TW514531B - Method for preparing microfluidised particles of atovaquone, and pharmaceutical compositions comprising microfluidized particles of atovaquone - Google Patents
Method for preparing microfluidised particles of atovaquone, and pharmaceutical compositions comprising microfluidized particles of atovaquone Download PDFInfo
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- TW514531B TW514531B TW088101847A TW88101847A TW514531B TW 514531 B TW514531 B TW 514531B TW 088101847 A TW088101847 A TW 088101847A TW 88101847 A TW88101847 A TW 88101847A TW 514531 B TW514531 B TW 514531B
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- 239000002245 particle Substances 0.000 title claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 title abstract description 6
- KUCQYCKVKVOKAY-CTYIDZIISA-N atovaquone Chemical compound C1([C@H]2CC[C@@H](CC2)C2=C(C(C3=CC=CC=C3C2=O)=O)O)=CC=C(Cl)C=C1 KUCQYCKVKVOKAY-CTYIDZIISA-N 0.000 title abstract description 5
- 229960003159 atovaquone Drugs 0.000 title abstract description 5
- 239000000725 suspension Substances 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000000375 suspending agent Substances 0.000 claims description 5
- 239000000230 xanthan gum Substances 0.000 claims description 4
- 229920001285 xanthan gum Polymers 0.000 claims description 4
- 229940082509 xanthan gum Drugs 0.000 claims description 4
- 235000010493 xanthan gum Nutrition 0.000 claims description 4
- 230000002079 cooperative effect Effects 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 208000030852 Parasitic disease Diseases 0.000 claims description 2
- 241000233872 Pneumocystis carinii Species 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 1
- 208000008953 Cryptosporidiosis Diseases 0.000 description 1
- 206010011502 Cryptosporidiosis infection Diseases 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical group CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- MJVAVZPDRWSRRC-UHFFFAOYSA-N Menadione Chemical compound C1=CC=C2C(=O)C(C)=CC(=O)C2=C1 MJVAVZPDRWSRRC-UHFFFAOYSA-N 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- 241000223777 Theileria Species 0.000 description 1
- 241000223779 Theileria parva Species 0.000 description 1
- 201000005485 Toxoplasmosis Diseases 0.000 description 1
- 241001586444 Trilophidia annulata Species 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 210000002500 microbody Anatomy 0.000 description 1
- -1 monochlorophenyl Chemical group 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000003981 vehicle 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Fertilizers (AREA)
- Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
- Medicines Containing Plant Substances (AREA)
Description
)丄4531 A7 B7 五、發明説明（1 ) 本發明是有關於2 -〔 4 一（4 一氯苯基）環己基〕 一 3 —羥基一 1 ，4 —菓醌的微流體化粒子，以及有關其 製備方法。本發明尤其是有關於含有2 —〔4 一（4 一氯 苯基）環己基〕一 3 -經基一 1 ，4 一棻醒（、阿托維康 〃 ，atovaquone)的微流體化粒子藥用組成物，及其在治 療上的用途。 之前已有人對阿托維康加以說明，比如參見歐洲專利 號碼0123238和美國專利號碼5053432 (在 此納入參考文獻），是有關於化學式（I)的2-取代一 3 -羥基一 1，4 一棻醌： 〇 (請先閱讀背面之注意事項再填寫本頁)
