TW524694B - Porous inorganic particles as carriers for drug substances - Google Patents
Porous inorganic particles as carriers for drug substances Download PDFInfo
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- TW524694B TW524694B TW087117781A TW87117781A TW524694B TW 524694 B TW524694 B TW 524694B TW 087117781 A TW087117781 A TW 087117781A TW 87117781 A TW87117781 A TW 87117781A TW 524694 B TW524694 B TW 524694B
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- 239000010954 inorganic particle Substances 0.000 title claims abstract description 7
- 239000000969 carrier Substances 0.000 title 1
- 229940088679 drug related substance Drugs 0.000 title 1
- 239000000126 substance Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000013543 active substance Substances 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 14
- 229910052588 hydroxylapatite Inorganic materials 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims description 11
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 229960003580 felodipine Drugs 0.000 claims description 10
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- DKWNMCUOEDMMIN-PKOBYXMFSA-N melagatran Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](NCC(O)=O)C2CCCCC2)CC1 DKWNMCUOEDMMIN-PKOBYXMFSA-N 0.000 claims description 4
- 229960002137 melagatran Drugs 0.000 claims description 4
- ZMHOBBKJBYLXFR-BPNWFJGMSA-N 4-[(2r)-3-[ethyl(3-propylsulfinylpropyl)amino]-2-hydroxypropoxy]benzonitrile Chemical compound CCCS(=O)CCCN(CC)C[C@@H](O)COC1=CC=C(C#N)C=C1 ZMHOBBKJBYLXFR-BPNWFJGMSA-N 0.000 claims description 3
- 229950003699 almokalant Drugs 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 239000008389 polyethoxylated castor oil Substances 0.000 claims description 3
- 239000004575 stone Substances 0.000 claims description 2
- 150000003626 triacylglycerols Chemical class 0.000 claims description 2
- 229910052586 apatite Inorganic materials 0.000 claims 1
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 claims 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims 1
- 238000012377 drug delivery Methods 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 239000002245 particle Substances 0.000 description 22
- 238000010494 dissociation reaction Methods 0.000 description 18
- 230000005593 dissociations Effects 0.000 description 18
- 239000011345 viscous material Substances 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 5
- 239000008159 sesame oil Substances 0.000 description 5
- 235000019738 Limestone Nutrition 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000006028 limestone Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 235000011803 sesame oil Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
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- 238000010348 incorporation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 239000011236 particulate material Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- GDAXJBDYNVDMDF-UHFFFAOYSA-N 1,2,4-benzotriazine Chemical compound N1=NC=NC2=CC=CC=C21 GDAXJBDYNVDMDF-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- CDPROXZBMHOBTQ-SJORKVTESA-N 2-[[(2r)-3-cyclohexyl-1-[(2s)-2-[3-(diaminomethylideneamino)propylcarbamoyl]piperidin-1-yl]-1-oxopropan-2-yl]amino]acetic acid Chemical compound NC(N)=NCCCNC(=O)[C@@H]1CCCCN1C(=O)[C@H](NCC(O)=O)CC1CCCCC1 CDPROXZBMHOBTQ-SJORKVTESA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000002628 heparin derivative Substances 0.000 description 1
