TW438597B - Pharmaceutical composition for controlled release - Google Patents
Pharmaceutical composition for controlled release Download PDFInfo
- Publication number
- TW438597B TW438597B TW083110673A TW83110673A TW438597B TW 438597 B TW438597 B TW 438597B TW 083110673 A TW083110673 A TW 083110673A TW 83110673 A TW83110673 A TW 83110673A TW 438597 B TW438597 B TW 438597B
- Authority
- TW
- Taiwan
- Prior art keywords
- pharmaceutical composition
- corrosive
- patent application
- scope
- corrosion
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 23
- 238000013270 controlled release Methods 0.000 title claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 6
- 239000008101 lactose Substances 0.000 claims abstract description 5
- 239000003607 modifier Substances 0.000 claims abstract description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000005260 corrosion Methods 0.000 claims description 21
- 230000007797 corrosion Effects 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 21
- -1 hydroxypropyl Chemical group 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 9
- 229920002554 vinyl polymer Polymers 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- VXAYBDRIOLMISA-UHFFFAOYSA-N 2,2-diethyl-4-oxobutanoic acid Chemical compound CCC(CC)(C(O)=O)CC=O VXAYBDRIOLMISA-UHFFFAOYSA-N 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 17
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 abstract description 5
- 239000013543 active substance Substances 0.000 abstract description 4
- 239000000314 lubricant Substances 0.000 abstract description 3
- 230000003628 erosive effect Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 239000011230 binding agent Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 50
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 26
- 239000011159 matrix material Substances 0.000 description 14
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 13
- 235000019359 magnesium stearate Nutrition 0.000 description 13