其中R1爲氨’ R2選自Ci-6院氧基、芳院氧基、C：t-6院 基一 Ci-6烷氧基、由一個或兩個選自鹵素和Ci-6烷基、 鹵素和高鹵素一 C 1-6烷基或取代的苯基，R 1和R 2二者 爲Ci-6烷基或苯基，且η爲〇或1 ，及其生理上可接受 的鹽類。該化合物據說有抵抗原生動物的活性。明確的講 ，11爲0之化學式（I )的化合物據說具有抵抗人體瘧疾 寄生Plasmodium falciparum的活性’並可抵抗像E. tene-Π a 和 R m e r v u 1 i n a 的 E i mer i a種一這是球蟲症（coccidi-os is)的病媒’而η == 1之分子式（I )的化合物據說具 本紙張尺度適用中國國家標準（CNS)A4規格（ 210X297公釐）一 4 _
I 經濟部中夬標隼局員工消費合作社印製 1 經濟部中央標準局員工消費合作社印製 514531 A7 ________ _B7_ 五、發明説明（2 ) 有抗泰蟲（Theileria)屬，尤其是T.annulate或T. parva ，原生動物的活性。在明確指明和所舉例的化合物 ，爲n = 0、R1爲氫且R2爲4 一氯苯基的化學式（I ) 化合物，比如阿托維康。 E P 0 3 6 2 9 9 6說明阿托維康在治療和/或預 防肺囊種carinii菌肺炎的用途。 阿托維康對毒漿體原蟲病弓蟲症（Toxoplasmosis)和 隱胞子蟲症（Cryptosporidiosis)的另外用途分別在歐洲 專利公布號碼044 5 1 4 1和049 6 72 9中有所說 明。 阿托維康作治療劑的功效會受其生物可應用性限制。 因此本發明的目的在提供有較多生物可應用形式的阿托維 康。 如今吾人發現只要確保粒子大小爲在某預定範圍內的 小粒子即可增加阿托維康的生物可應用性。然而，吾人亦 發現，使用減少阿托維康粒子大小的傳統方法來產製帶有 改良之生物可應用性所需大小的粒子並未成功。 微流化器爲Microfluidics公司自1 9 8 5年開始行 銷。其操作原則是根據浸入噴射技術。它主要被設計在食 品和製藥工業上用作均一化裝置以製備像乳液和脂質體（ 1 ipsomal )系統，稍後被使用在生物科技應用上作細胞一 破裂用。 吾人很訝異的發現利用微流化器所製成的阿托維康微 流體化粒子具有化合物之改良式生物可應用性。吾人確信 ---·--------裝------^訂^------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ~ 514531 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（3) 這是因爲微流體化阿托維康粒子的較小尺寸和窄的粒子範 圍以致。 在操作微流化器時，以馬達將氣流供應至特殊設計的 器室中，在此流體氣流會以非常高的速度和壓力來作用。 在作用室中的固定微通道可提供密集渦流的特別集中反應 帶，而可在空洞和剪力間引起能量的釋出。在不拘泥於理 論下，吾人確信由於所有產物通過大小固定的能量釋出區 域，使用微流體器會較傳統製造微細粒子的方法可達到較 大的粒子均一性和較小的尺寸。 於是第一，本發明可提供阿托維康的小粒子。粒子較 宜爲微流體化粒子。適宜至少9 0 %粒子的容積直徑在 0 · 1 — 3微米間。較宜至少9 5%粒子的容積直徑在 0 · 1 - 2微米間。 第二，本發明提供含有阿托維康粒子和一個或以上其 可供製藥載體的藥用組成物，其中至少9 5 %粒子的容積 直徑在0 · 1 - 2微米間。粒子較宜爲微流體化粒子。 載體必須是組成物中其他成份在相容性上可接受的， 並且不會對其受體有害處。 第三點，本發明提供製備阿托維康微流體化粒子的方 法，它包括使阿托維康和液體賦形劑（vehicle)混合來 提供其中阿托維康的濃度少於4 5 Omg/mL的混合物 ，並使該混合物通過微流化器3次以提供粒子形式爲至少 90%粒子的容積直徑在0.1—3微米間的阿托維康。 較宜爲至少95%粒子的容積直徑在0·1—2微米間。 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X297公釐）
(請先閲讀背面之注意事項再填寫本頁) 、言 ^14531 A7 B7 五、發明説明（4 ) 最後一點，本發明可提供一種製備藥用組成物的方法 ’它包括以下步驟： a )使阿托維康和液體賦形劑混合來提供阿托維康濃 度少於4 5 Omg/mL的混合物。 b )使該混合物通過微流化器3次以提供粒子形式爲 至少90%粒子的容積直徑在0·1-3微米間的阿托維 康。 c)使微流體化製備物和一個或以上其藥用可接受載 體混合。 適宜使混合物通過微體器1 0 — 5 0次，比如通過 25-30次。較宜使混合物通過微流體器15—25次 〇 在一個體系中，液體賦形劑爲表面活性劑。液體賦形 劑較宜爲表面活性劑溶液。在一個特別適宜的體系中，表 面活性劑爲Poloxamer 188溶液。在另外一個較適宜體系 中，藥用可接受載體包括懸浮劑。適用的懸浮劑包括甲基 纖維素和黃原（xan than)膠。懸浮劑較宜爲黃原膠。 經濟部中央標隼局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 藥用組成物包括口服劑和針劑（包含皮下、真皮、肌 肉和靜脈注射），以及鼻（naso) —胃管。在本發明範圍 內適用的組成物包括，舉例來說，像錠片的固體劑量形式 和像懸浮液-較適宜的組成物-的液體劑量形式。組成物 可在適合處方便以個別劑量單位存在，並可以製藥技術已 知的方法來由微流體化粒子製備。 量測阿托維康在活體（v i vo )上生物可應用性的試驗 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 一 7 一 514531 A7 B7 五、發明説明（5 ) 指出，和先前技術的組成物相較，微流體化阿托維康組成 物有改良之生物可應用性。因此本發明進一步提供具有治 療用途的微流體化阿托維康組成物，尤其是在原生動物寄 生感染-比如瘧疾和住血原蟲症一以及受P. car* ini i感染 等的治療和預防。 實施例1 阿托維康微流體化粒子的製備 經濟部中夬標準局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁) 阿托維康是以先前技術，比如美國專利號碼 5053432 (在此納入參考文獻），來製備。製備 600毫升含有2·5%w/v阿托維康的0·25% w / v Celacol M2500混合物，保留100毫升於 玻璃廣口瓶中作控制組。使實驗室級1 2 0 B型微流化器 和9 0 ps i壓縮空氣供應源相接，並調整生成的流體壓力 爲1 5000PS i 。將機器底座、微流化器的作用室和 管線浸入冷水浴中。將5 0 0毫升的混合物加入微流化器 的大瓶中，並在回流到巨室的頂端和側面前先通過微流體 器的作用室中。混合物持續流過反應室，並在10、20 、3 0、4 5和6 0分鐘時取樣。計算各個樣品的流通數 ，並列在下面的附表1中。 表1 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -8 - ^14531 A7 B7 i、發明説明（6 ) 微流體化時間 (分鐘） 積 容 品 樣 數 通 流 升 毫 控制組 〇 1 10 2 2 0 3 3 0 4 4 5 5 6 0 5 ο 5