- 239000002634 heparin fragment Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229950003291 inogatran Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 235000019155 vitamin A Nutrition 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
- A61K9/14—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
- A61K9/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/005—Enzyme inhibitors
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
-
- 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
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
524694 _案號87117781_年月日__ 五、發明說明（1) 發明範圍 本發明有關包括併入相當量油腻/油性/黏性物質的多孔 . 性無機顆粒的新穎醫藥劑型·，新穎劑型之特徵為乾燥、易 於處理和具有快速釋放性質。 發明背景 在很多醫療領域内，將吸收增強劑（如給予P h a r m a c i a的 、 世界專利9 5 / 0 0 1 5 2中所述，甘油酯用於增加肝素或肝素片 段或衍生物的吸收）、增溶劑（如給予A B H a s s 1 e的歐洲專 · 利Ο 24 9 5 8 7中所公佈的，聚乙氧基化氫化f麻油用於非洛 地平）或懸浮劑（如給予S an ◦ i i的美國專利5，5 9 7，5 8 2中所 公佈的，豆油或分餾椰子油用於1，2, 4 -氧化苯并三嗪）等 併入藥品釋放劑型的需要已經增加。 長期以來已經知道，將大量丨由腻、油性或黏性物質併入 醫藥劑型會導致技術問題。問題之一為不得不得到易於處 理的和就以這種物料使用的或在以後加工步驟中使用的醫 藥上可接受的乾燥物料。 繞過問題的早期方法包括就以這類油膩/油性/黏性物質 裝填入軟膠囊，如美國專利5589455 (Han Mi Pharm)中所 述，其中公佈了用於裝填軟膠囊的濃縮物包括環孢菌素和 油的成份（增加生物利用度）。 幾年間，很多研究人員已敘述了使用很多小顆粒（多單 位）作為劑型的優點（有關其體内表現，即尤其有關其使胃 排空的性質），例如參見B 〇 g e n t 〇 f t等「臨床藥理學雜誌」 1978， 14， 35卜5 ° 另一繞過問題的方法，符合以上結果，為使用微膠囊裝 -
55367-910801.ptc 第5頁 524694 案號 87117781 年 月 修正 五、發明說明（2) 填。然而，此法是昂貴的，因其包含很多步驟，並且也常 與按比例增加的困難有關。此法已例如由L u z z i在「藥物 科學雜誌」1 9 7 0， 5 9，（ 1 0 )， 1 3 6 7 - 7 6中所述。 先前的技藝 世界專利94/23703 (Kabi Pharmacia AB)公布了多孔性 纖維素基質和含有包括多孔性纖維素基質顆粒的生物活性 物質的多單位製劑之製造法。然而，此參考文獻既不涉及 處理油腻、油性或黏性物質，也不涉及無機基質。 歐洲專利2 9 4 2 0 6 ( U n i 1 e v e r N V )公佈具有某些特徵的 多孔性球狀二氧化硅，夾料諸如醫療劑佔高達S i 02的5 0重 量Λ。然而，此參考文獻既不涉及處理油膩、油性或黏性 物質，也不顯示快速釋放性質的任何結果。 詳細說明 _ 現已發現，一種用於口服投藥的藥品釋放系統可克服先 前技術的缺陷，藥品採取固體乾燥形式的油腻、油性或黏 性物質和醫藥活性物質或本身即為油膩、油性或黏性物 質，其特徵為具有併入相當量油膩、油性或黏性物質的大 量多孔性無機小顆粒，並且有快速釋放特徵。 因此，本發明提供新穎劑型成份要用於將油腻、油性或 黏性物質併入小顆粒，這樣使製造其多單位系統成為可 能。為了達到這一點，已經發現，高度多孔性無機顆粒有 助於使用。 本發明的一個特徵為多孔性顆粒的尺寸大小，在5至1 5 0 微米之間，以2 0至1 0 0微米較佳。 本發明的另一特徵為相當量的油膩、油性或黏性物質。
111 __1 m II 55367-910801.ptc 第6頁 524694 _，里_1-—^ g_修正__ 五、發明說明（3) . 在此詳細内容中’相當量意味著15重量/重量％至4〇重量/ 重量％，以2 0重量/重量％至4 〇重量/重量％較佳，以3 0重量/ . 重量％至4 0重量/重量％最佳。 併入的油膩、油性或黏性物質可為，但不限於，醫藥活 =物質，諸如阿爾摩卡蘭特（alm〇kalant)或維生素A ;醫 藥活性物質本身並非油膩、油性或黏性的，但與油膩、油-性或黏性物質一起尤適於併入調配物者為諸如非洛地平、 邁拉加特朗（melagatran)或伊諾加特朗（in〇gatran);吸 ’ 收增加劑為油膩、油性或黏性的，並係選自一-二-或三甘 油酯或其混合物，諸如Akol ine®、MCM、伊姆維脫308 (Imvitor 308)、伊姆維脫742、伊姆維脫928、伊姆維脫 _ 9 8 8和辛酸甘油酯；增溶劑，諸如半固體或液體非離子表 面活性劑，例如，含有作為g旨或醚的聚乙二醇，這些係選 自聚乙氧基化脂肪酸、羥化脂肪酸和脂肪醇，尤其係選自 聚乙氧基化萬麻油、聚氧伸乙基化氫化菌麻油 (Cremophors)、來自t麻油的聚乙氧基化脂肪酸或來自氫 化兔麻油的聚乙氧基化脂肪酸，以諸如Cremophor®、
Myrj 、硬月旨 i^P〇ly〇x〇l 40 S 旨、Emerest 2 6 7 5 - L i p a 1 395 和HCO 5 0等商標名稱而為人們所知。 技fe、本發明的藥品釋放糸統之特徵也為具有快速釋放性 質，當進行體外解離作用試驗時，釋放不小於6 0 % (較佳的 是7 0重量/重量％ )的醫藥活性物質和油腻/油性/黏性物 丨_ 質，當藥品為油膩、油性或黏性物質時，藥品在3 〇分鐘以 内或更短時間内釋放。 就油膩、油性或黏性物質而言，用美國藥典2號儀器（輪 ·.
