JPH0338248B2 - - Google Patents
Info
- Publication number
- JPH0338248B2 JPH0338248B2 JP57186884A JP18688482A JPH0338248B2 JP H0338248 B2 JPH0338248 B2 JP H0338248B2 JP 57186884 A JP57186884 A JP 57186884A JP 18688482 A JP18688482 A JP 18688482A JP H0338248 B2 JPH0338248 B2 JP H0338248B2
- Authority
- JP
- Japan
- Prior art keywords
- weight
- parts
- nifedipine
- tablets
- starch
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 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 claims description 38
- 229960001597 nifedipine Drugs 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 31
- 238000002360 preparation method Methods 0.000 claims description 23
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 21
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 21
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 21
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 21
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 21
- 229920002472 Starch Polymers 0.000 claims description 19
- 239000008107 starch Substances 0.000 claims description 19
- 235000019698 starch Nutrition 0.000 claims description 19
- 239000008187 granular material Substances 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 11
- NHOFYNWYKKGKKX-UHFFFAOYSA-N 1-(4-nitrophenyl)-2h-pyridine Chemical class C1=CC([N+](=O)[O-])=CC=C1N1C=CC=CC1 NHOFYNWYKKGKKX-UHFFFAOYSA-N 0.000 claims description 9
- 239000002775 capsule Substances 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 230000002745 absorbent Effects 0.000 claims description 4
- 239000002250 absorbent Substances 0.000 claims description 4
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 3
- 239000008298 dragée Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 235000009508 confectionery Nutrition 0.000 claims 1
- 238000001179 sorption measurement Methods 0.000 claims 1
- 239000007940 sugar coated tablet Substances 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 20
- 239000000243 solution Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 235000019359 magnesium stearate Nutrition 0.000 description 10
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 9
- 229960000715 nimodipine Drugs 0.000 description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 8
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 8
- 239000008108 microcrystalline cellulose Substances 0.000 description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound 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 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000004408 titanium dioxide Substances 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 239000012736 aqueous medium Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- -1 -isopropyl ester Chemical class 0.000 description 2
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920003085 Kollidon® CL Polymers 0.000 description 2
- 229920003072 Plasdone™ povidone Polymers 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K9/146—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 organic macromolecular 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Description
本発明は、４−ニトロフエニル−ジヒドロピリ
ジン誘導体及びポリビニルピロリドンを含有する
ある種の新規で、特に迅速吸収性の固体薬剤調製
物及びその製造方法に関する。
ニフエジピン（Nifedipine）〔ジメチル１，４
−ジヒドロ−２，６−ジメチル−４−（ｏ−ニト