- 239000004615 ingredient Substances 0.000 description 12
- 229960004977 anhydrous lactose Drugs 0.000 description 10
- 230000036571 hydration Effects 0.000 description 7
- 238000006703 hydration reaction Methods 0.000 description 7
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 5
- 239000007853 buffer solution Substances 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- KWVPFECTOKLOBL-KTKRTIGZSA-N 2-[(z)-octadec-9-enoxy]ethanol Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCO KWVPFECTOKLOBL-KTKRTIGZSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 125000001400 nonyl 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])[H] 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 241000512259 Ascophyllum nodosum Species 0.000 description 1
- 108090001008 Avidin Proteins 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- LTXSISCCXPUXBE-UHFFFAOYSA-N C(C=C/C(=O)O)(=O)O.C1=CC=CC=2C3=CC=CC=C3C=CC12 Chemical compound C(C=C/C(=O)O)(=O)O.C1=CC=CC=2C3=CC=CC=C3C=CC12 LTXSISCCXPUXBE-UHFFFAOYSA-N 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- IPOBOOXFSRWSHL-UHFFFAOYSA-N Cibenzoline Chemical compound C=1C=CC=CC=1C1(C=2C=CC=CC=2)CC1C1=NCCN1 IPOBOOXFSRWSHL-UHFFFAOYSA-N 0.000 description 1
- 150000000921 Gadolinium Chemical class 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- QPNTVQDJTQUQFX-UHFFFAOYSA-N benzo[b][1,10]phenanthroline Chemical compound C1=CN=C2C3=NC4=CC=CC=C4C=C3C=CC2=C1 QPNTVQDJTQUQFX-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000011953 bioanalysis Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 229960004757 cibenzoline Drugs 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N doxorubicine Natural products O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- KJNZTHUWRRLWOA-UHFFFAOYSA-K europium(3+);phosphate Chemical compound [Eu+3].[O-]P([O-])([O-])=O KJNZTHUWRRLWOA-UHFFFAOYSA-K 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 description 1
- 229960004381 flumazenil Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 150000002597 lactoses Chemical class 0.000 description 1
