JP4680894B2 - 安定化させた煙霧剤分散体 - Google Patents
安定化させた煙霧剤分散体 Download PDFInfo
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- JP4680894B2 JP4680894B2 JP2006509816A JP2006509816A JP4680894B2 JP 4680894 B2 JP4680894 B2 JP 4680894B2 JP 2006509816 A JP2006509816 A JP 2006509816A JP 2006509816 A JP2006509816 A JP 2006509816A JP 4680894 B2 JP4680894 B2 JP 4680894B2
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- dispersion
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- drug
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- propellant
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 1
- 229960004398 nedocromil Drugs 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- FTMKAMVLFVRZQX-UHFFFAOYSA-N octadecylphosphonic acid Chemical compound CCCCCCCCCCCCCCCCCCP(O)(O)=O FTMKAMVLFVRZQX-UHFFFAOYSA-N 0.000 description 1
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 1
- NJGCRMAPOWGWMW-UHFFFAOYSA-N octylphosphonic acid Chemical compound CCCCCCCCP(O)(O)=O NJGCRMAPOWGWMW-UHFFFAOYSA-N 0.000 description 1
- MSRJTTSHWYDFIU-UHFFFAOYSA-N octyltriethoxysilane Chemical compound CCCCCCCC[Si](OCC)(OCC)OCC MSRJTTSHWYDFIU-UHFFFAOYSA-N 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 229960001609 oxitropium bromide Drugs 0.000 description 1
- LCELQERNWLBPSY-KHSTUMNDSA-M oxitropium bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-KHSTUMNDSA-M 0.000 description 1
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- VTRUBDSFZJNXHI-UHFFFAOYSA-N oxoantimony Chemical compound [Sb]=O VTRUBDSFZJNXHI-UHFFFAOYSA-N 0.000 description 1
- RVTZCBVAJQQJTK-UHFFFAOYSA-N oxygen(2-);zirconium(4+) Chemical compound [O-2].[O-2].[Zr+4] RVTZCBVAJQQJTK-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- BRFMYUCUGXFMIO-UHFFFAOYSA-N phosphono dihydrogen phosphate phosphoric acid Chemical compound OP(O)(O)=O.OP(O)(=O)OP(O)(O)=O BRFMYUCUGXFMIO-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920006294 polydialkylsiloxane Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 229960002288 procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 1
- 229960002720 reproterol Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical class [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 description 1
- 229910001887 tin oxide Inorganic materials 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- DENFJSAFJTVPJR-UHFFFAOYSA-N triethoxy(ethyl)silane Chemical compound CCO[Si](CC)(OCC)OCC DENFJSAFJTVPJR-UHFFFAOYSA-N 0.000 description 1
- JCVQKRGIASEUKR-UHFFFAOYSA-N triethoxy(phenyl)silane Chemical compound CCO[Si](OCC)(OCC)C1=CC=CC=C1 JCVQKRGIASEUKR-UHFFFAOYSA-N 0.000 description 1
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 description 1