ロフエニル）−ピリジン−３，５−ジカルボキシ
レート〕は、循環系に作用する４−ニトロフエニ
ル−ジヒドロピリジン誘導体の物質群から公知の
活性化合物である（英国特許第1173862号参照）。
この化合物は光に対して非常に敏感であり且つ水
性媒体への溶解度が非常に低いために、活性化合
物の特定の処方物についての多くの特許出願及び
特許から明らかなように、特定の薬剤の製薬学的
調製において多くの困難が生ずる。
米国特許第3784684号は、例えばニフエジピン
の冠状脈への作用を有利に利用するために、ニフ
エジピンを溶解形で含有する特定のゼラチンの咬
みくだき可能なカプセル剤（bitable capsule）
に関するものである。
英国特許第1456618号は、ニフエジピンの良好
なバイオアベイラビリテイ（bio−availability）
を保証することを意図した固体の薬剤調製物につ
いて記述し、これを特許請求している。
独国特許出願公開明細書第2822882号は、同様
に、ニフエジピンの貧弱な溶解性を、ある種の溶
媒及び表面活性物質を用いることによつて補償し
た固体の薬剤調製物について記述している。
ヨーロツパ特許出願公開明細書第1247号では、
ニフエジピンの吸収性を、ポリエチレングリコー
ル（PEG）及びある種の多孔質賦形剤を用いる
ことによつて改良することが意図されている。こ
の特許出願では、ニフエジピンの貧弱な溶解度
は、ニフエジピンの共沈物が非晶質形で存在す
る、ニフエジピンとポリビニルピロリドン
（PVP）の共沈物の生成によつて補償できるとい
うことも述べられている。
これらの共沈物は、ニフエジピン及びPVPを
有機溶媒に溶解し、続いて溶媒を蒸発させてガラ
ス状の物体を得ることによつて製造される（独国
特許出願公開明細書第2822882号参照）。有機溶媒
のそのような蒸発は、PVP物体が有機溶媒を強
く結合し、乾燥直前に非常に粘稠になるから、工
業的には多くの費用をかけて始めて行なうことが
できる。乾燥工程の終了直前には非常に粘稠なか
さ高さの泡状物体が生成し、これは最早や撹拌す
ることができず、更なる処理が困難である。錠剤
において通常のPVP共沈物を用いる際の更なる
欠点は、この共沈物が他の助剤と混合できるだけ
であり、最早や水性溶液と共に直接粒状化しえな
いという事実である。しかしながら、PVP共沈
物と他の助剤との簡単な混合物は、例えば錠剤と
する更なる機械的工程中は又はカプセル中への導
入中に分離する傾向がある。これは最終的に、各
錠剤又はカプセル剤中の活性化合物含量が非常に
異なつている（「含量均一性」の欠けた）薬剤調
製物を与える。これはニフエジピンのような高活
性物質の場合に非常に望ましくない。更に、
PVPは同時に結合剤として働くから、特に錠剤
の製造に対して選択できる更なる助剤は非常に限
定され、錠剤又はカプセル剤の崩壊は多量（錠剤
又はカプセル剤当り30〜100mg）のPVPの存在に
よつて妨害される。
ニフエジピン〔１，４−ジヒドロ−２，６−ジ
メチル−４（3′−ニトロフエニル）−ピリジン−
３，５−ジカルボン酸３−β−メトキシエチルエ
ステル５−イソプロピルエステル）も同様に、脳
に作用する公知の４−ニトロフエニル−ジヒドロ
ピリジン誘導体である（独国特許出願公開明細書
第2815578号参照）。この化合物も、その物理化学
的性質のために、製薬学的調製とするのが難し
い。ニフエジピンは、例えばニフエジピンよりも
実質的に貧弱な、水性媒体への溶解度を示す。
本発明は、ジヒドロピリジン含有する新規な固
体で、迅速放出性の、過去に公知の調製物の欠点
を最早や有さない調製物及びその製造方法に関す
る。
本発明によれば、活性化号物としての４−ニト
ロフエニル−ジヒドロピリジン誘導体１重量部、
平均分子量が15000〜50000のPVP2.0〜6.0重量
部、並びにセルロース3.5〜15重量部、澱粉0.25
〜4.0重量部及び架橋した不溶性のPVPP0.25〜
4.0重量部からなる吸収性賦形剤からなり、且つ
適当ならば、更なる処方助剤及び／又は賦形剤を
含んでなる、活性化号物含量の相対標準偏差が最
高2.5％である均一な活性化合物含量をもつ迅速
吸収性の固体薬剤調製物が提供される。本発明に
おいて使用しうる４−ニトロフエニル−ジヒドロ
ピリジン誘導体には、ニフエジピン、ニモジピン
などのジアルキル１，４−ジヒドロ−４−ニトロ
フエニル−ピリジン−３，５−ジカルボキシレー
トが包含される。また、本明細書で使用する略号
「PVPP」は、重合体ポリビニルポリピロリドン
〔例えばアメリカ合衆国ニユーヨーク州のGAF
Corp.から販売されている“Plasdone XL”（商
品名）又は西ドイツ国ルドビツヒシヤーフエンの
BASFから販売されている“Kollidon CL（商標
名）〕を示す。このPVPPは水及び有機溶媒に不
溶である。その平均分子量は1000000より多く、
特に1000000〜3000000である。
これらの固体薬剤調製物は、４−ニトロフエニ
ル−ジヒドロピリジン誘導体１重量部及びPVP
の２〜６重量部を、この２種の固体成分が丁度溶
解しうる少量の有機溶媒に溶解し、この溶液を上
述の賦形剤４〜23重量部、好ましくは5.25〜17重
量部と共に粒状化し、次いでこれらの粒状物を、
所望により更なる処方助剤及び／又は賦形剤と共
に更に処理して固体の薬剤調製物とする方法によ
つて製造される。
次のものは有機溶媒として好適なものとして言
及できる：エターノール、アセトン、塩化メチレ
ン及びクロロホルム、及び特にこれらの溶媒の混
合物。これらは４−ニトロフエニル−ジヒドロピ
リジン誘導体に対して好ましくは２〜20重量％の
量で、特に８〜16重量部の量で用いられる。
セルロース４〜12重量部、澱粉0.25〜2.0重量
部及び架橋した不溶性PVPP1〜３重量部の粉末
混合物は、該吸収性賦形剤として特に適当であ
る。
本発明による好適な調製物は、活性成分含量の
相対標準偏差が最高2.5％であり、活性化合物の
50％が30分以内に放出されるもの；特に活性化合
物がニフエジピンで、その50％が15分以内に放出
されるものである。
次のものは、固体薬剤調製物を与えるために更
に処理する際に使用することのできる通常の助剤
及び賦形剤として好適に言及することができる：
ラクトース、粉糖、マンニトール、グリココール
及び炭酸カルシウム。
次のものは固体の薬剤調節物として好適に言及
しうる：錠剤、丸剤、糖衣錠、粒剤、粉末剤、カ
プセル剤及びサツセイ（sachet）。
このようにして製造される薬剤調製物が非常に
良好なバイオアベラビリテイと、同時に良好な含
量均一性とを有しているということは予期できる
ことではなかつた。本発明の方法によつて製造さ
れ且つ活性化合物／PVP溶液で湿らせた粉末混
合物からなる粒剤は、問題なく乾燥し、ふるい処
理し、更に加工し、他の助剤及び賦形剤と混合
し、また錠剤とするために加圧成形することがで
きる。
４−ニトロフエニル−ジヒドロピリジン誘導体
を含有する適当な薬剤調製物を製造するための、
従来の技術から公知の多くの試みによれば、良好
なバイアベライビリテイ及び最大標準差が2.5％
にすぎない活性化合物含量が特色である新規で有
用な薬剤調製物が、容易に且つ技術的努力なしに
行ないうる本発明の方法で得られるということは
予想できなかつた〔Sucker、Fuchs及びSpeises
出版の単行本「Pharmazeutische
Technologis」、32〜37頁及びU.S.
