JPS63267720A - Sustained release preparation of emorfazone - Google Patents
Sustained release preparation of emorfazoneInfo
- Publication number
- JPS63267720A JPS63267720A JP10284587A JP10284587A JPS63267720A JP S63267720 A JPS63267720 A JP S63267720A JP 10284587 A JP10284587 A JP 10284587A JP 10284587 A JP10284587 A JP 10284587A JP S63267720 A JPS63267720 A JP S63267720A
- Authority
- JP
- Japan
- Prior art keywords
- granules
- sustained release
- emorfazone
- release granules
- release
- 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.)
- Pending
Links
- URJQOOISAKEBKW-UHFFFAOYSA-N Emorfazone Chemical compound C1=NN(C)C(=O)C(OCC)=C1N1CCOCC1 URJQOOISAKEBKW-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 19
- 229950010243 emorfazone Drugs 0.000 title claims abstract description 17
- 239000008187 granular material Substances 0.000 claims abstract description 89
- 238000013268 sustained release Methods 0.000 claims abstract description 12
- 239000012730 sustained-release form Substances 0.000 claims abstract description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 10
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 9
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 7
- 229920001577 copolymer Polymers 0.000 claims abstract description 7
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 7
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 7
- 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 4
- 239000008101 lactose Substances 0.000 claims abstract description 4
- 229920002472 Starch Polymers 0.000 claims abstract description 3
- 239000011230 binding agent Substances 0.000 claims abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 3
- 235000019698 starch Nutrition 0.000 claims abstract description 3
- 230000003111 delayed effect Effects 0.000 claims description 26
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 22
- 238000009472 formulation Methods 0.000 claims description 12
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 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 claims description 3
- 238000005469 granulation Methods 0.000 claims description 3
- 230000003179 granulation Effects 0.000 claims description 3
- 239000003921 oil Substances 0.000 claims description 3
- 239000001993 wax Substances 0.000 claims description 3
- 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 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- -1 acrylic acid-methacrylate ester Chemical class 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 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 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000001761 ethyl methyl cellulose Substances 0.000 claims 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 claims 1
- 235000001727 glucose Nutrition 0.000 claims 1
- 229920003146 methacrylic ester copolymer Polymers 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 14
- 230000000694 effects Effects 0.000 abstract description 6
- 206010028813 Nausea Diseases 0.000 abstract description 3
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 3
- 230000008693 nausea Effects 0.000 abstract description 3
- 230000000202 analgesic effect Effects 0.000 abstract 1
- 239000008107 starch Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000008280 blood Substances 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000013270 controlled release Methods 0.000 description 6
- 229920003134 Eudragit® polymer Polymers 0.000 description 5
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 235000013336 milk Nutrition 0.000 description 3
- 239000008267 milk Substances 0.000 description 3
- 210000004080 milk Anatomy 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 239000011824 nuclear material Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 229920003067 (meth)acrylic acid ester copolymer Polymers 0.000 description 1
- MUZDXNQOSGWMJJ-UHFFFAOYSA-N 2-methylprop-2-enoic acid;prop-2-enoic acid Chemical compound OC(=O)C=C.CC(=C)C(O)=O MUZDXNQOSGWMJJ-UHFFFAOYSA-N 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229920003114 HPC-L Polymers 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940125368 controlled substance Drugs 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 239000003975 dentin desensitizing agent Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は消炎・鎮痛薬、エモルファゾン（化学名：４−
エトキシ−２−メチル−５−モルホリノ−３（２Ｈ）−
ピリダジノン）の徐放性製剤に関する。[Detailed Description of the Invention] [Industrial Application Field] The present invention provides an anti-inflammatory and analgesic drug, emorfazone (chemical name: 4-
Ethoxy-2-methyl-5-morpholino-3(2H)-
pyridazinone).
エモルファゾンは通常の錠剤として製剤化され既に市販
されているが、その徐放性製剤は未だ開発されていない
。Emorphazone is formulated as a regular tablet and is already on the market, but its sustained release formulation has not yet been developed.