- WBXXVIQNIMIONY-UHFFFAOYSA-H lutetium(3+);oxalate Chemical compound [Lu+3].[Lu+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O WBXXVIQNIMIONY-UHFFFAOYSA-H 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000013555 soy sauce Nutrition 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
A7 ______B7 五、發明説明(1 ) 本發明係關於一種提供獨特之零次控制釋放方式之可腐 蝕性醫藥组合物》此可腐蝕性組合物含有溶解度不大於80 毫克/毫升之活性治療物質,一種羥基丙基甲基纖维素衍生 物’及視藥物溶解度及藥物負荷而定之腐蝕調整劑如乳糖 及丙二醇之聚氧烯烴衍生物,還有其他之惰性物質如混合 劑及潤滑劑》此組合物在一定的時間内侵蝕β定量之體 積°服用後此基質形成兩層,外層爲進行腐蝕之水性基 質,内層爲核心之不變基質β此组合物提供零次釋出方 式,部分是因爲此藥物由基質擴散出來的速率爲可忽略 的,或相對對於基質之腐蝕速率爲可忽略的,而藥物在水 化層之濃度維持恒定》 零次釋出意指在此组合物之整個生命期中每段時間此活 性物質之釋放速率維持固定β例如、一個每小時釋放10% 活性成分之组合物,在十小時大約將釋放100 %之活性物 質》 更特定地説,本發明係關於成形並麈缩成固態單一劑型 之一種可腐蝕性醫藥组合物,其提供零次之控制釋出活性 治疾物質,此可腐杜性組合物含有約5 %到6 0 % w / W在2 5 °C水中溶解度不大於80毫克/毫升之活性治療物質,及至 少約5%最多約50% w/w之低黏稍度之超基丙基甲基纖維 素,且剩餘的部分由惰性載劑組成。 根據本發明,製備具有零次釋放之口服施用之可腐蚀组 合物之調SL物係由下列描述之方法製備。本活性成分與— 種纖维素瞇衍生物如美酥西耳K100 LV(Methh〇cel® -4- 本紙張尺度適用中國國家標準(CMS ) A4規格(210X 297公釐) --------_--装------ir------^ (請先閏讀背面之注意Ϋ項再填寫本頁) A7 _B7 五、發明説明(2 ) K100 LV)及一種腐蚀調整劑如乳糖或非離子性界面活性 劑如丙二醇之聚氧烯烴衍生物(以普羅尼克F-68(Pluronic F-08)之商品名出售)混合,可直接混合或 以濕顆粒與適當之混合劑如聚乙烯吡略统明或羥基丙基辍 維素混合》聚乙烯吡咯烷酮係以普威酮(Povidone)之商 品名取得。克魯西耳(Klucel LF)係商業上可取得之羥基 丙基纖维素》濕顆粒在50°C下乾燥並經由#30網眼之筛子 過篩》潤滑劑如硬脂酸鎂與乾顆粒混合。用合適之壓鍵 機,將顆粒壓製成具特定重量之錠劑。此活性成分在此組 合物中存在的量爲此组合物之5 %到60 % w/w® 此可腐蝕性组合物係結合活性治療物質,緘维素醚衍生 物及(若需要時)一種腐蝕調整劑如乳糖或普羅尼克F-68而 形成》織維素瞇衍生物存在基質中的量之範圍爲5%到 50% w/w*較佳之组合物含織維素醚衍生物之量的範圍 由 10% 到 25% w/w〇 根據未發明逋合應用之纖維素醚衍生物之實例包括短基 丙基甲基織維素成羥基丙基孅維素或其混合物。最佳之可 腐蝕性基質係具有曱氧基含量約19-30 %及羥基丙基含量 7-12%;取代之甲氧基程度由1」到2,0且分子量約 20,000到26,000道耳呑之羥基丙基甲基纖維素》2% w/w聚合物溶液表現出之凝膠點爲62〇-9〇Ό,且在25°C 疋黏網度範園由每秒轉速(cps}50到100 °· 本發明之零次釋放藥物輸送系統可適用之藥物如尼弗第 平(Nifedipine),(E)-4[[3-[2-(4-環丁基-2·崦嗖)乙 本紙張/^適用中賴家樣率(CNS) M規格(加❹7公羞) -------;--^------’玎------痒 (請先閱讀背面之注意事項再填寫本頁) A7 B7_ 五、發明説明(3 ) 烯基】笨基]胺]-2,2 -二乙基-4-氧基丁酸,( + )-順- 3- (乙 醯氧基)-2,3-二氫-2·(4-甲氡基苯基)-5·[2-二甲胺)乙 基)萘並[l,2-b]-l,4-咗氮雜革- 4-(5Η)酮’夕苯駢啉琥 J0 跋 里(Cibenzoline Succinate)第 爾 梯 嗓 (DUtiazem),弗馬珍尼爾(Flumazenil),氣菲安明 (Chlorphenamine),4-(2,2 -二苯基乙缔基)-1[1-氧-9-(3-毗啶基)壬基]哚啶,7 -氣-N-甲基- 5- (1Η-毗略· 2 -基)-3Η-1,4 -苯並二氩雜萆-2-胺及5-[3-【4-(2 -氣苯 基)-9-甲基-611-雀吩駢[3,24][1,2,4]三酢-[4,3-a][l,4]二氮雜革-2-基]-2-丙炔基]菲基啶-6(511)-酮。 