Pharmacopoea XX、955〜957頁参照〕。
本発明に従つて製造される最良の調製物の有利
な性質を例示するために、ニフエジピン及び
PVPの固体共沈物を、先ず溶媒の蒸発によつて
調製し、次いでこの固体粒状物を通常の助剤及び
賦形剤と混合し、更に処理して固体錠剤にすると
いう常法に従つて比較例Ａ〜Ｆの錠剤を製造し
た。これに対して、本発明による実施例１〜８で
は、ニフエジピン及びPVP或いはニモジピン及
びPVPの共沈物を分離しないで、溶液のまま固
体賦形剤の混合物と共に粒状化し、次いでこの粒
状物を常法で圧縮成形して錠剤とした。
次の表は、本発明による固体処方物が非常に迅
速に及び完全に吸収され（良好な放出性）及び同
時に活性化合物含量の相対標準偏差が非常に小さ
い（良好な含量均一性）ということを示してい
る。
The present invention relates to certain novel, particularly rapidly absorbing, solid drug preparations containing 4-nitrophenyl-dihydropyridine derivatives and polyvinylpyrrolidone, and to processes for their preparation. Nifedipine (dimethyl 1,4
-dihydro-2,6-dimethyl-4-(o-nitrophenyl)-pyridine-3,5-dicarboxylate] is an active compound known from the group of substances of 4-nitrophenyl-dihydropyridine derivatives that acts on the circulatory system. (See UK Patent No. 1173862).
This compound is very sensitive to light and has very low solubility in aqueous media, making it difficult for certain drugs to be used, as evidenced by the numerous patent applications and patents for specific formulations of active compounds. Many difficulties arise in pharmaceutical preparation. U.S. Pat. No. 3,784,684 discloses, for example, certain gelatin biteable capsules containing nifedipine in dissolved form in order to advantageously utilize the coronary action of nifedipine.
It is related to. British Patent No. 1456618 describes the good bio-availability of nifedipine.
describes and claims solid drug preparations intended to ensure that DE 2822882 likewise describes a solid drug preparation in which the poor solubility of nifedipine was compensated for by the use of certain solvents and surface-active substances. In European Patent Application Publication No. 1247,
It is intended to improve the absorption of nifedipine by using polyethylene glycol (PEG) and certain porous excipients. It is also stated in this patent application that the poor solubility of nifedipine can be compensated by the formation of a coprecipitate of nifedipine and polyvinylpyrrolidone (PVP), in which the coprecipitate of nifedipine exists in amorphous form. There is. These coprecipitates are produced by dissolving nifedipine and PVP in an organic solvent and subsequently evaporating the solvent to obtain a glassy body (see DE 2822882). . Such evaporation of the organic solvent can only be carried out industrially and at great expense, since the PVP body binds the organic solvent strongly and becomes very viscous just before drying. Just before the end of the drying process, a very viscous and bulky foam forms, which can no longer be stirred and is difficult to process further. A further disadvantage of using conventional PVP coprecipitates in tablets is the fact that this coprecipitate can only be mixed with other auxiliaries and can no longer be granulated directly with aqueous solutions. However, simple mixtures of PVP coprecipitates and other auxiliaries tend to separate during further mechanical processing, for example to form tablets or during introduction into capsules. This ultimately results in a drug preparation in which the active compound content in each tablet or capsule varies widely (lack of "content uniformity"). This is highly undesirable in the case of highly active substances such as nifedipine. Furthermore,
Since PVP simultaneously acts as a binder, the further auxiliaries that can be selected, especially for the manufacture of tablets, are very limited and the disintegration of tablets or capsules is inhibited by the presence of large amounts of PVP (30-100 mg per tablet or capsule). thwarted by. Nifedipine [1,4-dihydro-2,6-dimethyl-4(3'-nitrophenyl)-pyridine-
3,5-dicarboxylic acid 3-β-methoxyethyl ester (5-isopropyl ester) is also a known 4-nitrophenyl-dihydropyridine derivative that acts on the brain (see German Patent Application No. 2815578). This compound is also difficult to prepare pharmaceutically due to its physicochemical properties. Nifedipine exhibits substantially poorer solubility in aqueous media than, for example, nifedipine. The present invention relates to new solid, rapid-release preparations containing dihydropyridine that no longer have the disadvantages of previously known preparations and to a process for their production. According to the invention, 1 part by weight of 4-nitrophenyl-dihydropyridine derivative as activated product,
2.0 to 6.0 parts by weight of PVP with an average molecular weight of 15,000 to 50,000, as well as 3.5 to 15 parts by weight of cellulose, and 0.25 parts by weight of starch.
~4.0 parts by weight and 0.25 parts by weight of crosslinked insoluble PVPP
4.0 parts by weight of an absorbent excipient and, if appropriate, further formulation aids and/or excipients, with a relative standard deviation of the activated substance content of at most 2.5%. A rapidly absorbing solid drug preparation having a high active compound content is provided. 4-Nitrophenyl-dihydropyridine derivatives that can be used in the present invention include dialkyl 1,4-dihydro-4-nitrophenyl-pyridine-3,5-dicarboxylates such as nifedipine and nimodipine. In addition, the abbreviation "PVPP" used herein refers to polymeric polyvinylpolypyrrolidone [for example, GAF, New York, United States]
“Plasdone XL” (product name) sold by
"Kollidon CL (trade name)" sold by BASF. This PVPP is insoluble in water and organic solvents. Its average molecular weight is more than 1,000,000;
Especially between 1,000,000 and 3,000,000. These solid drug preparations contain 1 part by weight of 4-nitrophenyl-dihydropyridine derivative and PVP.