エモルファゾンは、経口投与後消化管から容易に吸収さ
れて１時間以内に最高血中濃度に達し、その俊速やかに
血中から消失する。その血中からの半減期は、約１．０
時間と短いことが知られている（林 敏廣ら、薬学雑誌
、１００，１０５ （１９８０））。このように吸収と
排泄が速いため、一般に用いられている錠剤や顆粒剤と
する製剤法では有効血中濃度を長時間に亘って維持する
ことが難しく、顧回の服用を必要とするのが現状である
。また、有効血中濃度を長くしようとすると一回の服用
量を多くしなければならないが、エモルファゾンの血中
濃度が急激に高くなると、吐き気など上部消化管の不快
感が生じ易く好ましくない。Emorphazone is easily absorbed from the gastrointestinal tract after oral administration, reaches maximum blood concentration within one hour, and disappears rapidly from the blood. Its half-life from the blood is approximately 1.0
It is known that it takes a short time (Toshihiro Hayashi et al., Pharmaceutical Journal, 100, 105 (1980)). Because of this rapid absorption and excretion, it is difficult to maintain an effective blood concentration over a long period of time using commonly used tablet or granule formulations, making it difficult to maintain effective blood concentrations over a long period of time. This is the current situation. Furthermore, in order to prolong the effective blood concentration, it is necessary to increase the dose at one time, but if the blood concentration of emorfazone increases rapidly, it is undesirable because it tends to cause discomfort in the upper gastrointestinal tract such as nausea.
したがって、本発明の目的は、エモルファゾンの急激な
血中濃度の上昇を程よく抑制し有効血中濃度をできるだ
け長くする製剤、すなわち適度の即効性を示し且つ作用
の持続性を存するエモルファゾンの製剤を提供すること
にある。Therefore, an object of the present invention is to provide a formulation of emorphazone that moderately suppresses the rapid increase in blood concentration of emorphazone and maintains the effective blood concentration as long as possible, that is, a formulation of emorphazone that exhibits an appropriate immediate effect and has a sustained action. It's about doing.
本発明者らは、徐放性製剤化の種々の方法を用いて鋭意
研究した。その結果、速放性顆粒剤と遅放性顆粒剤を組
み合わせた徐放性製剤とすることにより、所期の目的を
達成することができることを見出し本発明を完成するこ
とができた。The present inventors have conducted extensive research using various methods of producing sustained release formulations. As a result, the present invention was completed by discovering that the desired objective can be achieved by creating a sustained release preparation that is a combination of immediate release granules and delayed release granules.
すなわち本発明は、薬効成分としてエモルファゾンをそ
れぞれ含有する速放性顆粒剤と遅放性顆粒剤とを混合し
てなるエモルファゾンの徐放性製剤を提供するものであ
る。That is, the present invention provides a sustained release preparation of emorphazone, which is a mixture of immediate release granules and delayed release granules, each containing emorphazone as a medicinal ingredient.
本発明において、速放性顆粒剤とは、エモルファゾンに
、例えばデンプン類、乳糖、ブドウ糖。In the present invention, immediate release granules include emorfazone, for example, starches, lactose, and glucose.
マンニトール等の１種以上の賦形剤とヒドロキシプロピ
ルセルロース、エチルセルロース、メチルセルロース、
セルロース、ポリビニルピロリドン等の１種以上の結合
剤を加え、通常の製剤法で顆粒剤としたもので、必要に
よりヒドロキシメチルセルロース、ポリビニルアセター
ルジエチルアミノアセテート、メタアクリル酸−メチル
メタアクリレート共重合体等の１種又は２種以上を用い
て皮膜を施すことができる。one or more excipients such as mannitol and hydroxypropylcellulose, ethylcellulose, methylcellulose,
It is made into granules by adding one or more binders such as cellulose and polyvinylpyrrolidone, and is made into granules using a normal formulation method. A film can be applied using one or more species.
また、遅放性顆粒剤とは、例えば（１）：前記速放性顆
粒剤に放出制御物質の皮膜を施したもの、（２）：エモ
ルファゾンに放出制御物質、さらに必要に応じて添加剤
を加えエタノール、塩化メチレンなどの溶媒を用いて練
合し、これを顆粒剤としたもの、あるいは（３）：先の
（２）の混合物に白糖や乳糖等の核物質を加え、通常の
遠心流動造粒法により顆粒剤としたものなどである。（
２）と（３）の顆粒剤には（１）と同様に皮膜を施すこ
ともできる。In addition, delayed-release granules are, for example, (1): the above-mentioned immediate-release granules coated with a release-controlling substance, and (2): emorfazone with a release-controlling substance and, if necessary, additives. In addition, the mixture is kneaded with a solvent such as ethanol or methylene chloride and made into granules, or (3): A core substance such as sucrose or lactose is added to the mixture of (2) above, and the mixture is subjected to normal centrifugal flow. These include those made into granules by a granulation method. (
The granules in 2) and (3) can also be coated in the same manner as in (1).