- HQYALQRYBUJWDH-UHFFFAOYSA-N trimethoxy(propyl)silane Chemical compound CCC[Si](OC)(OC)OC HQYALQRYBUJWDH-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229910001928 zirconium oxide Inorganic materials 0.000 description 1
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 1
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
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Description
PEG変性シリカナノ粒子(PEG−ナノSiO2)の調製
PEG変性シリカナノ粒子(PEG−ナノSiO2)を次のようにして調製した。ガラス容器内で、イリノイ州ネーパービルのナルコ・ケミカル(Nalco Chemical Co.(Naperville、IL))からの平均粒度5nmおよび表面積約600m2/gを有する525gのアンモニア安定化コロイドシリカ(15%固形分)(NALCO 2326)をコネチカット州ミドルベリのクロンプトン・ケミカルズ(Crompton Chemicals(Middlebury、CT)から入手できる46.3gのポリエトキシル化トリアルコキシシラン(SILQUEST A1230)および203.5gの蒸留水と組み合わせた。容器を密封して、80℃のオーブンに16時間入れた。得られた沈殿組成物を蒸発によって乾燥させた。乾燥させた粒子にトルエンを添加して、溶液を無水酢酸と共に還流してあらゆる未反応−OH基をキャップした。ロータリーエバポレータを使用してトルエンを除去し、白色粉末を得た。
コロイド加水分解酸化鉄ナノ粒子を次のようにして調製した。2Lの0.375M 鉄硝酸九水和物溶液に、1Lの1.875M重炭酸アンモニウム溶液を迅速に撹拌しながら滴下して添加した。添加完了後、ジョージア州サバナのスペクトラム・ラボラトリーズ(Spectrum Laboratories,Inc.(Savannah、GA))からの透析管(ほぼ1メートルの長さ、1000 MWCO Spectra/Por)を加水分解した硝酸第二鉄の撹拌された溶液に浸漬し、脱イオン水を緩慢に通過させて、溶液を脱イオン水に対して透析した。約5相当容量の脱イオン水で透析した後、透析の残りの時間、コロイド加水分解酸化鉄ナノ粒子溶液を約65℃に加熱した。追加的な7相当容積の脱イオン水を使用して、透析を継続した。
アルドリッチ・ケミカル(Aldrich Chemical Company)からのポリ(酸化エチレン)(4または6腕、ヒドロキシ末端)を温度80℃で容器内の過剰な無水酢酸に添加した。窒素下で24時間、容器内の混合物を撹拌し、続いて過剰な無水酢酸を真空下で除去した。IR分析からはヒドロキシル基の形跡は示されなかった。
米国特許出願公開第2002/0128336号で述べられるようにして、イソ−オクチル置換シリカナノ粒子(IO−ナノSiO2)を調製した。
表面変性PAMAM(第2世代)デンドリマー(PAMAM G−2)を次のようにして調製した。
ドイツ国ザルツバッハ・アム・タウヌスのクラリアント(Clariant(Sulzbach am Taunus、Germany))から入手できる100gの単官能性ポリエチレングリコール(ポリグリコールM、1100 MW、以下MPEG 1100と称する)をトルエン内で24時間共沸的に乾燥させ、引き続いて50℃で絶えず撹拌しながら2モル過剰量のナトリウム金属(4.2g)を添加した。温度を75℃に上昇させて、反応を24時間進行させた。反応を室温に冷却してあらゆる未反応ナトリウムを除去し、さらに10℃に冷却した。アルドリッチ・ケミカル(Aldrich Chemical Company)からのt−ブチルブロモ酢酸(30mL、2.25モル過剰量)を添加して、反応を絶えず撹拌しながら48時間進行させ、温度を徐々に室温に上昇させた。反応を真空濾過してNaBr塩を除去し、トルエンをロータリーエバポレータ上で蒸発させた。M−PEG 1100 t−ブチルエステル生成物を300mLの塩化メチレンに溶解し、精製水(3×400mL)で抽出した。有機相を硫酸ナトリウムで乾燥させ、濾過して溶剤をロータリーエバポレータ上で蒸発させた。あらゆる残留揮発性物質を高真空下で110℃において蒸留によって除去した。175mLの精製水中の2.25gの水酸化リチウム一水和物で、生成物を50℃で48時間加水分解した。反応をHClでpH3.0に酸性化して、塩化メチレン(4×300mL)で抽出した。有機相を硫酸ナトリウムで乾燥させ、濾過して溶剤をロータリーエバポレータ上で蒸発させ、12gのM−PEG 1100酸を得て、それを150mLのテトラヒドロフランに溶解し、アルドリッチ・ケミカル(Aldrich Chemical Company)からの2.6gの1,3−ジシクロヘキシルカルボジイミド(1.1モル過剰量)と共に、アルドリッチ・ケミカル(Aldrich Chemical Company)からの2モル過剰量の2.6gのN−ヒドロキシスクシンイミドを添加した。反応を絶えず撹拌しながら0℃で24時間進行させた。次に得られた混合物を真空濾過して、1,3−ジシクロヘキシルカルボジイミドから得られた尿素を除去し、続いてTHFをロータリーエバポレータ上で除去した。
100mLのN,N−ジメチルホルムアミドに、アルドリッチ・ケミカル(Aldrich Chemical Company)からの0.5gスターバースト(STARBURST)PAMAM G−2を0℃で溶解し、5.4gのMPEG 1100−N−ヒドロキシスクシンイミドエステルを添加した。絶えず撹拌しながら反応を2時間進行させた。室温に暖まったら、100mLのトルエンを添加した。得られた溶液を精製水(5×300mL)および1.0NaOH(5×200mL)ですすいだ。ロータリーエバポレータ上でトルエンを蒸発させ、生成物を高真空下で乾燥させた。