2 to 6 parts by weight of the solid components are dissolved in a small amount of organic solvent in which the two solid components are just soluble, and this solution is granulated with 4 to 23 parts by weight, preferably 5.25 to 17 parts by weight, of the excipients mentioned above. and then these granules are
It is prepared by further processing to give a solid drug preparation, optionally with further formulation aids and/or excipients. The following may be mentioned as suitable organic solvents: ethanol, acetone, methylene chloride and chloroform, and especially mixtures of these solvents. These are preferably used in amounts of 2 to 20% by weight, in particular 8 to 16 parts by weight, based on the 4-nitrophenyl-dihydropyridine derivative. Powder mixtures of 4 to 12 parts by weight of cellulose, 0.25 to 2.0 parts by weight of starch and 1 to 3 parts by weight of crosslinked insoluble PVPP are particularly suitable as the absorbent excipient. Preferred preparations according to the invention have a relative standard deviation of the active ingredient content of up to 2.5% and a
50% of which is released within 30 minutes; in particular, where the active compound is nifedipine, 50% of which is released within 15 minutes. The following may suitably be mentioned as customary auxiliaries and excipients that can be used in further processing to give solid drug preparations:
Lactose, powdered sugar, mannitol, glycocol and calcium carbonate. The following may suitably be mentioned as solid pharmaceutical preparations: tablets, pills, dragees, granules, powders, capsules and sachets. It was unexpected that the drug preparations produced in this way had very good bioavailability and at the same time good content uniformity. The granules produced by the method of the invention and consisting of a powder mixture moistened with an active compound/PVP solution can be easily dried, sieved, further processed and mixed with other auxiliaries and excipients. It can also be compressed to form tablets. For producing suitable pharmaceutical preparations containing 4-nitrophenyl-dihydropyridine derivatives,
According to many attempts known from the prior art, good vialability and a maximum standard difference of 2.5%
It could not have been foreseen that new and useful pharmaceutical preparations, characterized by an active compound content of no more than
Published book “Pharmazeutische
Technology”, pp. 32-37 and US
See Pharmacopoea XX, pages 955-957]. To illustrate the advantageous properties of the best preparation produced according to the invention, nifedipine and
A solid coprecipitate of PVP is first prepared by evaporation of the solvent, then this solid granulate is mixed with customary auxiliaries and excipients and further processed into solid tablets. Tablets of Comparative Examples A-F were manufactured. In contrast, in Examples 1 to 8 according to the present invention, the coprecipitate of nifedipine and PVP or nimodipine and PVP was not separated, but was granulated as a solution with a mixture of solid excipients, and then this granulate was regularly It was compressed into tablets using a method. The following table shows that the solid formulation according to the invention is absorbed very quickly and completely (good release) and at the same time has a very small relative standard deviation of the active compound content (good content uniformity). It shows.
【表】
ピンの偏差
(mg)
[Table] Pin deviation
(mg)
【表】
また、本発明の固体調製物の臨床試験によれ
ば、共沈物状態で10mgのニフエジピンを含む本発
明の錠剤は、投与後ニフエジピンの血中濃度が迅
速に上昇し、30〜60分後に最大になる。その血中
農度曲線の形は本出願人会社からアダラート
（Adaalat）なる商標名で販売されているニフエ
ジピンの液体カプセル製剤の血中濃度曲線と非常
によく似ている。しかして本試験は本発明の錠剤
が上記アダラートと生理活性的に同等であること
を示している。
公知の方法による固体のニフエジピン調製物の製
造例
比較例Ａ〜Ｆ及び実施例１の混合物はそれぞれ
10000個の錠剤の製造に関するものである。実施
例２〜４はそれぞれ15000個の錠剤に関するもの
である。
比較例 Ａ
ニフエジピン100ｇ及びPVP25（平均分子量
25000）400ｇを塩化メチレン1500ｇに溶解した。
この溶媒を蒸発させた時、撹拌することのできな
い非常に粘稠な物体が最初に生成し、その後この
物体は泡様のガラス状物体になつた。この共沈物
を、振動ふるいにより最高粒径1.0mmにした。別
の操作において、微結晶質セルロース（商品名−
「アビセル（Avicel」）1050ｇ、トウモノコシ澱
粉350ｇ及び沸とう水でペーストにしたトウモロ
コシ澱粉50ｇから顆粒を製造した。これらの顆粒
を、ニフエジピン共沈物500ｇ、ステアリン酸マ
グネシウム４ｇ及び不溶性の架橋したPVP（例え
ば商品名−プラスドン（Plasdone）XL、又はコ
