TWI483738B - 具有改良之味道遮蔽性的擠出物 - Google Patents
具有改良之味道遮蔽性的擠出物 Download PDFInfo
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- TWI483738B TWI483738B TW097121022A TW97121022A TWI483738B TW I483738 B TWI483738 B TW I483738B TW 097121022 A TW097121022 A TW 097121022A TW 97121022 A TW97121022 A TW 97121022A TW I483738 B TWI483738 B TW I483738B
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- 239000010452 phosphate Substances 0.000 description 1
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- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- JOHZPMXAZQZXHR-UHFFFAOYSA-N pipemidic acid Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CN=C1N1CCNCC1 JOHZPMXAZQZXHR-UHFFFAOYSA-N 0.000 description 1
- 229960001732 pipemidic acid Drugs 0.000 description 1
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- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
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- 229960003508 ponazuril Drugs 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
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- 239000011877 solvent mixture Substances 0.000 description 1
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- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 229960004954 sparfloxacin Drugs 0.000 description 1
- DZZWHBIBMUVIIW-DTORHVGOSA-N sparfloxacin Chemical compound C1[C@@H](C)N[C@@H](C)CN1C1=C(F)C(N)=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1F DZZWHBIBMUVIIW-DTORHVGOSA-N 0.000 description 1
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- 239000000021 stimulant Substances 0.000 description 1