前記放出制御物質としては、（１）及び（２）の場合、
ｐＨ６以上で溶解するメタアクリル酸−メチルメタアク
リレート共重合体、ｐＨ５，５以上で溶解するヒドロキ
シプロピルメチルセルロースフタレート、エチルセルロ
ース、アクリル酸−メタアクリル酸エステル共重合体、
硬化油、ワックス類あるいはこれらの混合物が好ましく
、また、前記（３）の場合はそれらのほか、カルボキシ
ビニルポリマー、ヒドロキシプロピルセルロース、ヒド
ロキシプロピルメチルセルロース、アクリル酸重合体又
はこれらの混合物も好適に使用できる。In the case of (1) and (2), the controlled release substance is
Methacrylic acid-methyl methacrylate copolymer that dissolves at pH 6 or higher, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, acrylic acid-methacrylate ester copolymer that dissolves at pH 5 or higher,
Hydrogenated oils, waxes, or mixtures thereof are preferred, and in the case of (3) above, carboxyvinyl polymers, hydroxypropyl cellulose, hydroxypropyl methylcellulose, acrylic acid polymers, or mixtures thereof can also be suitably used. .
前記（１）における放出制御物質皮膜の顆粒中に占める
割合は、５〜６０Ｗ／Ｗ％の範囲が好ましい。The ratio of the release-controlled substance coating in the above (1) in the granules is preferably in the range of 5 to 60 W/W%.
皮膜を施す場合、一般に使用されている含水溶媒等に放
出制御物質を溶解して常法に従って行うが、そのときの
固形分の濃度は５〜２０−／−％の範囲が好ましく、さ
らに好ましくは５〜１２Ｗ／Ｗ％の範囲である。このと
き可望剤としてグリセリン脂肪酸エステル、ポリソルベ
ート類、マクロゴール類、トリアセチン、プロピレング
リコール等が使用できる。また、皮膜を施す操作中に強
い静電気が発生して支障を来すことがあり、静電気防止
剤としてタルク、酸化チタン等を添加してもよい。When applying a film, the controlled-release substance is dissolved in a commonly used water-containing solvent and the like is carried out according to a conventional method, and the solid content concentration at this time is preferably in the range of 5 to 20-/-%, more preferably It is in the range of 5 to 12 W/W%. At this time, glycerin fatty acid esters, polysorbates, macrogols, triacetin, propylene glycol, etc. can be used as desensitizing agents. In addition, strong static electricity may be generated during the coating operation, causing problems, so talc, titanium oxide, etc. may be added as an antistatic agent.
前記（２）の放出制御物質の顆粒中に占める割合は、１
５〜５０Ｗ／Ｗ％の範囲が好ましい。The proportion of the controlled release substance in the above (2) in the granules is 1
A range of 5 to 50 W/W% is preferable.
前記（３）の場合、エモルファゾンか放出制御物質のい
ずれかを含水エタノールなどの溶媒に溶解し常法に従っ
て造粒すればよいが、溶液中の固形物濃度は、５〜３０
−／−％の範囲が好適である。In the case of (3) above, either emorfazone or the controlled release substance may be dissolved in a solvent such as aqueous ethanol and granulated according to a conventional method, but the solid concentration in the solution is 5 to 30%.
A range of -/-% is preferred.
また、放出制御物質の顆粒中に占める割合は２０〜５０
Ｗ／Ｗ％の範囲にあることが望ましい。In addition, the proportion of the controlled release substance in the granules is 20 to 50.
It is desirable that it be in the range of W/W%.
以上の如くして得られる速放性顆粒剤と遅放性顆粒剤の
好ましい混合割合は、前者１重量部に対し後者が０．５
〜３重量部、さらに好適には１〜２重量部の範囲である
。The preferred mixing ratio of the immediate release granules and delayed release granules obtained as described above is 0.5 parts by weight of the former to 1 part by weight of the latter.
-3 parts by weight, more preferably 1-2 parts by weight.
次に実施例を挙げて本発明を説明するが、これにより本
発明は何ら限定されるものではない。Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto.