ο r-H
5 5 ο 3 IX ο 8 9 I 9 5 3 I IX 3
5 2 6 4 IX 7 7 4 4 2 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標隼局員工消費合作社印製 514531 Α7 Β7 五、發明説明（7 ) 圓形，成單分散。 實施例2 混合下列的成份來製備口服懸浮液成份物： 阿托維康的微流體化粒子 15 0 • 0毫克 Poloxaraer 1 8 8 5 • 0毫克 苯甲醇 10 • 0毫克 黃原膠 7 • 5毫克 純水 需製造 1 • 0毫升 (請先閱讀背面之注意事項再填寫本頁) 實施例3 在一個隨機交叉研究中，九名健康、斷食男性自願者 接受單一劑量爲5mg/mL的懸浮液，其中含有2 5 0 毫克、平均大小爲3微米的阿托維康懸浮液和1微米微流 體化懸浮液。在最後一劑服完後，間隔最多兩週抽取血獎 樣品，並以Η P L C分析。結果列在下面的附表2。 經濟部中央標隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X 297公釐） 514531 A7 B7五、發明説明（8 ) 附表2 3微米懸浮液 1微米懸浮液 平均（SD)AUC 9 5 ( 6 2 ) // g/mL. h 2 4 7 ( 8 5 ) H g/mL. h 平均（SD)Cmax 1.2(0.7)// g/mL 5.0(1.6)^ g/mL 中間Tmax 5小時 1小時 1微米懸浮液的A U C相對於3微米懸浮液的平均（9 5 %CI)遞增爲 2 · 6 倍（1 · 9 — 3 · 5)，而 Cmax 則爲 4 · 1 倍（2 . 5 - 6 . 6 )。 · ,0 批衣I 訂 線 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -11 -
Claims (1)
- 514531 A8 B8 C8 D8 六、申請專利範圍 附件A L '•-"':·'ί·.-·:^ (請先閱讀背面之注意事項再填寫本頁) 第881G1847號專利申請案 中文申請專利範圍修正本 民國8 8年3月呈 1 · 一種用於治療感染之呈懸浮液形式之醫藥組成物 ，含有阿托維康粒子和一種或一種以上藥用可接受載體， 其特徵在於：該阿托維康粒子係經微流體化，且至少9 0 %粒子的容積直徑在0.1-3微米之間。 2 .如申請專利範爵第1項之醫藥組成物，其中該藥 用可接受載體包括懸浮劑。 3 .如申請專利範圍第2項之醫藥組成物，其中該懸 浮劑爲黃原膠。 4.如申請專利範圍第1至3項中任一項之醫藥組成 物，其係用於治療及/或預防原生動物寄生感染和由 P.carinii所引起的感染。 經濟部中央標隼局員工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）
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| GB929226905A GB9226905D0 (en) | 1992-12-24 | 1992-12-24 | Pharmaceutical preparation |
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| TW088101847A TW514531B (en) | 1992-12-24 | 1993-12-23 | Method for preparing microfluidised particles of atovaquone, and pharmaceutical compositions comprising microfluidized particles of atovaquone |
| TW082110927A TW443935B (en) | 1992-12-24 | 1993-12-23 | Method for preparing microfluidized particles of atovaquone, and pharmaceutical compositions comprising microfluidized particles of atovaquone |
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| TW082110927A TW443935B (en) | 1992-12-24 | 1993-12-23 | Method for preparing microfluidized particles of atovaquone, and pharmaceutical compositions comprising microfluidized particles of atovaquone |
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| AU (2) | AU675102B2 (zh) |
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| GE (1) | GEP19991515B (zh) |
| HK (1) | HK1004086A1 (zh) |
| HR (1) | HRP931516B1 (zh) |
| HU (1) | HU220215B (zh) |
| IL (1) | IL108154A (zh) |
| MY (1) | MY109990A (zh) |
| NO (1) | NO316745B1 (zh) |
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| PL (1) | PL175374B1 (zh) |