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- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 229960004576 temafloxacin Drugs 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229960000898 toltrazuril Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950008187 tosufloxacin Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 150000005691 triesters Chemical class 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- JATLJHBAMQKRDH-UHFFFAOYSA-N vebufloxacin Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)CCC3=C1N1CCN(C)CC1 JATLJHBAMQKRDH-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
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- 150000003751 zinc Chemical class 0.000 description 1
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Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Seasonings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- General Preparation And Processing Of Foods (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Fats And Perfumes (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
本發明係關於包含一或多種醫藥活性物質之擠出物,其中該等擠出物具有0.5毫米或更小之條直徑,及關於這些擠出物用於製造醫藥品之用途。
醫藥物質之控制釋放能隱藏活性成份之不悅的味道就消費者而言是有利的。其能增加服用個別醫藥形式之容易度,而對最適的治療是重要的。就此而論,在醫藥技術中隱藏味道有各種可能性。綜觀許多方法以及交互參照適當文獻,得到Roy[Roy,1994]或Sohi[Sohi等人,2004]。
隱藏味道最簡單的方法為增加風味,但要隱藏非常苦及非常易溶於水之物質可能有問題。找出正確的添加物之過程係如Bienz[Bienz,1996]所述。
藉由以疏水性載體處理活性成份(六氫吡衍生物)遮蔽味道而得到顆粒,亦已有描述(WO 98/03157)。
又,常描述的可能性係在醫藥形式上應使用膜衣。除了防止環境影響外,其可藉由膜衣在各方面控制活性成份由醫藥形式中釋放,尤其是導致隱藏味道。用於此目的之物質可能在來源及結構上不同,例如Eudragit E[Cerea等人,2004,Lovrecich等人,1996,Ohta及Buckton,2004,Petereit及Weisbrod,1999]、蟲膠(shellac)[Pearnchob等人,2003b,Pearnchob等人,2003a]或纖維素衍生物[Al-Omran等人,2002,
Li等人,2002,Shirai等人,1993]。然而,使用Eudragit E之缺點為味道遮蔽係由陽離子賦形劑及陰離子活性成份間之離子交互作用所產生。使用蟲膠同樣的為不利的,因為蟲膠為天然的聚合物其組成可能各式各樣。除此之外,塗膜涉及製造上另外的工作,造成時間及金錢支出。然而,WO 2002/058669描述了一種喹啉酮-或萘啶酮羧酸於不溶性基質中(特別的可能性為蟲膠基質)之固體分散物。
使用離子交換樹脂或包合物可能同樣的適用於味道遮蔽。然而,因離子性質必須存在,離子交換樹脂對許多醫藥物質缺乏廣泛應用性[Chun及Choi,2004,Lu等人,1991,Prompruk等人,2005]。包合物具有僅可能承載低量活性成份之缺點[Sohi等人,2004]。