リドン（Kollidon）CL246ｇと混合した。この混
合物から重量220mg及び平均ニフエジピン含量10
mgの錠剤を製造した。
比較例Ｂ及びＣ
Ａの場合と同一の方法で製造した共沈物を、振
動ふるいにより、比較例Ｂの場合に最高粒径0.8
mm及び比較例Ｃの場合に0.6mmとし、次いで比較
例Ａと同一の方法で更に処理して錠剤とした。
比較例 Ｄ
比較例Ａと同様に製造した共沈物をハンマーミ
ルで粉砕し、次いで比較例Ａにおける如く更に処
理して錠剤とした。
比較例 Ｅ
ニフエジピン100ｇ及びPVP25の400ｇを塩化
メチレン1200ｇに溶解し、溶液を真空下に乾燥し
た。得られた共沈物を、セルロース100ｇ、澱粉
450ｇ及び沸とう水でペーストにして澱粉50ｇか
ら製造した顆粒、及びステアリン酸マグネシウム
５ｇ、澱粉195ｇ及び不溶性のポリビニルピロリ
ドン200ｇと混合し、次いでこの混合物を加圧成
形して重さ240mgの錠剤とした。
比較例 Ｆ
比較例Ｅと同様に製造した共沈物をセルロース
及び澱粉の混合物と直接混合し、澱粉ペースト
（即ち水性媒体中）で粒状化し、次いで比較例Ｅ
と同様に加圧成形して錠剤とした。この方法で製
造した錠剤は改良された含量均一性を有したが、
放出性が不満足であつた。
次の実施例は本発明による薬剤及びその製造方
法を例示するものである。
実施例 １
ニフエジピン100ｇ及びPVP25の400ｇを塩化
メチレン1800ｇに溶解した。粒状化装置におい
て、セルロース1050ｇ、澱粉200ｇ及び不溶性の
PVPP100ｇを乾燥状態で混合し、ニフエジピ
ン／PVP溶液で粒状化した。得られる湿つた粒
状物を乾燥し、ふるいにかけ、次いで不溶性の
PVPP145ｇ、澱粉200ｇ及びステアリン酸マグネ
シウム４ｇを添加し、成分を混合し、この混合物
を加圧成形して220mgの錠剤とした。この錠剤は
非常に良好な含量均一性と有利な放出性が特色で
あつた。
実施例 ２
実施例１と同様にして、ニフエジピン150ｇ及
びPVP25の600ｇを塩化メチレン1800ｇに溶解
し、この溶液を、微結晶質セルロース（アビセ
ル）1575ｇ及びトウモロコシ澱粉600ｇの混合物
で直接粒状化した。粒状物を乾燥し、ふるいにか
けた後、これをステアリン酸マグネシウム６ｇ及
び不溶性PVPP369ｇと混合し、混合物を加圧成
形して重さ220mgの錠剤とした。
実施例 ３
実施例２と同様に、ニフエジピン150ｇ及び
PVP25の600ｇを塩化メチレン2200ｇに溶解し
た。この溶液を、微結晶質セルロース1575ｇ、ト
ウモロコシ澱粉600ｇ及び不溶性PVPP300ｇの混
合物を粒状化するために使用した。粒状物を乾燥
し、ふるいにかけた後、これをステアリン酸マグ
ネシウム６ｇ及び不溶性PVPP69ｇと混合し、混
合物を加圧成形して重さ220mgの錠剤とした。
実施例 ４
ニフエジピン150ｇ及びPVP25の600ｇを塩化
メチレン2100ｇに溶解した。この溶液を、微結晶
質セルロース1575ｇ、トウモロコシ澱粉600ｇ及
び不溶性PVPP150ｇの混合物を粒状化するため
に使用した。粒状物を乾燥し、ふるいにかけた
後、これをステアリン酸マグネシウム66ｇ及び不
溶性PVPP219ｇと混合し、この混合物を圧縮成
形して重さ220mgの錠剤とした。
実施例 ５
それぞれニフエジピン10mgを含有する錠剤
100000個を製造するために次の量を使用した：ニ
フエジピン１Kg及びPVP25の４Kgをアセトン７
Kgに溶解した。この溶液を、微結晶質セルロース
（アビセル）10.5Kg、澱粉２Kg及び不溶性PYPP1
Kgの混合物を粒状化するために使用した。この物
体を真空下に乾燥し、ふるいにかけ、不溶性
PVPP1.46ｇ、澱粉２Kg及びステアリン酸マグネ
シウム0.04Kgと混合した。この混合物を加圧成形
して重さ220mg及び直径９mmの錠剤とした。錠剤
20Kgに、ヒドロキシプロピルメチルセルロース
0.3Kg、ポリエチレングリコール4000の0.1Kg、二
酸化チタン0.09Kg及び赤色酸化鉄0.01Kgの、水
6.17Kg中懸濁液を噴霧した。
実施例 ６
それぞれニフエジピン20mgを含有する錠剤
250000個を製造するために次の量を使用した：ニ
フエジピン５Kg及びPVP25の20Kgをアセトン35
Kg及び塩化メチレン10Kgに溶解した。この溶液
を、微結晶質セルロース52.5Kg、澱粉10Kg及び不
溶性PVPP5Kgの混合物を粒状化するために使用
した。この物体を真空下に乾燥し、ふるいにか
け、不溶性PVPP7.3ｇ、澱粉10Kg及びステアリ
ン酸マグネシウム0.2Kgと混合した。この混合物
を加圧成形して重さ440mgの錠剤とした。錠剤10
Kgに、ヒドロキシプロピルメチルセルロース1.5
Kg、ポリエリレングリコール4000の0.5Kg、二酸
化チタン0.4Kg、赤色酸化鉄0.1Kg及び水30.83Kgの
懸濁液を噴霧することによつてコーテイングし
た。
実施例 ７
それぞれニモジピン30mgを含有する錠剤20000
個を製造するために次の量を使用した：ニモジピ
ン0.6Kg及びPVP25の1.5Kgをアセトン1.4Kgに溶解
した。この溶液を、微結晶質セルロース2.85Kg、
澱粉0.150Kg及び不溶性PVPP0.6Kgの混合物の粒
状化するために使用した。この物体を真空下に乾
燥し、ふるいにかけ、不溶性PVPP0.288ｇ、澱
粉0.566Kg及びステアリン酸マグネシウム0.011Kg
と混合した。この混合物を加圧成形して重さ330
mg及び直径10mmの錠剤とした。錠剤６Kgに、ヒド
ロキシプロピルメチルセルロース0.225Kg、ポリ
エチレングリコール4000の0.075Kg及び二酸化チ
タン0.075Kgの、水11.1Kg中懸濁液を噴霧するこ
とによつてコーテイングした。個々の錠剤のニモ
ジピン含量の分析結果は29.78mg〜31.18mgであ
り、相対標準偏差は1.156％であつた。
実施例 ８
それぞれニモジピン40mgを含有する錠剤60000
個に対して十分な錠剤混合物26.4Kgのバツチを次
の方法で製造した：ニモジピン2.4Kg及びPVP25
の6.0Kgを、透明で粘稠な溶液となるまでアセト
ン5.76Kg中で撹拌した。微結晶質セルロース11.4
Kg、澱粉0.6Kg及び不溶性のPVPP2.4Kgを粒状化
装置中で混合した。次いでニモジピンを含有する
上述の溶液を添加した。この溶液を粉末成分と粒
状化した後、物体を真空下に乾燥し、次いでふる
いにかけて平均粒径1.0mmにした。この目的のた
めに、澱粉2.4Kg、不溶性PVPP1.152Kg及びステ
アリン酸マグネシウム0.48ｇを混合した。この混
合物から重さ440mgの錠剤を加圧成形した。これ
らの錠剤24Kgに、ヒドロキシプロピル−メチルセ
ルロース0.54Kg、ポリエチレングリコール4000の
0.18Kg及び二酸化チタン0.18Kgの、水11.1Kg中懸
濁液を噴霧した。個々の錠剤中のニモジピンの平
均含量は40.5mgであつた。相対標準偏差は2.21％
であつた。[Table] In addition, according to clinical tests of the solid preparation of the present invention, the tablet of the present invention containing 10 mg of nifedipine in the coprecipitate state rapidly increased the blood concentration of nifedipine after administration, and the blood concentration of nifedipine increased rapidly from 30 to 60. Maximum after minutes. The shape of the blood concentration curve is very similar to the blood concentration curve of the liquid capsule formulation of nifedipine sold under the trade name Adaalat by the applicant company. This test thus shows that the tablets of the present invention are bioactively equivalent to the above-mentioned adalates. Example of Preparation of Solid Nifedipine Preparation by Known Methods The mixtures of Comparative Examples A to F and Example 1 were each
It concerns the production of 10,000 tablets. Examples 2-4 each relate to 15,000 tablets. Comparative example A Nifedipine 100g and PVP25 (average molecular weight
25000) was dissolved in 1500 g of methylene chloride.
