロピルメチルセルロースまたはポビドンの、メタノールまたは適当な溶媒、および水の溶液を調製する。
c. 上記工程(b)の溶液を工程1(a)の乾燥混合希釈物に吸着させる。
d. 上記工程(c)の結果物を乾燥し、水で顆粒する。
e. 濡れた顆粒を60℃で乾燥し、乾燥した顆粒を#30メッシュのふるいにかける。
f. 工程(e)顆粒を、クロスカルメロースナトリウム、コロイド状二酸化ケイ素、微結晶セルロースおよびステアリン酸マグネシウムで潤滑化し、混合機で混合する。
g. 工程(IV)で得た顆粒を錠剤に加圧する、または顆粒をカプセルに充填する。
あるいは、
(I) ネビボロールまたは医薬的に許容しうる塩、ラクトース、スターチおよびクロスカルメロースナトリウムをメッシュ#60のふるいに通し、適当に混合する。
(II) 水性または非水性の造粒溶媒中ヒドロキシプロピルメチルセルロースまたはポビドンを使用して結合剤溶液を調製する。
(III)工程(I)−cまたは(I’)の粉末混合物を工程IIの結合剤溶液で高速ミキサー中で顆粒化し、流動床乾燥機中で顆粒を乾燥する。
(IV) 工程(III)の顆粒をクロスカルメロースナトリウム、コロイド状二酸化ケイ素、微結晶セルロースおよびステアリン酸マグネシウムで潤滑化し、ケージブレンダー中で混合する。
(V) 工程(IV)で得た顆粒を錠剤に加圧し、または顆粒をカプセルに充填する。
6−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−2−カルボン酸ピペリジンアミド(V)の調製
6−フルオロ−3,4−ジヒドロ−2H−1−ベンゾピラン−2−カルボキシアルデヒド(Vl)の調製
6−フルオロ−3,4−ジヒドロ−2−オキシラニル−2H−1−ベンゾピラン(VII)の調製
(A)−6−フルオロジヒドロ−α−[[(フェニルメチル)アミノ]−メチル]−2H−1−ベンゾピラン−2−メタノール(中間体−1)の調製
ベンジル化ネビボロール塩基(VIII)の調製
ネビボロール塩基(IX)の調製
反応溶媒にメタノールを使用したネビボロールHCl(I)の調製、およびネビボロールHCl(I)の精製
m.p.範囲:223−227℃
収率(%):96.33%
HPLC純度:99.89%
反応溶媒にイソプロピルアルコールを使用したネビボロールHCl(I)の調製およびネビボロールHCl(I)の精製
m.p.範囲:223−227℃
収率(%):97.24%
HPLC純度:99.16%
反応溶媒にエタノールを使用したネビボロール塩基(IX)からネビボロールHCl(I)の調製およびネビボロールHCl(I)の精製
m.p.範囲:223−227℃
収率(%):96.33%
HPLC純度:99.45%
ベンジル化ネビボロール塩基(VIII)からの塩酸ネビボロール(I)の調製
ベンジル化ネビボロール塩基(40.0g)を、2−メトキシエタノール(300ml)および10%パラジウム炭素(6.0g)とともに、還元装置に加えた。水素ガスで圧力を160−170psiとし、70−75℃に加熱した。温度および圧力条件を3.0時間維持し、反応完了をTLC/HPLCで確認した。反応混合物を室温に冷却し、高流動床でろ過し、触媒を分離した。ろ液を65−70℃に加熱し、続いて塩酸(35%)14.0mlを添加した。反応マスを2.0時間攪拌した。該物質をろ過し、続いて、メタノール(800.0ml)を添加し、60−65℃に加熱し、澄明溶液を得た。高流動床でろ過した。ろ液を容量20%まで真空蒸留した。その後、反応マスを0−5℃に冷却し、同一温度で2.0時間攪拌した。該物質をろ過し、55−60℃で乾燥し、表題の化合物28.0gを得た。
HPLC純度:99.99%
フォームT1の調製
フォームT1の調製
粉末X−線回折データ:Table1に示される。
錠剤の調製
錠剤の調製
錠剤の調製
錠剤の調製
錠剤の調製
錠剤の調製
錠剤の調製
錠剤の調製
本発明のネビボロール錠剤(テスト処方)とnebilet錠剤(参考処方)の、バイオアベイラビリティーデータの比較
Claims (33)
- 2H−1−ベンゾピラン−2−メタノール,α,α’[イミノビス(メチレン)]ビス[6−フルオロ−3,4−ジヒドロ−,[2R*[R*[R*(S*)]]]]、すなわち式(IX)のネビボロール塩基、またはその塩酸塩の改良製造方法であって、
(a) 本明細書において規定されるような適当な有機溶媒の存在下、(A)−6−フルオロジヒドロ−α−[[(フェニルメチル)アミノ]−メチル]−2H−1−ベンゾピラン−2−メタノール、すなわち中間体−I