第7頁 524694 案號 87Π7781 年 月 修正 五、發明說明（4) 葉式）測定解離速度，在每分鐘100轉運作。解離介質溫度 為3 7 °C。對解離介質的數量和獨創性有進一步的要求，即 能使受試整劑在今質内釋出的油膩、油性或黏性物質呈非 阻滯性均勻分佈。 就實例中顯示的特定油腻、油性或黏性物質而言，在每 一個實例中公佈的介質為合適的介質。 就藥品物質而言，用美國藥典2號儀器（輪葉式）測定解 離速度，在每分鐘1 0 0轉運作。解離介質溫度為3 7 °C。對 解離介質的數量和獨創性有進一步的要求，即能使受試整 劑在介質内釋出的藥品呈非阻滯性均句分佈（吸收條件）。 就實例中顯示的特定藥品而言，在每一個實例中公佈的 介質為合適的介質。 - 應當注意，對於同一調配物」可選擇不同的解離介質， 取決於受試物質的性質，調配物中如有油腻、油性或黏性 物質與醫藥活性物質共存，則取決於其中受試的一種。 本發明中所用無機多孔顆粒物料為硅酸鹽羥磷灰石。硅 酸鹽羥磷灰石之特徵為具有5至1 5 0微米之間的顆粒直徑大 小範圍，以在2 0至8 0微米之間較佳，近似的孔直徑在5至 100微米之間，以50至100微米和表面積40至50米V克較 佳。娃酸鹽羥填灰石商品可從如BIO-RAD Laboratories以 註冊名稱Macro-Prep®購得。 多孔性顆粒之裝填 可用通常已知方法完成油腻、油性或黏性物質之併入顆 粒。方法之一為將油溶於合適的溶劑内，然後與多孔性顆 粒物料混合並乾燥之。油另外也可與多孔性顆粒物料直接
55367-910801.ptc 第8頁 524694 _案號87117781_年月日_ίΜ-_ 五、發明說明（5) 混合。另一方法為通過添加非溶劑從含有顆粒的溶液使用 相分離。 顆粒孔隙率為5 0 - 7 0體積/體積％，較佳的是6 2體積/體積 % 〇 當用於藥品釋放系統時，裝填的多孔性顆粒可就以這種 物料使用，或以本技藝範圍内熟知的方法裝入膠囊、壓縮 · 至片劑或進行塗層。裝入膠囊、壓縮至片劑或進行塗層應 以這樣方式實施，即其快速釋放特徵並無實質上的變化。 如需在小腸内快速釋放，裝填的多孔性顆粒可以包有腸 衣。 工作實例 ❿ 實例1-含有非洛地平和19.5% Cremophor® 1?}140的#里填灰 石顆粒 油腻/油性物質（^6111〇?11〇1*@1^40(312毫克）在約30°(3熔 融，並用以溶入非洛地平（8 8毫克）。在用手輕輕混和下， 將溶液傾倒在具有平均直徑8 0微米的1 2 0 0毫克羥磷灰石 (Macro Prep® 石圭酸鹽經填灰石，BIO-RAD Laboratories) 上，繼續混和，直至均勻。 使用在每分鐘100轉運作的美國藥典2號解離儀器（輪葉 式），就非洛地平的解離作用分析所得顆粒。具有3 7 °C溫 度的所用解離介質為含0 . 4 %鯨蠟基三甲基溴化銨的pH 6. 5 磷酸鹽缓衝液。釋放的非洛地平量以紫外線分光術測定。❶ 3 0分鐘後，溶解的非洛地平量為求得含量的8 4% (作為平 均值5 η = 2 ) 〇 實例2 -含有邁拉加特朗和3 7 % A k ο 1 i n e ®的經填灰石顆粒 …
55367-910801.ptc 第9頁 524694 _案號 87117781_年月日 絛正_ 五、發明說明（6) 油膩/油性物質Akoline® ( 7 7 9毫克）在約30 °C熔融，並 用以溶入邁拉加特朗（2 1毫克）。在輕輕混和下，將溶液傾 倒在具有平均顆粒直徑8 0微米的羥磷灰石顆粒（1 2 0 0毫克） (Macro Prep® 硅酸鹽羥磷灰石，BIO-RAD Laboratories) 上，繼續混和，直至均勻。 使用在每分鐘100轉運作的美國藥典2號解離儀器（輪葉 式），就Akoline® MCM和邁拉加特朗的解離作用分析所得 顆粒。具有37 C溫度的所用解離介質為6.8鱗酸鹽缓衝 液，添加2 mM卵磷脂和5 mM牛磺膽酸酯，使樣品攝取均 句。以液相色譜術分開樣品成份。使用光散射檢測器測定 A k ο 1 1 n e釋放量，並以紫外線分光術測定邁拉加特朗釋放 量0 _ 2 0分鐘後，溶解A kο 1 i ne® MCΜ量為求得含量的7 1 % (作為 平均值，η= 2 )。2 0分鐘後溶解的邁拉加特朗量為求得含量 的94%(作為平均值，1^ = 2)。 實例3_含有33· 3%阿爾摩卡蘭特的羥磷灰石顆粒 在用手輕輕混和下，將油性/黏性物質阿爾摩卡蘭特（〇· 6克，芒溫）傾倒在具有平均值直徑8 〇微米的羥磷灰石顆粒 (1200 ¾ 克）（Macro Prep® 硅酸鹽羥磷灰石，bi〇-RAD Laboratories) Ji，繼續混和，直至均句。 使用在母分鐘100轉運作的美國藥典/號解離儀器（輪葉 式），就阿爾摩卡蘭特的解離作用分析所得顆粒。具有π