〔実施例１〕
エモルファゾン１４４０ｇ、コーンスターチ４００ｇ、
乳１！９６０ｇ、微結晶セＪＬｔローフ、粉末４００ｇ
及びヒドロキシプロピルセルロース（商品名： ＨＰＣ
−３Ｌ、日本曹達＞１６０ｇを品用ニーダ−（品用製作
所）で５分間混合した後３０％エタノール水溶液１６０
０−を徐々に加えながら２分間練合した。練合物を押し
出し造粒機（不ニパウダル）で粉砕整粒し１２〜３２メ
ツシユのものを素顆粒として３１７０ｇ得た。この素顆
粒４００ｇに、常法に従ってメタアクリル酸−メチルメ
タアクリレート共重合体（商品名：オイドラギットＥ１
樋口商会）の皮膜（素顆粒のＩＩＷ／Ｗ％）を施し、乾
燥して速放性顆粒剤４４０ｇを得た。[Example 1] Emorphazone 1440g, cornstarch 400g,
Milk 1!960g, Microcrystalline JLt Loaf, Powder 400g
and hydroxypropylcellulose (product name: HPC
-3L, Nippon Soda>160g was mixed for 5 minutes in a Shinyo Kneader (Shinyo Seisakusho), then 30% ethanol aqueous solution 160g
The mixture was kneaded for 2 minutes while gradually adding 0-. The kneaded product was extruded and pulverized into granules using a granulator (Funipaudal) to obtain 3,170 g of elementary granules having 12 to 32 meshes. Add methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit E1) to 400 g of these elementary granules in a conventional manner.
Higuchi Shokai) coating (IIW/W% of the elementary granules) was applied and dried to obtain 440 g of immediate release granules.
また、上記素顆粒４００ｇにヒドロキシプロピルメチル
セルロースフタレート（商品名：ＨＰ５５Ｓ、信越化学
）の皮膜（素顆粒の６７賀八％）を施し、乾燥して遅放
性顆粒剤６４５ｇを得た。Further, 400 g of the above elementary granules were coated with hydroxypropyl methyl cellulose phthalate (trade name: HP55S, Shin-Etsu Chemical) (67% to 8% of the elementary granules) and dried to obtain 645 g of delayed-release granules.
これらの速放性顆粒剤と速放性顆粒剤を、前者１重量部
、後者２重量部の割合で混合することにより徐放性製剤
を得た。A sustained release preparation was obtained by mixing these immediate release granules and immediate release granules at a ratio of 1 part by weight of the former and 2 parts by weight of the latter.
〔実施例２〕
核物質として２４〜３２メツシユの白糖粒（商品名：ノ
ンバレル、フロイント産業）１０００ｇに対し、１００
メツシユの篩で経過したエモルファゾンの粉末６００
ｇ、及び結合剤としてヒドロキシプロピルセルロース（
商品名：ＨＰＣ−Ｌ。[Example 2] For 1000 g of white sugar grains (trade name: Nonbarrel, Freund Sangyo) of 24 to 32 mesh as a nuclear material, 100
Emorphazon powder 600 spent in Metshiyu's Sieve
g, and hydroxypropyl cellulose (
Product name: HPC-L.
日本曹達）の５％エタノール溶液を使用し、遠心流動造
粒装置ＣＦ−３６Ｏ３（フロイント産業）を用いて常法
にしたがって造粒し、乾燥して球形素顆粒１６１０ｇを
得た。Using a 5% ethanol solution of Nippon Soda), the mixture was granulated using a centrifugal flow granulator CF-36O3 (Freund Sangyo) according to a conventional method, and dried to obtain 1610 g of spherical elementary granules.
この球形素顆粒４００ｇに実施例１と同様オイドラギソ
トＥの皮膜（素顆粒のＩＩＷ／Ｗ％）を施し、乾燥して
速放性顆粒剤４３２ｇを得た。400 g of the spherical elementary granules were coated with Eudragisoto E (IIW/W% of the elementary granules) in the same manner as in Example 1, and dried to obtain 432 g of immediate release granules.
また、上記球形素顆粒４００ｇにアクリル酸−メタアク
リル酸エステル共重合体（商品名：オイドラギソトＲ３
，褪ロ商会）の皮Ｖ！Ｉ（素顆粒の２５−／−％）を施
し、乾燥して遅放性顆粒剤４８１ｇを得た。In addition, acrylic acid-methacrylic acid ester copolymer (trade name: Eudragisoto R3) was added to 400 g of the above spherical elementary granules.
, Wairo Shokai) skin V! I (25-/-% of the base granules) was applied and dried to obtain 481 g of delayed-release granules.
これらの速放性顆粒剤と遅放性顆粒剤を、前者１重量部
、後者２重量部の割合で混合することにより徐放性製剤
を得た。A sustained release preparation was obtained by mixing these immediate release granules and delayed release granules at a ratio of 1 part by weight of the former and 2 parts by weight of the latter.