脂肪基底同樣用於味道隱藏醫藥形式之製造。已知以硬質脂肪(Witepsol,Witocan)為主之單一醫藥形式之研究[Suzuki等人,2003,Suzuki等人,2004],其中係額外使用卵磷脂及甜味劑以改善味道。此案例之缺點為脂肪基底必須熔化,而可能導致不穩定。依照這些數據,直徑2公分之模鑄錠太大而造成不能用於動物飼料之結果。此外,硬質脂肪、二硬脂酸甘油酯及硬脂酸在冷的擠壓物中作為親脂性黏合劑之比較已有所知[Breitkreutz等人,2003],且在此案例中必須使用Eudragit E作為膜衣以隱藏味道。在其熔點以下擠出脂肪以製造醫藥基底同樣已有描述[Reitz及Kleinebudde,2007]。
EP 855 183 A2揭示帶有喹啉酮類旋轉酶抑制劑之味道
遮蔽的口服調配物,其係藉由將活性成份與較長鏈的脂肪混合,且若適當,進一步加添加物、加熱及冷卻後造粒或製成粉末所製造。
亦有製造以蠟為基底之小藥丸[Adeyeye及Price,1991,Adeyeye及Price,1994,Zhou等人,1996,Zhou等人,1998]。在此案例中,已發現活性成份之釋放係依照蠟之熔點及其在藥丸中之濃度而定。當熔點及蠟含量增加時,釋放變得較緩慢。
另一個隱藏味道之可能係由Kin及Choi所述[Kim及Choi,2004],其製造了一個可可脂或硬脂及活性成份之脂肪核心,並提供一海藻酸鈉或角叉菜膠之外殼。然而,在此情形下,脂肪完全熔化且在製造上塗膜步驟代表額外的操作。
此外,Compritol888 ATO已描述作為基質形成的組份[Mirghani等人,2000]。其描述由熔化的Compritol、活性成份及多糖外膜所組成的藥丸之製造。以多糖塗膜,又再次是一項工作,其應免除。Li[Li等人,2006]相反地描述由粉末混合物或由粉末的固體分散物以旋轉機藉由打壓所製造之基質錠劑之比較。然而,該Compritol888 ATO完全溶解以產生固體分散物。Barthelemy[Barthelemy等人,1999]使用Compritol888 ATO塗覆茶鹼(theophylline)藥丸及顆粒。再次,脂肪會完全熔化。
此外,使用磷脂質為一改良味道之可能。就此而論,已發現磷脂質只遮蔽了苦味而對其他味覺沒有影響[Katsuragi等人,1997,Takagi等人,2001]。因此,一方面因
為僅可隱藏苦味,於此處無通用之可能,另一方面,已知添加磷脂質會影響脂質的結晶性,而可能導致不穩定[Schubert,2005]。
另一項研究顯示粉末混合物之組成同樣可用於味道遮蔽[Barra等人,1999]。賦形劑粒子(纖維素衍生物)必須小於活性成份粒子才可能隱藏味道,因為賦形劑係堆積在活性成份上。此案例之缺點為需要符合大小的活性成份粒子,無法使用微粒化物質。
WO 2003/030653係關於其中併入活性成份之動物飼料,且其可藉由擠出來製造。
WO 2003/072083描述了鹼性醫藥物質及(甲基)丙烯酸酯聚合物之混合物的熔化擠出;隨後將擠出物弄碎成顆粒或粉末。在生成的產物中被認為已達到活性成份之味道封閉。WO 2004/066976揭示了藉由將陰離子活性成份、甲基丙烯酸酯聚合物及中至長鏈脂肪酸熔化混合,製造口服立即崩解的醫藥形式之方法。固化後,研磨產物並併入水溶性基質中。
US 6 171 615 B1係關於茶鹼於半固體基質中的持續釋放調配物,係包含聚乙二醇化甘油酯及促進晶核形成物質之混合物("成核促進劑")。FR 2 753 904係關於控制釋放之醫藥品,其包含溶於脂質基質(其另包含一山嵛酯(behenic ester)及疏水性稀釋劑)之活性成份。
WO 2004/014346係關於適合用於寵物之控制釋放的美味調配物。該調配物包含適合控制釋放之小粒子("多粒化")形式的活性成份及改良風味的添加物。
WO 2005/097064係關於包含大量包膜粒子之醫藥品,該粒子之核心係包含一基質物質及一水膨脹性之膨潤劑。
目前已發現擠出物非常適合用於製造味道遮蔽的製備物或隱藏味道的製備物,其中條直徑特別具有意料不到的重要性。熟習技術者通常期望以較小粒子增加成份之釋放,因此隱藏味道較差。通常醫藥上使用的擠出物係以規格約1毫米之條直徑來製造。目前已發現當條直徑減小,同樣會使成份釋放減少,所以較小的條直徑擠出物可用來製造隱藏味道之醫藥品。
因此本發明係關於:
.包含一或多種醫藥活性物質之擠出物,其特徵為該擠出物具有0.5毫米或更小之條直徑。