開始試薬としてアルドリッチ・ケミカル(Aldrich Chemical Company)からの0.16gのスターバーストPAMAM G−2デンドリマーおよびカリフォルニア州サン・カルロスのネクター(Nektar(San Carlos、CA))から入手できる1.5gのM−PEG 2000スクシンイミジルプロピオネート(MPEG−SPA)を使用したこと以外は、上述のアセチル化PAMAM G−2 MPEG 1100誘導体を製造するのに使用したのと同一の手順に従って、PAMAM G−2 MPEG2000誘導体を調製した。
アセチル化PAMAM G−2 MPEG 1100誘導体の合成のために、アルドリッチ・ケミカル(Aldrich Chemical Company)からの0.4gスターバーストPAMAM G−4(第4世代)デンドリマーを上述のように5.0gのMPEG1100−N−ヒドロキシスクシンイミドエステルで処理した。2時間の反応後に、さらに4.0gのM−PEG−N−ヒドロキシスクシンイミドエステルを添加して、反応をより完全に完了させるために反応をさらに2時間継続した。
MDIキャニスター内に(存在すれば)賦形剤、薬、およびエタノールの量を計量して入れ、次にキャニスター上に連続バルブを圧接して試験する分散体を調製した。連続バルブを通じて既知量の噴霧剤をキャニスター内に押し込んだ。キャニスターをドライアイスにのせて冷却し、キャニスターおよびキャニスターに圧接した定量バルブから連続バルブが除去できるように、分散体の揮発性を十分に低下させた。試験に先だって少なくとも12時間、各分散体を暖めて安定化させた。
懸濁液品質振盪試験を使用して、実施例1〜12および22〜29および比較例A〜DのMDI分散体の物理的安定性を評価した。表2および3で示すような適切な量の薬、ナノ粒子分散剤、噴霧剤、アルコール、およびいずれかの賦形剤をポリシールキャップ付きガラスバイアル内に入れた。各バイアルを30秒間振盪した。次にバイアルを20分間静置した。20分間後、バイアルの懸濁液特性を視覚的に観察して記録した。分散体を表1に明らかにする評価システムに従って評価した。
振盪−遅延薬物デリバリ(SDMD)試験を使用して、振盪と引き続く投与の計量容積補給との間の遅延の影響を評価した。SDMD試験を行うために、MDIを排気フード内でMDIを4回作動させてMDIをプライムし、MDIを各作動直前に振盪した。MDIをプライムした後それを振盪して、排気フード内でもう1回作動させるのに先だって、規定の時間直立位置に保った。MDIを引き続いて単位スプレー収集装置(USCA−米国薬局方、621節、1996)内で作動させた。30Lpmの流量をUSCA装置に通過させた。MDIが放出した用量をUSCAの壁またはUSCAのフィルター上に収集した。USCAの壁およびフィルターへの付着薬量は、これらの構成要素を適切な溶剤ですすいで薬を溶解し、次に引き続いて適切なHPLC法で溶液を分析して測定した。試験を振盪遅延時間0、30、および60秒間で行った。
薬と表面変性無機ナノ粒子分散体を含む調合物を製作して、実施例1〜12および比較例A〜Dに上述の懸濁液品質振盪試験を行った。試験結果を下に表2で示す。比較例はナノ粒子分散剤を含有しない。結果は、小量の無機ナノ粒子分散体のMDI調合物への添加が、懸濁液品質振盪試験において分散を保つ調合物を作り出すことを実証する。
実施例22〜28の分散体および視覚試験結果を下に表3で示す。これらの実施例では、表2の比較例A〜Dが該当比較対照である。推定される質量−中央値薬粒度は全ての実施例で2.5μmであった。
Claims (4)
- 薬を含んでなる分散した固相、および
噴霧剤および賦形剤ナノ粒子を含んでなる連続液相
を含み、前記ナノ粒子が100nm未満の平均粒子直径を有する、安定した医薬品分散体。 - 計量バルブを有する煙霧剤容器、および
容器内に配置された請求項1に記載の安定した医薬品分散体
を含んでなる定量吸入器。 - 煙霧剤容器を提供するステップと、
前記容器に請求項1に記載の医薬品分散体を装填するステップと、
を含んでなる、煙霧剤分散体を製造する方法。 - 薬を含んでなる分散した固相と、噴霧剤を含んでなる連続液相とを含んでなる分散体に、ナノ粒子を添加するステップを含んでなり、前記ナノ粒子が分散体中に0.001〜2wt%の量で存在する、医薬品分散体を安定化する方法。
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PCT/US2004/010847 WO2004108118A1 (en) | 2003-05-30 | 2004-04-08 | Stabilized aerosol dispersions |
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US (1) | US7459146B2 (ja) |
EP (1) | EP1628645A1 (ja) |
JP (1) | JP4680894B2 (ja) |
KR (1) | KR20060038938A (ja) |
CN (1) | CN1798549B (ja) |
WO (1) | WO2004108118A1 (ja) |
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CN1798549B (zh) | 2011-03-09 |
US7459146B2 (en) | 2008-12-02 |
JP2006526624A (ja) | 2006-11-24 |
US20040241101A1 (en) | 2004-12-02 |
CN1798549A (zh) | 2006-07-05 |
WO2004108118A1 (en) | 2004-12-16 |
KR20060038938A (ko) | 2006-05-04 |
EP1628645A1 (en) | 2006-03-01 |
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