| RO (1) | RO119686B1 (zh) |
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| TW (2) | TW514531B (zh) |
| UA (1) | UA39879C2 (zh) |
| WO (1) | WO1994014426A1 (zh) |
| YU (1) | YU48919B (zh) |
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-
1992
- 1992-12-24 GB GB929226905A patent/GB9226905D0/en active Pending
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1993
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- 1993-12-22 YU YU80893A patent/YU48919B/sh unknown
- 1993-12-23 JP JP51496894A patent/JP3461353B2/ja not_active Expired - Lifetime
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- 1993-12-23 DK DK94902952T patent/DK0675711T3/da active
- 1993-12-23 RU RU95122758A patent/RU2127585C1/ru active
- 1993-12-23 TW TW088101847A patent/TW514531B/zh not_active IP Right Cessation
- 1993-12-23 SI SI9300678A patent/SI9300678A/sl unknown
- 1993-12-23 EP EP94902952A patent/EP0675711B1/en not_active Expired - Lifetime
- 1993-12-23 CA CA002152615A patent/CA2152615C/en not_active Expired - Lifetime
- 1993-12-23 UA UA95062971A patent/UA39879C2/uk unknown
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- 1993-12-23 AT AT94902952T patent/ATE169215T1/de active
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- 1993-12-23 MY MYPI93002823A patent/MY109990A/en unknown
- 1993-12-23 BR BR9307719-0A patent/BR9307719A/pt not_active Application Discontinuation
- 1993-12-23 AU AU57105/94A patent/AU675102B2/en not_active Expired
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- 1993-12-23 WO PCT/GB1993/002646 patent/WO1994014426A1/en active IP Right Grant
- 1993-12-23 SK SK828-95A patent/SK281924B6/sk not_active IP Right Cessation
- 1993-12-23 NZ NZ258995A patent/NZ258995A/en not_active IP Right Cessation
- 1993-12-23 CN CN93121376A patent/CN1076194C/zh not_active Expired - Fee Related
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- 1993-12-23 TW TW082110927A patent/TW443935B/zh not_active IP Right Cessation
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- 1993-12-23 KR KR1019950702217A patent/KR0175193B1/ko not_active IP Right Cessation
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1994
- 1994-04-03 SA SA94140644A patent/SA94140644B1/ar unknown
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1995
- 1995-06-15 BG BG99723A patent/BG61932B1/bg unknown
- 1995-06-22 FI FI953139A patent/FI114007B/fi not_active IP Right Cessation
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1997
- 1997-03-14 AU AU16279/97A patent/AU696662B2/en not_active Ceased
- 1997-11-19 US US08/974,248 patent/US6018080A/en not_active Expired - Lifetime
-
1998
- 1998-04-20 HK HK98103299A patent/HK1004086A1/xx not_active IP Right Cessation
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1999
- 1999-10-04 US US09/411,381 patent/US6649659B1/en not_active Expired - Lifetime
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