When the solvent was evaporated, a very viscous mass that could not be stirred was first formed, which then turned into a foam-like glassy mass. This coprecipitate was sieved to a maximum particle size of 1.0 mm using a vibrating sieve. In another operation, microcrystalline cellulose (trade name -
Granules were prepared from 1050 g of "Avicel", 350 g of corn starch and 50 g of corn starch made into a paste with boiling water. These granules were mixed with 500 g of nifedipine coprecipitate, 4 g of magnesium stearate and 246 g of insoluble cross-linked PVP (e.g. trade name - Plasdone XL, or Kollidon CL). From this mixture a weight of 220 mg and an average of nifedipine were obtained. Content 10
mg tablets were manufactured. Comparative Examples B and C A coprecipitate prepared in the same manner as in A was sieved with a vibrating sieve to obtain a maximum particle size of 0.8 in Comparative Example B.
mm and 0.6 mm in case of Comparative Example C and then further processed in the same manner as Comparative Example A to form tablets. Comparative Example D A coprecipitate prepared as in Comparative Example A was ground in a hammer mill and then further processed as in Comparative Example A into tablets. Comparative Example E 100 g of nifedipine and 400 g of PVP25 were dissolved in 1200 g of methylene chloride and the solution was dried under vacuum. The resulting coprecipitate was mixed with 100 g of cellulose and starch.
Granules prepared from 450 g and 50 g of starch pasted with boiling water were mixed with 5 g of magnesium stearate, 195 g of starch and 200 g of insoluble polyvinylpyrrolidone, and the mixture was then pressed into tablets weighing 240 mg. . Comparative Example F A coprecipitate prepared as in Comparative Example E was mixed directly with a mixture of cellulose and starch, granulated with starch paste (i.e. in an aqueous medium) and then
It was press-molded into tablets in the same manner as above. Tablets made with this method had improved content uniformity, but
The release properties were unsatisfactory. The following examples illustrate medicaments according to the invention and methods for their manufacture. Example 1 100 g of nifedipine and 400 g of PVP25 were dissolved in 1800 g of methylene chloride. In a granulator, 1050 g of cellulose, 200 g of starch and insoluble
100 g of PVPP was dry mixed and granulated with the nifedipine/PVP solution. The resulting wet granules are dried, sieved and then the insoluble
145 g of PVPP, 200 g of starch and 4 g of magnesium stearate were added, the ingredients were mixed and the mixture was pressed into 220 mg tablets. The tablets were distinguished by very good content uniformity and favorable release properties. Example 2 Analogously to Example 1, 150 g of nifedipine and 600 g of PVP25 were dissolved in 1800 g of methylene chloride, and this solution was directly granulated with a mixture of 1575 g of microcrystalline cellulose (Avicel) and 600 g of corn starch. After drying and sieving the granules, they were mixed with 6 g of magnesium stearate and 369 g of insoluble PVPP and the mixture was pressed into tablets weighing 220 mg. Example 3 Similar to Example 2, 150 g of nifedipine and
600 g of PVP25 was dissolved in 2200 g of methylene chloride. This solution was used to granulate a mixture of 1575 g of microcrystalline cellulose, 600 g of corn starch and 300 g of insoluble PVPP. After drying and sieving the granulate, it was mixed with 6 g of magnesium stearate and 69 g of insoluble PVPP and the mixture was pressed into tablets weighing 220 mg. Example 4 150 g of nifedipine and 600 g of PVP25 were dissolved in 2100 g of methylene chloride. This solution was used to granulate a mixture of 1575 g of microcrystalline cellulose, 600 g of corn starch and 150 g of insoluble PVPP. After drying and sieving the granulate, it was mixed with 66 g of magnesium stearate and 219 g of insoluble PVPP and the mixture was compressed into tablets weighing 220 mg. Example 5 Tablets each containing 10 mg of nifedipine
The following quantities were used to produce 100,000 units: 1 Kg of Nifedipine and 4 Kg of PVP25 in 7 Acetone.
Dissolved in Kg. This solution was mixed with 10.5 kg of microcrystalline cellulose (Avicel), 2 kg of starch and 1 kg of insoluble PYPP.