.前述擠出物用於製造醫藥品之用途。
本發明擠出物之條直徑不超過0.5毫米且較佳不超過0.3毫米。通常可使用0.2毫米以上條直徑之擠出物。以非圓柱狀擠出物之情況,最大邊長或橢圓長度不超過0.5毫米且較佳的不超過0.3毫米。
擠出物包括適合擠出及由熱成型物質或多種熱成型混合物所組成之基底,其中若適當另包括醫藥上可接受賦形劑及添加物。
基底係由熱可成形物質所組成,例如聚合物,如聚丙烯酸酯或纖維素衍生物、脂質例如酯醯甘油酯、界面活性劑例
如單硬脂酸甘油酯或硬脂酸鈉、聚乙二醇(macrogol)例如聚乙二醇6000、糖或糖醇例如甘露醇或木糖醇。較佳係使用脂質基底。適合作為脂質基底之實例有脂肪基底,特別是甘油酯,較佳的帶有C12
-C24
脂肪酸之酯類。可提及之甘油酯有甘油二酯例如二山嵛酸甘油酯、甘油三酯例如三月桂酸甘油酯、甘油單、二或三酯之混合物,例如硬脂酸棕櫚酸甘油酯。亦可提及的三酸甘油酯係以椰子油、棕櫚油及/或棕櫚核仁油為主,例如市售商品名Witocan之硬脂。亦可使用檸檬酸及/或乳酸之單或二甘油酯。
再者,可提及的有蠟,特別是具有30至60個碳原子之蠟,例如棕櫚酸鯨蠟酯。此等脂質可從市面上購得,例如商品名Precirol、Compritol及Dynasan。特佳的實例有二山嵛酸甘油酯及三肉荳蔻酸甘油酯。脂系基底較佳的為粉末形式。許多的脂質具多形性且在某些情況下,當溫度和壓力改變可形成亞穩定形式。在儲存期間,在某些情況下可能發生修飾性轉變並形成較穩定的修飾。根據文獻描述[Reitz及Kleinebudde,2007],三肉荳蔻酸甘油酯(Dynasan 114)為比較穩定趨向此等變化,而因此特別適合作為醫藥品之脂質基底。
特別用作脂系基底之物質通常係以混合物販售,例如單-、二-及/或三酸甘油酯。與這些相比較,可參照基本上僅由一種組份所組成之均勻的脂系基底。以這些賦形劑所製造的調配物的特徵為良好的儲存穩定性。
所用之基底量(熱成形物質)係依照擠出物其他成份脂
量而定。一般係使用從20至99%[m/m],較佳地25至80%[m/m],特佳地30至70%[m/m]。
本發明之擠出物(若適當)可包含一或多種另外的賦形劑及添加劑。適合的有,例如:流量調節劑,較佳地濃度從0.2%至2%[m/m]之膠體二氧化矽;潤滑劑,較佳地濃度從0.2%至5%[m/m]之硬脂酸鎂或二山嵛酸鈣;界面活性劑,較佳地濃度從0.5%至10%[m/m]之卵磷脂。另外亦可使用抗氧化劑,適合的實例有丁基羥基茴香醚(BHA)或丁基羥基甲苯(BHT),使用之習用量通常係從0.01至0.5%[m/m],較佳地0.05至0.2%[m/m]。活性成份釋放例如可藉由添加所謂的造孔劑來控制。這些有,例如糖特別是乳糖、多元醇特別是甘露醇或聚乙二醇例如Macrogol 1500。造孔劑係使用從5%至40%[m/m]之濃度,較佳地係從5%至20%[m/m]之濃度。另一種影響活性成份釋放之可能係以添加崩解助劑來呈現。就此目的,可能使用所謂的超崩解劑例如交鏈聚維酮、交鏈羧甲基纖維素鈉或交鏈羧甲基澱粉鈉。超崩解劑係使用從1%至15%[m/m]之濃度,較佳地從3%至10%[m/m]之濃度。此外,可用作替代物之物質為該等可溶於酸及/或釋出二氧化碳之物質,例如碳酸鎂或碳酸鈣。二氧化碳釋放物質可使用係使用從5%至15%[m/m]之濃度,較佳地從5%至10%[m/m]之濃度。
可能使用醫藥活性物質活性醫藥成份,特別是該等欲隱藏其不悅味道之成份。
可提及的實例有抗生素,例如喹啉酮抗生素,此名稱亦
希望包括由萘啶酮所衍生之化合物。
喹啉酮,較佳地氟喹啉酮,尤其是像下列文件中揭示之化合物:US 4 670 444(Bayer AG)、US 4 472 405(Riker Labs)、US 4 730 000(Abbott)、US 4 861 779(Pfizer)、US 4 382 892(Daiichi)、US 4 704 