If 解1介質為ρΗ 6. 8碟酸鹽缓衝液。釋放的阿 爾摩卡闌特里以紫外線分光術測定。 3 0分鐘後，溶解的阿爾摩卡蘭特量為求得含量的
55367-910801.ptc 第10頁 524694 案號 87117781 年 月 修正 五、發明說明（7) 1 0 0 % (作為平均值，η = 2 )。 實例4 -含有1 7. 4%阿爾摩卡蘭特的羥磷灰石顆粒 在用手輕輕混和下，將油性/黏性物質阿爾摩卡蘭特（0 . 3 5克，室溫）傾倒在具有平均值直徑8 0微米的羥磷灰石顆 粒（1,7克）（Macro Prep®石圭酸鹽經麟灰石，BIO-RAD Laboratories) Jl，繼續混和，直至均勻。 使用在每分鐘1 0 0轉運作的美國藥典2號解離儀器（輪葉 式），就阿爾摩卡蘭特的解離作用分析所得顆粒。具有3 7 °C溫度的所用解離介質為p Η 6 . 8磷酸鹽缓衝液。釋放的阿 爾摩卡蘭特量以紫外線分光術測定。 3 0分鐘後，溶解的阿爾摩卡蘭特量為求得含量的8 0 % (作 為平均值，η = 2)。 實例5 _ 實例1中所得顆粒裝入3號硬膠囊。每一個膠囊裝1 9 0毫克 非洛地平/經填灰石顆粒。
55367-910801.ptc 第11頁 524694 案號 87117781 年月日 修正
55367-910801.ptc 第12頁
Claims (1)
- :號 87117781 修 2 n y I ff M 月>3日丨 修正本 Ί、申請專利範圍 1. 一種用於口服之乾燥、固體藥品釋放組合物，其包 含： (i) 一種油腻、油性或黏性物質，其為克瑞莫爾 (Cremophor)，或' —二-或三甘油酯或其混合物 ， 和一 拉加特(i 摩卡蘭 其特 石所組 有快速 或（ii) 2.根 種醫藥活性物質，其為非洛地平（f e 1 〇 d i p i n e )或邁 朗（melagatran)，或 i ) 一種油腻、油性或黏性醫藥活性物質，其為阿爾 特（almokalant) 徵為該組合物係以直徑5至1 5 0微米之硅酸鹽羥磷灰 成的多數多孔性無機顆粒的形式存在，該組合物具 釋放特徵，且併入15重量％至40重量％的成份（i) 據申請專利範圍第1項之藥品釋放組合物，其中硅 酸鹽羥磷灰石的直徑大小為2 0至8 0微米。 種製備用於口服之乾燥、固體藥品釋放組合物的方 包括： )一種油腻、油性或黏性物質，其為克瑞莫爾 法 3. — 其 (i (Cr emophor )，或' —二-或三甘油酯或其混合物 ，和一種醫藥活性物質，其為非洛地平（f e 1 〇 d i p i n e )或邁 拉力口特朗（melagatran)，或 (i i ) 一種油膩、油性或黏性醫藥活性物質，其為阿爾 摩卡蘭特（almokalant) 其特徵為通過混合1 5重量％至4 0重量％的成份（i)或 (i i )和由硅酸鹽經磷灰石組成的具有5至1 5 0微米直徑的大O:\55\55367-911223.ptc 第13頁 524694 案號 87117781 六、申請專利範圍 量多孔性無機顆粒 liBi 第14頁 修正 O:\55\55367-911223.ptc
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| CN100450483C (zh) * | 2000-04-11 | 2009-01-14 | 三共株式会社 | 含有钙阻滞剂的稳定药物组合物 |
| IT1319202B1 (it) | 2000-10-12 | 2003-09-26 | Nicox Sa | Farmaci per le malattie a base infiammatoria. |
| US6462021B1 (en) | 2000-11-06 | 2002-10-08 | Astrazeneca Ab | Use of low molecular weight thrombin inhibitor |
| US7479502B2 (en) | 2002-12-03 | 2009-01-20 | Pharmacyclics, Inc. | 2-(2-hydroxybiphenyl-3-yl)-1H-benzoimidazole-5-carboxamidine derivatives as factor VIIA inhibitors |