を含む改良製造方法。 - 2H−1−ベンゾピラン−2−メタノール,α,α’[イミノビス(メチレン)]ビス[6−フルオロ−3,4−ジヒドロ−,[2R*[R*[R*(S*)]]]]、すなわち式(IX)のネビボロール塩基またはその塩酸塩の改良製造方法であり、
- 工程(a)で使用する有機溶媒が、アルコール、エステルおよびケトンを含む群から選ばれる請求項1に記載の方法。
- アルコールがメタノール、エタノール、イソプロピルアルコール、n−プロピルアルコール、n−ブタノール、イソブタノールを含む群から選ばれる請求項3に記載の方法。
- アルコールがメタノールである請求項3に記載の方法。
- エステルが、酢酸エチル、酢酸n−ブチルを含む群から選ばれる請求項3に記載の方法。
- ケトンがアセトン、メチルエチルケトン、メチルイソブチルケトン(MIBK)を含む群から選ばれる請求項3に記載の方法。
- 工程(a)の単離を温度−10°から−15℃で行う請求項1に記載の方法。
- 工程(a)の反応マスを該単離温度に10−15時間維持する請求項1に記載の方法。
- 工程(c)で使用する有機溶媒がアルコール、エステル、ケトン、ハロゲン化溶媒、アセトニトリルおよび水またはその混合を含む群から選ばれる請求項1に記載の方法。
- アルコールがメタノール、エタノール、n−プロパノール、イソプロパノール、n−ブタノール、イソブタノールおよび同類のものを含む群から選ばれる請求項10に記載の方法。
- アルコールがメタノールである請求項10に記載の方法。
- アルコールがイソプロピルアルコールである請求項10に記載の方法。
- アルコールがエタノールである請求項10に記載の方法。
- 工程(c)で得た塩酸ネビボロールが、RSSSおよびSRRR異性体のジアステレオマーとして純粋な混合物である請求項1に記載の方法。
- ジアステレオマーとして純粋な前記混合物の純度が99.0%以上である請求項15に記載の方法。
- ジアステレオマーとして純粋な前記混合物の純度が99.5%以上である請求項15に記載の方法。
- ジアステレオマーとして純粋な前記混合物の純度が99.8%以上である請求項15に記載の方法。
- 塩酸ネビボロールおよび医薬的に許容しうる担体を含み、湿潤剤を含まず、任意に結合剤および/または崩壊剤を含むことを特徴とする医薬組成物。
- 医薬組成物が錠剤またはカプセルである請求項19に記載の医薬組成物。
- 塩酸ネビボロールが0.5%から10%w/w;希釈剤が78%から93.05%w/w;滑沢剤が0.25%から3%w/w;および流動促進剤が0.25%から3%w/w;任意の結合剤が0.5%から5%w/w;および/または崩壊剤が0.5%から10%w/wの範囲である請求項19に記載の医薬組成物。
- 45分で75%以上の溶解性を有することを特徴とする請求項20に記載の錠剤。
- 非晶形のネビボロールまたはその医薬的に許容しうる塩。
- 非晶フォームT1の塩酸ネビボロール。
- 約5.4330±0.2、11.1544±0.2および19.7730±0.2(度2−シータ)にピークを有する粉末X−線回折パターンを特徴とする塩酸ネビボロールフォームT1。
- 約11.67±0.2、16.54±0.2、22.75±0.2、25.41±0.2、29.81±0.2、31.56±0.2、32.09±0.2(度2−シータ)にピークを有さない粉末X−線回折パターンを特徴とする塩酸ネビボロールフォームT1。
- 塩酸ネビボロールフォームT1の製造方法であって、以下の工程;
(a)塩酸ネビボロールをアルコールに溶解し、澄明溶液を得る工程;
(b)溶液を噴霧または凍結乾燥して塩酸ネビボロールフォームT1を得る工程;および、
(c)塩酸ネビボロールフォームT1を単離する工程
を含む方法。 - 塩酸ネビボロールフォームT1の製造方法であって、以下の工程;
(a)ネビボロール塩基をアルコールに溶解または懸濁する工程;
(b)塩酸または塩化水素を加え、溶液または懸濁液のpHを2.0より下げる工程;
(c)溶液/懸濁液を噴霧乾燥/凍結乾燥し、塩酸ネビボロールフォームT1を得る工程;および
(d)塩酸ネビボロールフォームT1を単離する工程
を含む方法。 - 実質的に本明細書および特許請求の範囲に記載する、特に本明細書に記載の実施例に準拠する、塩酸ネビボロールおよび医薬的に許容しうる担体を含み、湿潤剤を使用しない医薬組成物。
- 実質的にFigure1に示されるX−線回折パターンを特徴とする非晶質塩酸ネビボロール。
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