藥物由可腐蝕基質中釋放情形之評估可用籃子法或槳輪 法(Basket or Paddle Method)在特定速度下以美國國 家藥典溶解試驗步驟檢測。籃子法和槳輪法之説明載於美 國國家藥典(USP) XXII及國家處方集(National Formulary>XVII第1578頁(美國藥典成規, Inc. .Rockville, MD,1990)。簡單地説,兩種方法都 是將一顆錠劑放置於下文説明之含有特定量之溶解介質之 正確裝置中,並啓動攪拌元件。藥物在溶液中的量係由此 技藝中已知之紫外線光譜色析法測定〇用於籃予法之装備 由下列各物所组成:名義上容量1000毫升之有蓋玻璃容 器;一個發動機;一個金屬從動軸;及一個圆柱形籃子》 將盛裝900毫升特定溶解介質(如水,1 %磷酸霣緩衝液中 之非離子性界面活性刺£«111丨卩|1〇1'0>1-870,卩1^7..5或 3%月桂基破酸納(sodium lauryl sulfate); pH 9,0) 本紙張尺度適用十國國家橾準(CNS ) A4規格(2丨0X297公釐) -----.—.—择------ir------# (請先閏讀背面之注意事項再填寫本萸) A7 _________B7 五、發明説明(4 ) 之容器部分浸入合適之水浴中,並於37。士 〇_5»C中達成 平衡》可蓋上合適之蓋子以延緩蒸發β從動軸之位置需使 其袖與容器之垂直軸之任何一點都小於2毫米且可平順之 旋轉無明顥之搖動》使用速度調節裝置以使從動軸之旋轉 速度可選擇且维持在特定速率中》建議之籃子速度爲每分 Μ100轉(100 rpm)»試驗期間容器内底和籃子之距離維 持2 5 ± 2毫米。 用於槳輪法之装置和用於籃子法之裝置相同,但其槳輪 係由刀片形成,且用軸作爲攪拌元件 軸之裝置需使其軸 和容器之垂直軸之任何一黠都不大於2毫米,且可平順轉 動且無明顯之震動。槳輪之建議速度爲5〇 rpm。刀片和 容器内底之距離在整個試玢中都維持25±2毫米。使用之 溶解介質爲特定的(如900毫升之擬f液或1%於磷酸緩衝 液之非離子性界面活性劑Emulphor ON-870,pH 7.5 於37 t下)》用紫外線色析法作蕖物分析β 錠劑之腐蝕過程係用美因國家藥典裝置1(籃子法)來測 定。此步驟和上文説明評估藥物釋放之方法類似。將錠劑 置於美國國家藥典筮中,且漫於900毫升純水中用100 rpm之轉速。經過一特定之時間後,將篮子和剩餘之錠劑 由介質中移開,並將錠劑放在50"C之烤爐上烘至少18小 時且/或直到重量穩定不再改變。腐蝕百分比根據錠劑損耗 之重量計算。 此輸送系統之釋放機轉的圖解請見圖1 » Η1描畫出基質 其外層水化層進行腐蝕,而内部核心則不變。本發明之组 -7- 本紙張尺度適用中國國家標隼(CNS ) Α4規格(210Χ297公釐) -----:--:--^------、玎------線、 (請先閲讀背面之注意事項再填寫本I> A7 B7 五、發明説明(5 ) 合物_藥物由基質中之接散速率可忽略不計’或其和基質 之腐蚀速率比起來可忽略不計,且藥物在水化層之渡定維 持穗定•此藥物之釋放是由基質之穩定腐蝕體積所控制。 時間t(Mt)時之藥物釋放數量由下列方程式表示:
Mt = VtC (方程式1) dVt/dt = k0 (方程式 2) 其中Vt係水化層在時間〖時之腐蝕體積;C係藥物在水化 層之滾度;且dVt/dt係腐蝕速率(k〇),其爲常數》 當藥物在水化層之濃度C保持固定時,藥物之釋放速率 dMt/dt爲零次。基質本身之溶解成腐蝕係緊接在HpMc 水化之後,可導致分散於基質中之活性成分釋放出來9 如厨2-7及9 -16所類示’本發明之醫菜组合物在特定之 溶解介質中產生零次釋放過程。如闽8所示在一種赞藥組 合物中使用如氣菲安明顺丁烯二酸鹽這種高溶解度之藥物 與本發明之聚合物不會產生零次釋放過程,這是由於活性 物質額外擴散》 商4顯示活性治療劑由醫藥组合物中釋放之速率與此組 合物之腐蝕速率呈非常密切的關係* 本發明之基質組合物的控制釋出由下列實例進—步聞 述,但非僅限於此。 本紙張从通财關家縣(CNS)-A婦{ 21_7公 --------^--t.