459(Toyama);可提及之特別的喹啉酮實例有吡哌酸及萘啶酸;可提及之氟喹啉酮實例有:培諾沙星(benofloxacin)、賓氟沙星(binfloxacin)、西諾沙星(cinoxacin)、環丙沙星(ciprofloxacin)、達氟沙星(danofloxacin)、雙氟沙星(difloxacin)、依諾沙星(enoxacin)、恩諾沙星(enrofloxacin)、氟羅沙星(fleroxacin)、依巴沙星(ibafloxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lomefloxacin)、馬波沙星(marbofloxacin)、莫西沙星(moxifloxacin)、諾氟沙星(norfloxacin)、奧比沙星(ofloxacin)、氧氟沙星(orbifloxacin)、培氟沙星(perfloxacin)、替馬沙星(temafloxacin)、托氟沙星(tosufloxacin)、沙氟沙星(sarafloxacin)、司帕沙星(sparfloxacin)。
較佳的氟喹啉酮之群為該等式(I)或(II)之群:
其中X為氫、鹵素、C14-烷基、C14-烷氧基、NH2
,
Y為下列結構之基
其中R4
為視需要經羥基-或甲氧基-取代之直鏈或支鏈C1
-C4
-烷基、環丙基、具有1至3個C原子之醯基,R5
為氫、甲基、苯基、噻吩基或吡啶基,R6
為氫或C1-4
-烷基,R7
為氫或C1-4
-烷基,R8
為氫或C1-4
-烷基,及R1
為具有1至3個碳原子之烷基、環丙基、2-氟乙基、甲氧基、4-氟苯基、2,4-二氟苯基或甲基胺基,R2
為氫或視需要經甲氧基-或2-甲氧基乙氧基-取代之具有1至6個碳原子之烷基、環己基、苯甲基、2-氧丙基、苯甲醯甲基、乙氧基羰基甲基、新戊醯基氧基,R3
為氫、甲基或乙基,及A為氮、=CH-、=C(鹵素)-、=C(OCH3
)-、=C(CH3
)-或=C(CN),B為氧、視需要經甲基-或苯基-取代之=NH或=CH2
,Z為=CH-或=N-,,及其醫藥上可使用鹽類和水合物。
式(I)及(II)之化合物可以其外消旋物或鏡像異構物形式存在。
較佳的為式(I)化合物其中A為=CH-或=C-CN,R1
為視需要經鹵素-取代之C1
-C3
-烷基或環丙基,R2
為氫或C1-4
-烷基,Y為下列結構之基
其中R4
為視需要經羥基-取代之直鏈或支鏈C1
-C3
-烷基、具有1至4個C原子之氧烷基,R5
為氫、甲基或苯基,R7
為氫或甲基,R6
及R8
為氫,及其醫藥上可使用水合物和鹽類。
特佳的為式(I)化合物其中A為=CH-或=C-CN,R1
為環丙基,R2
為氫、甲基或乙基,Y為下列結構之基
其中R4
為甲基、視需要經羥基-取代之乙基,R5
為氫或甲基,R7
為氫或甲基,R6
及R8
為氫,及其醫藥上可使用鹽類和水合物。
適合的鹽類為醫藥上可使用之酸加成鹽及鹼鹽。
醫藥上可使用鹽類之實例有鹽酸、硫酸、乙酸、甘醇酸、乳酸、琥珀酸、檸檬酸、酒石酸、甲磺酸、4-甲苯磺酸、半乳糖醛酸、葡萄糖酸、恩貝酸(embonic acid)、麩胺酸或天們冬胺酸之鹽類。本發明化合物亦可與酸性或鹼性離子交換劑結合。可提及之醫藥上可使用鹼性鹽類有鹼金屬鹽類,例如鈉或鉀鹽,鹼土金屬鹽類,例如鎂或鈣鹽;鋅鹽、銀鹽及鈲鹽(guanidinium salt)。
水合物係指氟喹啉酮本身之水合物及其鹽類之水合物二者。
可提及之特佳的氟喹啉酮有WO 97/31001中所描述之化合物,特別是具有下式之8-氰基-1-環丙基-7-((1S,6S)-2,8-二氮雜雙環[4.3.0]壬烷-8-基)-6-氟-1,4-二氫-4-酮基-3-喹啉羧酸(普多沙星(pradofloxacin))
普多沙星較佳地係使用其無水之游離形式,例如修飾型B(參照WO 00/31076),或三水合物(參照WO 2005/097 789)。
又特佳地係使用恩諾沙星(enrofloxacin):1-環丙基-7-(4-乙基-1-哌基)-6-氟-1,4-二氫-4-酮基-3-喹啉-羧酸
除了恩諾沙星及普多沙星,亦可提及的為馬波沙星、氧氟沙星、雙氟沙星、依巴沙星之較佳的喹啉酮抗感染劑。
另外適合的活性醫藥成份有例如三酮,如地克珠利(diclazuril)及特別是帕托珠利(ponazuril)和妥曲珠利(toltrazuril)。
另可提及的為具有驅蟲效用之24-員環酯肽類(depsipeptide),例如PF 1022及特別是伊摩酯肽(emodespide)。
其他的驅蟲劑亦為適合的。可提及之實例有依西太爾(epsiprantel)及特別是吡喹酮(praziquantel)。