Kg mixture was used to granulate it. This material is dried under vacuum, sieved and insoluble
Mixed with 1.46g PVPP, 2Kg starch and 0.04Kg magnesium stearate. This mixture was pressure molded into tablets weighing 220 mg and having a diameter of 9 mm. tablet
20Kg, hydroxypropyl methylcellulose
0.3Kg, polyethylene glycol 4000 0.1Kg, titanium dioxide 0.09Kg and red iron oxide 0.01Kg, water
The suspension in 6.17Kg was sprayed. Example 6 Tablets each containing 20 mg of nifedipine
The following quantities were used to produce 250,000 units: 5 Kg of Nifedipine and 20 Kg of PVP25 to 35 Kg of acetone.
Kg and 10 Kg of methylene chloride. This solution was used to granulate a mixture of 52.5 Kg microcrystalline cellulose, 10 Kg starch and 5 Kg insoluble PVPP. This mass was dried under vacuum, sieved and mixed with 7.3 g of insoluble PVPP, 10 Kg of starch and 0.2 Kg of magnesium stearate. This mixture was pressure molded into tablets weighing 440 mg. tablets 10
Kg Hydroxypropyl Methyl Cellulose 1.5
The coating was made by spraying a suspension of 0.5 Kg of polyethylene glycol 4000, 0.4 Kg of titanium dioxide, 0.1 Kg of red iron oxide and 30.83 Kg of water. Example 7 20000 tablets each containing 30 mg of nimodipine
The following amounts were used to prepare the following: 0.6 Kg of nimodipine and 1.5 Kg of PVP25 were dissolved in 1.4 Kg of acetone. This solution was mixed with 2.85 kg of microcrystalline cellulose,
It was used to granulate a mixture of 0.150Kg of starch and 0.6Kg of insoluble PVPP. This mass was dried under vacuum and sieved to contain 0.288 g of insoluble PVPP, 0.566 Kg of starch and 0.011 Kg of magnesium stearate.
mixed with. Pressure mold this mixture to a weight of 330
tablets with a diameter of 10 mm. 6 Kg tablets were coated by spraying a suspension of 0.225 Kg hydroxypropyl methylcellulose, 0.075 Kg polyethylene glycol 4000 and 0.075 Kg titanium dioxide in 11.1 Kg water. Analysis of the nimodipine content of individual tablets ranged from 29.78 mg to 31.18 mg, with a relative standard deviation of 1.156%. Example 8 60000 tablets each containing 40 mg of nimodipine
A batch of 26.4 Kg of tablet mixture, sufficient for 200 mg of tablets, was prepared in the following manner: 2.4 Kg of Nimodipine and 25 PVP.
6.0Kg of was stirred in 5.76Kg of acetone until a clear viscous solution was obtained. Microcrystalline cellulose 11.4
Kg, 0.6 Kg starch and 2.4 Kg insoluble PVPP were mixed in a granulator. The solution described above containing nimodipine was then added. After granulating this solution with the powder component, the mass was dried under vacuum and then sieved to an average particle size of 1.0 mm. For this purpose, 2.4 Kg of starch, 1.152 Kg of insoluble PVPP and 0.48 g of magnesium stearate were mixed. Tablets weighing 440 mg were pressed from this mixture. 24Kg of these tablets contain 0.54Kg of hydroxypropyl-methylcellulose and 4000g of polyethylene glycol.
A suspension of 0.18 Kg and 0.18 Kg of titanium dioxide in 11.1 Kg of water was sprayed. The average content of nimodipine in individual tablets was 40.5 mg. Relative standard deviation is 2.21%
It was hot.
Claims (1)
−ジヒドロピリジン誘導体１重量部及び (b) 平均分子量15000〜50000のポリビニルピロリ
ドン（PVP）2.0〜6.0重量部 を、これら２成分の丁度溶解しうる溶媒中の溶
液の状態で、 (c) セルロース3.5〜15重量部 (d) 澱粉0.25〜4.0重量部及び (e) 架橋した不溶性のポリビニルポリピロリドン
（PVPP）0.25〜4.0重量部 の混合物からなる吸収性賦形剤に吸収付着させる
ことにより得られる、活性化合物含量の最大相対
標準偏差が2.5％であることを特徴とする固体で
迅速吸収性の薬剤調製物。 ２ １種又はそれ以上の更なる処方助剤及び／又
は賦形剤を含んでなる特許請求の範囲第１項記載
の調製物。 ３ 活性化合物の50％が30分以内に放出される特
許請求の範囲第１項又は２項記載の調製物。 ４ 活性化合物がニフエジピンであり、そのニフ
エジピンの50％が15分以内に放出される特許請求
の範囲第３項記載の調製物。 ５ 吸収性賦形剤がセルロース４〜12重量部、澱
粉0.25〜2.0重量部及び架橋した不溶性のPVPP1
〜３重量部の混合物からなる特許請求の範囲第１
〜４項のいずれかに記載の調製物。 ６ 錠剤、丸剤、糖衣錠、顆粒剤、散剤、カプセ
ル剤又はサツセイの形態の特許請求の範囲第１〜
５項記載のいずれかに記載の調製物。[Scope of Claims] 1. (a) 1 part by weight of a 4-nitrophenyl-dihydropyridine derivative as an active compound, and (b) 2.0 to 6.0 parts by weight of polyvinylpyrrolidone (PVP) having an average molecular weight of 15,000 to 50,000, in exactly the amount of these two components. A mixture of (c) 3.5 to 15 parts by weight of cellulose, (d) 0.25 to 4.0 parts by weight of starch, and (e) 0.25 to 4.0 parts by weight of crosslinked insoluble polyvinylpolypyrrolidone (PVPP), in solution in a soluble solvent. A solid, rapidly absorbing drug preparation, characterized in that it has a maximum relative standard deviation of the active compound content of 2.5%, obtained by adsorption onto an absorbent excipient consisting of: 2. A preparation according to claim 1, comprising one or more further formulation auxiliaries and/or excipients. 3. Preparation according to claim 1 or 2, in which 50% of the active compound is released within 30 minutes. 4. A preparation according to claim 3, wherein the active compound is nifedipine and 50% of the nifedipine is released within 15 minutes. 5 Absorbent excipients include 4 to 12 parts by weight of cellulose, 0.25 to 2.0 parts by weight of starch, and crosslinked insoluble PVPP1
Claim 1 consisting of a mixture of ~3 parts by weight
4. Preparation according to any of paragraphs 1 to 4. 6. Claims 1 to 6 in the form of tablets, pills, sugar-coated tablets, granules, powders, capsules, or sweets.