------IT------.41 {請先閱讀背面之注意ί項再填寫本頁) 438597 A7 B7 五、發明説明(6 ) 實例1 成分 毫克/錠 (E)-4-[[3-[2-C4 -環丁基· 2-嘍哇基)乙烯基]苯基]胺]- 2,2-二乙基-4-氧丁酸) 100.0 普羅尼克F6 8 1 0 0.0 美酥西耳K 1 00L V 135.0 含水乳糖 135.0 普威酮K30 2 8.5 硬脂酸鎂 1.5 100毫克之控制釋出錠之釋出過程潁示於圖2及3» 100 毫克之(E)-4-[[3-[2-(4-環丁基-3-嘧唑基)乙烯基]苯基] 胺]-2,2 -二乙基-4-氧丁酸)之控制釋出錠之釋出和腐蝕過 程之比較請見圈4 * 實例2 成分 毫克/鍵 (£)-4*[[3-[2-(:4-環丁基- 2-崦唑基)乙烯基]苯基J 胺]-2,2-二乙基-4-氧丁酸) 100.0 普威酮K30 20.0 美酥西耳K100LV 3 1.2 無水乳糖 46.8 硬脂酸鎂 2.0 -9- 本紙張尺度適用中國國家標準(CNS)A4規格(210X297公嫠) ----------^------ΪΤ------^ (請先閲讀背面之注意事項再填寫本頁) 妁 / -) u r; G f .i · ·-*- 一 A7 B7五、發明説明(7 ) 100毫克之(E)-4[[3-[2-(4-環丁基-2-4唑基)乙烯基】 苯基]胺]-2,2 -二乙基-4-氧丁酸)之控制釋出錠之釋出過 程請見圖5 * 實例3 成分 毫克/錠 ( + )-順·3<乙毯氧基)-2,3· 二氫-2-(4-甲氧基苯基)-5- [2-(二甲胺)乙基]萘[1,2- bj-l,4-嘧者平·4(5Η)-嗣 5 4.0 無水乳糖 2 00.0 美酥西耳Κ 1 00L V 12 5.0 普威明Κ30 20.0 硬脂酸鎂 3.0 54毫克之CR( + )順_ 3弋乙酼氧)-2,3 -二氫- 2- (4 -甲氧基 笨基)-5-[2-(二甲胺)乙基萘[l,2-b]-l,4-嶁者平-4(5H)-酮錠之釋放過程請見阖6。 實例4 成分 毫克/錠 夕苯胼啉琥珀酸鹽 23 2.0 美酥西耳K100LV 2 00.0 普威酮Κ30 5 0.0 硬脂酸 5.0 夕洛伊(Syloid> 244 5.0 硬脂酸鎂 10.0 夕苯駢啉琥珀酸鹽CR錠之釋出過程請見圈7。 -10- 本紙浪尺度適用t國國家標準(CNS)A4规格{ 210X297公釐) (請先閲讀背面之注意事項再填寫本頁) 五、發明説明(8 ) A7 B7 實例5 成分 毫克/錠 氣菲安明順丁烯二酸璺 54 無水乳糖 200 美酥西耳K 1 00LV 125 普威酮K30 20 硬脂酸鎂 6 氯菲安明順丁烯二酸躉錠之釋出過程請見囷8。 實例6 成分 毫克/錠 (Ε)-4·[ [3-[2-(4環丁基-2-嶁唑基)乙烯基]苯基】胺_l- 2.2- 二乙基-4-氧丁酸) 3 0 0.0 美酥西耳K1 00LV 52.9 此錠之釋出過程請見圈9 » 實例7 成分 毫克/键 (Ε)-4ί[3-[2-(4·環丁基-2_嘧唑基)乙烯基]苯基]胺]- 2.2- 二乙基-4-氧丁酸) 300 克魯西耳K100LV 18 美酥西耳K100LV 60 無水乳糖 216 硬脂酸鎂 6 此錠之釋出過程請見ΒΠ 〇。 -11- 本紙張尺度適用t國國家標隼(CNS ) A4規格(2丨0X297公釐) (請先聞讀背面之注意事項再填寫本頁) 裝 、tr 五、發明説明(9 ) A7 B7 實例8 成分 毫克/錠 (Ε)-4·[[3-[2-(4-環丁基-2_嘧唑基)乙烯基]苯基]胺卜 2.2- 二乙基-4-氡丁酸) 300 克魯西耳LF 18 美酥西耳K100LV 30 無水乳糖 246 硬脂酸鎂 6 此錠之釋出過程請見困1 1。 實例9 成分 毫克/錠 (Ε ) - 4·[ [ 3 - [ 2 - ( 4 -環丁基-2 -嘍哇基)乙烯基]苯基]胺 1- 2.2- 二乙基-4-氧丁酸) 300 美酥西耳K100LV 90 克魯西耳L F 18 無水乳糖 186 硬脂酸鎂 6 此錠之釋出過程諳見® 1 2。 -12- 本紙張尺度適用令團國家橾準(CNS ) Α4規格(2ΙΟΧ297公釐> -------:--------ΐτ------0 (請先閱讀背面之注意事項再填寫本頁) i^4385 9 7 A7 B7五、發明説明(1(>) 實例1 0 成分 毫克/錠 4-(2,2-二苯基乙烯基)-1-[1 -氧-9 - ( 3 -吡啶基)壬 基]嵘啶、微粒 300 克魯西耳L F 1 S 無水乳糖 150 美酥西耳K100LV 126 硬脂酸鎂 6 此錠之屬Η過程諝見圈13。 