另外可使用之活性醫藥成份為藥學上可接受之膦酸衍
生物,這些通常是有機化合物適合作為代謝刺激劑及收縮劑,特別是用於生產性動物及家畜。可提及之較佳實例有,長久以來已知之化合物,托定膦(toldimfos)及布他磷butaphosphan)(例如用於產品Catosal),尤其是作為礦物質(磷)補充劑。
許多其他活性醫藥成份亦適用於本發明之擠出物,因為不需要熔化活性成份。由於擠出物之味道遮蔽效用,其較佳地係適合具有不悅味道(例如苦味)之活性成份。
併入親脂性基質-依照所用活性成份之性質-能延遲釋放且因此亦能達到緩慢釋放效果。
所有的醫藥活性成份亦可能-如上述喹啉酮之詳細解釋-使用對應的醫藥上可接受鹽、水合物、溶劑化物及(若適合)不同的修飾物。
光學活性物質亦可以其立體異構物之形式或立體異構物混合物來使用,例如純的或富含鏡像異構物或為外消旋物。
用於擠出物之活性成份之量係依照效力及所欲的劑量而定。其顯示,亦可製造具有高至80%[m/m]之高活性成份濃度,較佳地高至70%[m/m],特佳地高至60%[m/m]。正常的濃度範圍,例如從1至80%[m/m],較佳的5至70%[m/m],特佳地30至60%[m/m]。
本發明擠出物係藉由將原料(醫藥活性物質、基底及(若適合)賦形劑及添加劑)混合,然後擠出所製造。擠出較佳地係在不會導致熱成形物質完全溶解之溫度下進行,且特而言
之一般係在室溫範圍,較佳地40℃,至熱成形物質熔化範圍以下的溫度進行。擠出過程應在儘可能恆定的溫度下進行。適合此目的特別是可加熱的螺旋擠出機,特別是雙螺旋擠出機。擠出的條帶較佳地係具有圓形截面及如上所指之直徑。擠出地條帶可直接在擠壓時以刀子粒化,或於分開的步驟藉由於習用的研磨機(例如離心研磨機)中緩和研磨。所生成產物之粒子大小依照所用的模直徑,粒化條帶的最大長度相當於條直徑之三倍。典型的粒子大小例如從300至500微米。在一較佳的實施例中,已研磨的物質亦可過篩。因而可移除微細粒子。
有時候本文所作之敘述擠出物係在其熔點以下擠出,應了解係指擠出物-如上述-係在所用的熱塑性基底尚未熔化之溫度下擠出。其他成份例如活性成份通常具有較高的熔點。
就此等擠出物,當條直徑較小時活性成份釋放會減少。因此,此等擠出物適合用於隱藏具有不悅味道之成份的味道。
本發明擠出物可在和緩粒化後進一步加工(若適當)成適合的醫藥形式。(若適當)對於進一步加工,添加另外的賦形劑為必須的。根據本發明較佳的醫藥形式為錠劑,其可(弱適當)塑造成適合所欲用途之形狀。其他適合的醫藥形式有糊漿、懸浮液、袋劑、膠囊等。
本發明之擠出物及醫藥品一般係適合用於人類及動物。其較佳地係用於生產性及育種家畜、動物園、實驗室、
試驗動物及寵物(特別是哺乳類)之動物管理及動物育種。
生產及育種家畜包括哺乳動物例如,牛、馬、綿羊、豬、山羊、駱駝、水牛、驢、兔、黇鹿、馴鹿、毛皮動物例如貂、栗鼠、浣熊及鳥類例如雞、鵝、火雞、鴨、鴿子及駝鳥。
實驗室及試驗動物包括狗、貓、兔及囓齒類如小鼠、大鼠、天竺鼠和黃金倉鼠。
寵物包括養在家裡及動物園中之狗、貓、馬、兔、囓齒類如黃金倉鼠、天竺鼠、小鼠以及爬蟲類、兩棲類及鳥類。
擠出物一般係直接或以適合的製備物形式(醫藥形式)用於腸內,特別是口服。
活性成份之腸內使用係例如以顆粒、膠囊、糊漿、成粒、懸浮液或加藥飼料口服來進行。
適合的製備物有:固體製備物例如顆粒、藥丸、錠劑、玻利(boli)及含活性成份之成型粒子。
固體製備物係藉由將活性成份與適合的載劑(若適當)與添加的賦形劑混合並轉變為所欲的形式。
可提及的載體為所有生理上耐受的固體惰性物質。可使用無機及有機物質。無機物質之實例有氯化鈉、碳酸鹽例如碳酸鈣、碳酸氫鈣、氧化鋁、矽氧、鋁石、沉澱或膠體二氧化矽、磷酸鹽。
有機物質之實例有糖、纖維素、人類及動物飼料,例如奶粉、動物粉料、研磨及粉碎的榖類或澱粉。
賦形劑有防腐劑、抗氧化劑、色素。適合的賦形劑及
所用之需要量原則上已為熟習技術者所知。可提及之防腐劑實例為抗壞血酸。適合的抗氧化劑之實例有丁基羥基茴香醚(BHA)或丁基羥基甲苯(BHT)。適合的色素有有機及無機色素及適合醫藥目的之色素例如氧化鐵。
另外適合的賦形劑有潤滑劑及助滑劑,例如硬脂酸鎂、硬脂酸、滑石、澎潤土、崩解促進物質例如澱粉或交鏈聚乙烯吡咯酮、黏合劑例如澱粉、明膠或直鏈聚乙烯吡咯酮及亁燥結著劑例如微晶纖維素。