Preparation according to any of paragraph 5.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE31428533 | 1981-10-29 | ||
| DE19813142853 DE3142853A1 (en) | 1981-10-29 | 1981-10-29 | Solid pharmaceutical compositions containing nifedipine and process for their production |
| DE32053991 | 1982-02-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5883617A JPS5883617A (en) | 1983-05-19 |
| JPH0338248B2 true JPH0338248B2 (en) | 1991-06-10 |
Family
ID=6145080
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP57186884A Granted JPS5883617A (en) | 1981-10-29 | 1982-10-26 | Solid quick-release drug blend containing dihydropyridine and manufacture |
| JP61223924A Pending JPS62228017A (en) | 1981-10-29 | 1986-09-24 | Manufacture of solid quick release drug composition containing dihydropyridine |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61223924A Pending JPS62228017A (en) | 1981-10-29 | 1986-09-24 | Manufacture of solid quick release drug composition containing dihydropyridine |
Country Status (2)
| Country | Link |
|---|---|
| JP (2) | JPS5883617A (en) |
| DE (1) | DE3142853A1 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3142853A1 (en) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | Solid pharmaceutical compositions containing nifedipine and process for their production |
| JPS59101423A (en) * | 1982-12-02 | 1984-06-12 | Takada Seiyaku Kk | Novel solid pharmaceutical preparation of nifedipine |
| DE3318649A1 (en) * | 1983-05-21 | 1984-11-22 | Bayer Ag, 5090 Leverkusen | TWO-PHASE FORMULATION |
| US4794111A (en) * | 1984-05-23 | 1988-12-27 | Bayer Aktiengesellschaft | Dihydropyridine preparations containing β-blockers |
| DE3424553A1 (en) * | 1984-07-04 | 1986-01-09 | Bayer Ag, 5090 Leverkusen | SOLID DRUG PREPARATIONS WITH DIHYDROPYRIDINE AND METHOD FOR THE PRODUCTION THEREOF |
| DE3433239A1 (en) * | 1984-09-11 | 1986-03-20 | Bayer Ag, 5090 Leverkusen | SOLID PHARMACEUTICAL PREPARATION CONTAINING NITRENDIPINE AND METHOD FOR THE PRODUCTION THEREOF |
| US5543099A (en) * | 1994-09-29 | 1996-08-06 | Hallmark Pharmaceutical, Inc. | Process to manufacture micronized nifedipine granules for sustained release medicaments |
| DE19515972A1 (en) * | 1995-05-02 | 1996-11-07 | Bayer Ag | Controlled release pharmaceutical preparations and process for their preparation |
| TW527195B (en) | 1997-10-09 | 2003-04-11 | Ssp Co Ltd | Fast-soluble solid pharmaceutical combinations |
| DE602005018387D1 (en) * | 2004-10-06 | 2010-01-28 | Eisai R&D Man Co Ltd | MEDICAL COMPOSITION, PROCESS FOR YOUR HDI-HYDROPYRIDINE COMPOUND IN A MEDICAL COMPOSITION |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2200778B2 (en) * | 1971-01-13 | 1974-04-18 | Sandoz Ag, Basel (Schweiz) | Use of high molecular weight, insoluble, cross-linked polyvinylpyrrolidone as a disintegrant in solid drug forms |
| JPS5283919A (en) * | 1976-01-01 | 1977-07-13 | Sandoz Ag | Pharmaceutical tablet |
| FR2391882A1 (en) * | 1977-05-25 | 1978-12-22 | Ducellier & Cie | WINDSCREEN WIPER BLADE FOR MOTOR VEHICLES |
| JPS542316A (en) * | 1977-06-07 | 1979-01-09 | Yamanouchi Pharmaceut Co Ltd | Solid pharmaceutical composition containing nifedipene |
| GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
| JPS5420127A (en) * | 1977-07-14 | 1979-02-15 | Yamanouchi Pharmaceut Co Ltd | Solid nifedipine preparaton |
| DE2815578C2 (en) * | 1978-04-11 | 1986-01-16 | Bayer Ag, 5090 Leverkusen | New pharmaceutical use of nimodipine |
| DE3142853A1 (en) * | 1981-10-29 | 1983-05-11 | Bayer Ag, 5090 Leverkusen | Solid pharmaceutical compositions containing nifedipine and process for their production |
-
1981
- 1981-10-29 DE DE19813142853 patent/DE3142853A1/en active Granted
-
1982
- 1982-10-26 JP JP57186884A patent/JPS5883617A/en active Granted
-
1986
- 1986-09-24 JP JP61223924A patent/JPS62228017A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62228017A (en) | 1987-10-06 |
| DE3142853C2 (en) | 1989-06-29 |
| DE3142853A1 (en) | 1983-05-11 |
| JPS5883617A (en) | 1983-05-19 |
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