| KR101207553B1 (ko) | 2005-06-02 | 2012-12-03 | (주)씨앤팜 | 금속 이중층 수산화물을 포함하는 생체 주사제용 약물 담체 |
| TW200736245A (en) * | 2005-11-29 | 2007-10-01 | Sankyo Co | Acid addition salts of optically active dihydropyridine derivatives |
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| JP5027410B2 (ja) * | 2005-12-13 | 2012-09-19 | 株式会社サンギ | ユビキノン含有組成物 |
| US8287914B2 (en) * | 2006-01-12 | 2012-10-16 | Rutgers, The State University Of New Jersey | Biomimetic hydroxyapatite synthesis |
| US20100040668A1 (en) * | 2006-01-12 | 2010-02-18 | Rutgers, The State University Of New Jersey | Biomimetic Hydroxyapatite Composite Materials and Methods for the Preparation Thereof |
| GB0909460D0 (en) | 2009-06-02 | 2009-07-15 | Intrinsiq Materials Global Ltd | Mesoporus material |
| ES2908958T3 (es) | 2013-02-01 | 2022-05-04 | Grace W R & Co | Gel de sílice porosa como portador para tecnologías líquidas |
| AU2014322985B2 (en) * | 2013-09-20 | 2019-05-16 | Tillotts Pharma Ag | Delayed release pharmaceutical formulation |
| CN104133014B (zh) * | 2014-07-16 | 2015-09-16 | 广州法尔麦兰药物技术有限公司 | 一种考察布洛伪麻缓释制剂释放度的方法 |
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| GB8713263D0 (en) | 1987-06-05 | 1987-07-08 | Unilever Plc | Spheroidal silica |
| EP0376331A3 (en) | 1988-12-29 | 1991-03-13 | Asahi Kogaku Kogyo Kabushiki Kaisha | Slow release drug delivery granules and process for production thereof |
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| US5834496A (en) * | 1991-12-02 | 1998-11-10 | Sepracor, Inc. | Methods for treating hypertension using optically pure S(-) felodipine |
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| DE69820674D1 (de) | 2004-01-29 |
| RU2219907C2 (ru) | 2003-12-27 |
| KR20010032557A (ko) | 2001-04-25 |
| HUP0100303A3 (en) | 2004-03-29 |
| CA2311780A1 (en) | 1999-06-10 |
| PL340927A1 (en) | 2001-03-12 |
| AR016683A1 (es) | 2001-07-25 |
| ZA9810463B (en) | 1999-05-21 |
| ATE256453T1 (de) | 2004-01-15 |
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