另外可使用之佐劑有油例如植物油(如橄欖油、大豆油、葵花油)或動物來源的油,例如魚油。通常之量為0.5至20%[m/m],較佳地0.5至10%[m/m],特佳地1至2%[m/m]。
懸浮液可口服使用。其係藉由將活性成份懸浮於載體溶液中所製造,(若適當)添加另外的賦形劑例如濕潤劑、色素、吸收促進物質、防腐劑、抗氧化劑、光穩定劑。
適合的載體液體有均質的溶劑或溶劑混合物,其中個別的擠出物並不會被其溶解。可提及之實例有生理上耐受溶劑例如水、醇類例如乙醇、丁醇、甘油、丙二醇、乙二醇及其混合物。
可使用之濕潤劑(分散劑)有界面活性劑。可提及的實例有:非離子性界面活性劑,例如聚氧乙烯蓖麻油、聚氧乙烯山梨糖醇酐單硬脂酸酯、山梨糖醇酐單硬脂酸酯、單硬脂酸甘油酯、聚氧乙基硬酯酸酯、烷基酚聚乙二醇醚;兩性界面活性劑例如N-月桂基-13-亞胺基二丙酸二-鈉或卵
磷脂;陰離子界面活性劑例如月桂基硫酸鈉、脂系醇醚硫酸鹽、單/二烷基聚乙二醇醚正磷酸酯單乙醇胺鹽;陽離子界面活性劑例如鯨蠟基三甲基氯化銨。
另外可提及之賦形劑有例如:增加黏度及懸浮液穩定物質,例如羧甲基纖維素、甲基纖維素及其他纖維素和澱粉衍生物、聚醯酸酯、藻酸鹽、明膠、阿拉伯膠、聚乙烯吡咯酮、聚乙烯醇、甲基乙烯醚及丙二酸酐之共聚物、聚乙二醇、蠟、膠體矽氧或所提物質之混合物。
半固體製備物亦可口服給藥。其與上述懸浮液及乳液之差異僅在於其黏度較高。
活性成份亦可與協同劑或與另外的活性成份組合使用。
除非另有指出,否則百分比數據為以完成的混合物為基準之重量百分比。
將由活性成份恩諾沙星(50%[m/m])及賦形劑Compritol888 ATO(49%[m/m])、主要成份甘油二山嵛酸酯之脂系基底(其亦含有單及三酯類及小量帶有C16
-C20
脂肪酸之酯類)及Aerosil200(1%[m/m])(一種致熱性膠體二氧化矽,係用來增進粉末組合物之流動性)所組成之粉末混合
物,在擠出前以實驗室攪拌機(15分鐘,40 rpm)在室溫下混合,並將粉末混合物轉置於擠出機之重量供料元件中。
使用具有圓截面模型及鈍的擰螺器之同向雙螺旋擠出機供熔化擠出。供料速度及螺旋速度之設定係適應所用之模盤,以確保可重複加工。個別的設定係如表1所列。
6個不同的模盤用來製造不同的批件。其差異係在於模直徑、模數目及模長度。就此而論,係以具有模直徑小於或等於1.0毫米開口面積之模盤並讓長度與模直徑之比率維持恆定,以便使擠出組合物上的壓力一直相同。表2顯示個別模盤之個別的參數。
熔化擠出常係在相同溫度下發生,且係在Compritol888 ATO熔化範圍(約70℃)以下進行。模盤溫度為60℃,而擠出器筒身之溫度從模盤在粉末入料之方位係如下:60℃、55℃、55℃、55℃、55℃、25℃、25℃、25℃。熔化擠出後,將擠出物以離心研磨機於6000 rpm、12-牙旋轉軸及嵌入1.5毫米篩孔之篩網研磨。所有的分析係使用各批次315-400微米之篩分粒級。
擠出物之另外調配物(除非另有指出,否則百分比數據為%重量比):
將三種原料混合並擠出(模直徑:0.4 mm,模盤溫度60℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.5 mm,模盤溫度60℃)。擠出條之進一步加工可如實例1來進行
將三種原料混合並擠出(模直徑:0.5 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.4 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.33 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.33 mm,模盤溫度56℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.33 mm,模盤溫度65℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.4 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.4 mm,模盤溫度
56℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.4 mm,模盤溫度65℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.33 mm,模盤溫度56℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.33 mm,模盤溫度65℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.33 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.4 mm,模盤溫度56℃)。擠出條之進一步加工可如實例1來進行。
將三種原料混合並擠出(模直徑:0.4 mm,模盤溫度65℃)。擠出條之進一步加工可如實例1來進行。
將原料混合並擠出(模直徑:0.4 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
將原料混合並擠出(模直徑:0.33 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
將原料混合並擠出(模直徑:0.33 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
將原料混合並擠出(模直徑:0.33 mm,模盤溫度50℃)。擠出條之進一步加工可如實例1來進行。
醫藥物質釋放之長期分析係使用Ph.Eur.2.9.3,裝置2之釋放系統來進行。亦使用沉墬容器放置樣本。此沉墬容器係位於釋放容器的底部,且至槳攪拌器的下方邊緣之距離為2.5公分。所有的測量係以槳攪拌器於50 rpm在900毫升的媒劑中於37℃±0.5℃進行每批次6個樣本。釋放係在7.4之pH(根據USP27 "緩衝溶液")添加0.001%聚山梨醇酯20下進行。
在pH 7.4之媒劑中出顯現不同的釋放性質,其係對應口中之pH範圍(參見圖1:所有分析批次在pH 7.4之釋放性質[6個測定值之平均])。此處每單位時間恩諾沙星釋放之增加如原直徑擠出物增加,並不明顯。二個最大原直徑擠出物之磨碎產物其釋放性質並無差異。
就技術理由,以長期釋放分析之方法來進行起初釋放之短期分析是不可能的。因此使用下列方法進行短期分析:使用崩解試驗機以700毫升的pH 7.4媒劑(如長期分析)在37℃±.0.5℃進行這些分析。將樣本放入三個沉墜容器,
導入樣本架(根據Ph.Eur.5.5,2.9.1.試驗B之裝置)並進行試驗15秒或1分鐘。所有的試驗,樣本架上升或下降速率為恆定。亦進行60分鐘之短期試驗流程,以便與長期分析相比較。
圖2係顯示15秒及1分鐘後之短期試驗結果(6個樣本之平均±標準差)。將活性物質之釋放量對批件的條直徑作圖。相當明顯的,當條直徑減小,每單位時間活性物質之釋放減少。觀察到不同的釋放減少,特別是條直徑低於0.5毫米。
確認比較二種所用的釋放分析之可能性,長期分析結果與短期分析之結果具相關性。在各情況下,短期試驗之1分鐘及60分鐘的試驗值與長期研究之數據相關聯。很容易地可找出該等值關連;具有線性關係(參見圖3)。圖中之各點係指特定的直徑。
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Claims (7)
- 一種包含一或多種醫藥活性物質及一脂質基底作為賦形劑之擠出物,其中該脂質基底為帶有C12- C24 脂肪酸之甘油酯,其特徵為該擠出物具有0.5mm或更小之條直徑,且該擠出物係在其熔點以下擠出。
- 如申請專利範圍第1項之擠出物,具有0.3mm或更小之條直徑。
- 如前述申請專利範圍第1項之擠出物,係包含二山嵛酸甘油酯作為脂質基底。
- 如申請專利範圍第1或2項之擠出物,係包含三肉荳蔻酸甘油酯、三棕櫚酸甘油酯或三硬脂酸甘油酯作為脂質基底。
- 如申請專利範圍第1或2項之擠出物,係包含三肉荳蔻酸甘油酯作為脂質基底。
- 一種如申請專利範圍第1至5項中任一項擠出物之用途,係用於製造醫藥品。
- 一種醫藥品,係包含如申請專利範圍第1至5項中任一項之擠出物及一或多種醫藥上可接受的賦形劑及/或添加劑。
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