實例1 1 成分 毫克/錠 7-氣-Ν-甲基-5-(1Η-吡咯 -2-基)-3Η-1,4-笨駢待爾 靜平-2-胺微粉粒 300 克魯西耳L F 18 無水乳糖 150 美稣西耳K100LV 126 硬脂酸鎂 6 此錠之釋出過程諳見爾14 » -13- 本紙浪尺度適用中國國家樣準(CNS ) Λ4规格(210X297公釐) -----------------IT------it (請先閱讀背£r之注意事項再填寫本頁) ψ /) ^ 8 5 9 7 第83110673號專利申請案 中文說明書修正頁(88年元月) 五、發明説明(n) 經濟部中央標準局員工消费合作社印褽 實例1 2 成分 毫克/錠 5-[3-[4-(2-氯苯基)-9-甲 基-6 H-嶁吩駢[3, 2-f] [1,2,4]三酢[4,3-a][l,4] 待爾靜平-2-基]-2 -丙炔基] 菲基啶-6 ( 5 Η )酮 微粒 7 5 克魯西耳L F 9 無水乳糖 113 美酥西耳K100LV 10 0 硬脂酸鎂 3 此叙之腐ίέ過程請見圖15 ^ 實例1 3 成分 毫克/錠 弗馬珍尼爾 10 0 美酥西耳K100LV 2 5 0 無水乳糖 6 0 普威酮Κ3 0 3 6 硬脂酸鎂 4 . 此錠之腐蝕過程請見圖1 6。 圖表之簡要說明 圖〗為以圖描繪出本發明之零次控制釋出醫藥组合物 的劑型。 -14 - 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ 297公釐) H— 1— 1....... --- I- -- - - - I - ------ 1: HI - - - TJ 、-tL -« (請先κί讀背面之注意事項再填寫本頁) A7 ____B7 五、發明説明(12) 闽2顯示出實例1之醫藥組合物在9〇〇毫升之1 % Emulphor 〇>1-870_跋緩衝液(pH 7.5)中,於37*C 用 籃子法以每分鐘100轉之速度測出之釋出過程圖β 阖3類示出實例1之醫藥组合物在9〇〇毫升之1% 丑111111?11〇11〇1^-870碑酸缓衝液(9117.5)中,於37°〇用 槳輪法在每分鐘50轉之速度下測出之釋出過程圈, 闺4類示出實例1之醫藥组合物於900毫升之1 %
Emulphor ΟΝ-870 嶙酸缓衝液(pH 7.5),在 37SC"F 用 籃予法以每分鐘100轉之速度測得之释出及腐蝕過程圖9 圖5顯示出實例2之醫藥組合物於900毫升之1%
Emulphor ON-870辨酸緩衝液(pH 7.5),在 37°C 下用 槳輪法β每分鐘50轉之速度測得之釋出過程明。 阐6顯示出實例3之醫藥组合物於900毫升擬胃液中,在 37 Τ:以槳輪法用每分鐘50轉之速度測得之釋出過程围。 圖7联示出實例4之醫藥組合物於900毫升水中,在37 eC 下用货子法以每分鐘100轉之速度測得之釋出過程圖。 圈8顯示出實例5之醫藥組合物溶於900毫升水中,在 37 eC下用籃子法以每分鐘100轉之速度測得之釋出過程 圈* ®9顯示出實例6之醫藥组合物溶解於900毫升含3%月 桂基硫酸鈉(pH 9.0)之水中,在37Ό下用籃子法以每分 鐘100轉之速度測得之釋出過程圈- -15- 本紙張尺度逋用中國國家標孳(CNS } Α4规格(210Χ297公釐) ί請先閱讀背面之注意事項再填寫本頁} .裝 A7 _____B7五、發明説明(13) S10顯示出實例7之醫藥紐合物溶解於900毫升含3%月 桂基硫酸鈉(pH 9.0)之水中,在37 Ό下用籃子法以每分 鐘100轉之速度測得之釋出過程Η » 圈11顯示出實例8之醫藥組合物溶解於900毫升含3 %月 桂基硫酸衲(pH 9.0)之水中,在37*C下用籃子法以每分 鐘100轉之速度測得之釋出過程g * 圈12顯示出實例9之酱藥紐合物溶解於900毫升含3%月 桂基硫酸鈉(pH 9.0)之水中,在37 °C下用籃子法以每分 鐘100轉之速度測得之釋出過程圈。 躅13顯示出實例10之醫藥组合物溶解於900毫升含3 % 月桂基硫酸鈉(pH 9_0)之水中,在37 eC下用籃子法以每 分鐘100速度測得之腐蝕過程圃。 圖14顯示出實例11之組合物溶解於900毫升之水中,在 3 7 °C下用®子法以每分鐘100轉之速度測得之腐蝕過程 闽0 圈15顯示出實例12之组合物溶解於900毫升之水中,在 37 °C下用藍子法以每分鐘1〇〇轉之速度測得之腐杜過程 S16頻示出實例13之组合物溶解於900毫升之鱗酸緩衝 液(pH 7.4)中,在37 下用籃予法以每分鐘1〇〇轉之速 度測得之腐蝕過程圖》 ί請先閱讀背面之注意事項再填寫本頁) .裝 線 -16 - 本紙張尺度適用中國國家標率(CNS ) A4現格(297公釐)
Claims (1)
- Α8 Β8 C8 D8 稱49 85 9 7 第83110673號專利申請案 中文申請專利範圍條正本(85年8月) 六、申請專利範圍 (請先聞讀背面之注項再填寫本頁J 1· 一種經定型並壓縮成固態單—劑型之可腐蝕性醫藥組合 物,其可提供活性治療物質之零次控制釋虫,該可腐蝕 性组合物含有用量介於5 %到6 0 % w / W '且具有在2 5 °C水中不大於8 0毫克/毫升之溶解度之活性治療物質, 以及至少5 %、最多5 0 %的羥基丙基甲基纖維素,其係 具有曱氧基含量19-30%,羥基丙基含量爲7-12%,曱 氧基之取代程度由1 . 1到2 0,分子量2 0,0 0 〇到 26, 〇〇〇道耳呑,且其中2% w/w聚合溶液在25 °C之黏 稠度在50到100 cps之範圍内,而可腐蝕组合物之其 餘部份則由惰性載劑组成》- 2,根據申請專利範圍第1項之可腐蝕性醫藥組合物,其中 經基丙基甲基纖維素的存在量,係介於基質的丨〇 %到 25% w/w之間 Λ 3.根據申請專利範圍第丨項之可腐蝕性醫藥組合物,其中 可另外添加10%、最多60% w/w之腐蚀調節劑。 4·根據申請專利範圍第3項之可腐蝕性醫藥組合物,其中 之腐蝕調節劑係乳糖。 經濟部中夬標準局貞工消費合作社印装 5·根據申請專利範園第3項之可腐蝕性醫藥組合物,其中 之腐蝕調節劑係非離予性界面活性劑。 6.根據申請專利範圍第1項之可腐蝕性醫藥组合物,其中 之活性治療物質係(E ) - 4 - [[ 3 - [ 2 - (4 -環丁基-2 ·嘧唑 基)乙烯基]苯基]胺]·2,2_二乙基_4_氧丁酸。 7·根據申請專利範圍第1項之可腐蝕性醫藥組合物,其中 之活性治療物質係弗馬珍尼爾。 本紙張尺度適用中國國家榇準(CNS ) A4^ ( 21GX297公釐)
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US3870790A (en) * | 1970-01-22 | 1975-03-11 | Forest Laboratories | Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose |
US4226849A (en) * | 1979-06-14 | 1980-10-07 | Forest Laboratories Inc. | Sustained release therapeutic compositions |
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US4556678A (en) * | 1982-06-24 | 1985-12-03 | Key Pharmaceuticals, Inc. | Sustained release propranolol tablet |
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ATE135214T1 (de) * | 1992-02-17 | 1996-03-15 | Siegfried Ag Pharma | Darreichungsformen mit verlaengerter wirkstoffreigabe |
-
1993
- 1993-12-13 US US08/166,123 patent/US5393765A/en not_active Expired - Fee Related
-
1994
- 1994-11-17 TW TW083110673A patent/TW438597B/zh not_active IP Right Cessation
- 1994-11-18 CA CA002136118A patent/CA2136118A1/en not_active Abandoned
- 1994-12-05 ES ES94119113T patent/ES2171431T3/es not_active Expired - Lifetime
- 1994-12-05 EP EP94119113A patent/EP0662322B1/en not_active Expired - Lifetime
- 1994-12-05 AT AT94119113T patent/ATE214919T1/de not_active IP Right Cessation
- 1994-12-05 NZ NZ270058A patent/NZ270058A/xx unknown
- 1994-12-05 DE DE69430237T patent/DE69430237T2/de not_active Expired - Fee Related
- 1994-12-06 AU AU80232/94A patent/AU688807B2/en not_active Ceased
- 1994-12-06 ZA ZA949711A patent/ZA949711B/xx unknown
- 1994-12-07 IL IL11192094A patent/IL111920A/xx not_active IP Right Cessation
- 1994-12-07 HU HU9403496A patent/HU219227B/hu not_active IP Right Cessation
- 1994-12-08 JP JP6330524A patent/JP2966745B2/ja not_active Expired - Fee Related
- 1994-12-12 CO CO94056072A patent/CO4340618A1/es unknown
- 1994-12-12 UA UA94129170A patent/UA41887C2/uk unknown
- 1994-12-12 KR KR1019940033656A patent/KR950016783A/ko active IP Right Grant
- 1994-12-12 BR BR9404953A patent/BR9404953A/pt not_active Application Discontinuation
- 1994-12-12 NO NO944803A patent/NO944803L/no not_active Application Discontinuation
- 1994-12-12 CZ CZ19943127A patent/CZ287718B6/cs not_active IP Right Cessation
- 1994-12-12 CN CN94119315A patent/CN1110135A/zh active Pending
- 1994-12-12 PL PL94306245A patent/PL306245A1/xx unknown
- 1994-12-13 RU RU94043809/14A patent/RU2174832C2/ru not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
UA41887C2 (uk) | 2001-10-15 |
AU8023294A (en) | 1995-06-22 |
CN1110135A (zh) | 1995-10-18 |
HUT75456A (en) | 1997-05-28 |
ATE214919T1 (de) | 2002-04-15 |
EP0662322A2 (en) | 1995-07-12 |
ZA949711B (en) | 1995-08-21 |
JP2966745B2 (ja) | 1999-10-25 |
NO944803L (no) | 1995-06-14 |
JPH07196535A (ja) | 1995-08-01 |
EP0662322B1 (en) | 2002-03-27 |
HU9403496D0 (en) | 1995-02-28 |
CZ312794A3 (en) | 1995-09-13 |
CO4340618A1 (es) | 1996-07-30 |
DE69430237T2 (de) | 2002-07-18 |
RU2174832C2 (ru) | 2001-10-20 |
IL111920A (en) | 1999-08-17 |
HU219227B (en) | 2001-03-28 |
US5393765A (en) | 1995-02-28 |
ES2171431T3 (es) | 2002-09-16 |
IL111920A0 (en) | 1995-03-15 |
BR9404953A (pt) | 1995-08-08 |
NZ270058A (en) | 1996-07-26 |
PL306245A1 (en) | 1995-06-26 |
CA2136118A1 (en) | 1995-06-14 |
EP0662322A3 (en) | 1997-01-29 |
NO944803D0 (no) | 1994-12-12 |
DE69430237D1 (de) | 2002-05-02 |
KR950016783A (ko) | 1995-07-20 |
AU688807B2 (en) | 1998-03-19 |
CZ287718B6 (en) | 2001-01-17 |
RU94043809A (ru) | 1996-11-10 |
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