〔実施例３〕
エモルファゾン２０００ｇ、コーンスターチ４００ｇ、
エチルセルロース（商品名：エトセル、和光純薬）６０
０ｇ及び乳１！６００ｇを混合し、これにエタノール−
塩化メチレン（１： １）を加えて練合した後、押し出
し造粒を行った。これを整粒して１２〜３２メツシユの
遅放性顆粒剤３４８０ｇを得た。この遅放性顆粒剤２重
量部と実施例１の速放性顆粒剤１重量部を混合して徐放
製剤を得た。[Example 3] Emorphazone 2000g, cornstarch 400g,
Ethyl cellulose (product name: Ethocel, Wako Pure Chemical) 60
Mix 0g of milk and 1.600g of milk, and add ethanol to this.
After adding methylene chloride (1:1) and kneading, extrusion granulation was performed. This was sized to obtain 3480 g of delayed release granules with 12 to 32 meshes. 2 parts by weight of this delayed release granule and 1 part by weight of the immediate release granule of Example 1 were mixed to obtain a sustained release preparation.
〔実施例４〕
核物質として２４〜３２メツシユのノンバレル１０００
ｇに対し、１００メツシユの篩で経過したエモルファゾ
ンの粉末１０００ｇ、及び放出制御物質オイドラギット
Ｒ３の５％エタノール溶液を使用し、遠心流動造粒装置
ＣＦ−３６０３を用いて常法に従ってエモルファプンと
オイドラギン）Ｒ３を膜状に積層した。これを乾燥して
球形の遅放性顆粒剤２６１０ｇを得た。この速放性顆粒
剤２重量部と実施例２の連放顆粒製Ｍ１重量部を混合し
て徐放性製剤を得た。[Example 4] 1000 non-barrels with 24 to 32 meshes as nuclear material
Using a 5% ethanol solution of the controlled release substance Eudragit R3 and 1000 g of Emorphazone powder passed through a 100-mesh sieve per g, emorphazone and Eudragit R3 were prepared in a conventional manner using a centrifugal fluid granulator CF-3603. were laminated into a film. This was dried to obtain 2610 g of spherical delayed release granules. Two parts by weight of this immediate release granule and 1 part by weight M1 of continuous release granules of Example 2 were mixed to obtain a sustained release preparation.
【実施例５〕
実施例１の素顆粒にオイドラギン）Ｒ３の皮膜（素顆粒
の４３Ｗ／−％）を施した遅放性顆粒剤２重量部と実施
例１の速放性顆粒剤１重量部を混合して徐放性製剤を得
た。[Example 5] 2 parts by weight of the delayed-release granules obtained by applying a coating of Eudragin) R3 (43W/-% of the elementary granules) to the elementary granules of Example 1 and 1 part by weight of the immediate-release granules of Example 1. were mixed to obtain a sustained release formulation.
〔実施例６〕
実施例１の素顆粒にオイドラギットＬの皮膜（素顆粒の
６７Ｗ／Ｗ％）を施した遅放性顆粒剤２重量部と実施例
１の速放性顆粒剤１重量部を混合して徐放性製剤を得た
。[Example 6] 2 parts by weight of the delayed release granules obtained by applying a film of Eudragit L (67 W/W% of the basic granules) to the elementary granules of Example 1 and 1 part by weight of the immediate release granules of Example 1. A sustained release formulation was obtained by mixing.
〔実施例７〕
実施例１の素顆粒にオイドラギットＲ３（素顆粒の７０
−八％）とオイドラギッ）Ｌ（素顆粒の５０−／−％）
の混合皮膜を施した速放性顆粒剤２重重量部と実施例１
の速放性顆粒剤１重量部を混合して徐放性製剤を得た。[Example 7] Eudragit R3 (70% of elementary granules) was added to the elementary granules of Example 1.
-8%) and Eudragit) L (50-/-% of elementary granules)
2 parts by weight of immediate release granules coated with a mixed film and Example 1
A sustained release preparation was obtained by mixing 1 part by weight of immediate release granules.
〔実施例８〕
実施例３のエトセルをＨＰＣ−３Ｌに代えて以下同様に
して徐放性製剤を得た。[Example 8] A sustained release preparation was obtained in the same manner as in Example 3 except that Ethocel was replaced with HPC-3L.
以下試験例によって本発明の作用を示す。 The effects of the present invention will be shown below through test examples.
（試験例１）
第十−改正日本薬局方の崩壊試験法第１液を用いて同局
方溶出試験第２法（パドル法）に準拠し、前記実施例で
得た速放性顆粒剤と遅放性顆粒剤の溶出試験を行った。(Test Example 1) Using the disintegration test method No. 1 of the Japanese Pharmacopoeia, 10th revised edition, and in accordance with the dissolution test method No. 2 (paddle method) of the Japanese Pharmacopoeia, the immediate-release granules obtained in the above example and the slow-release A dissolution test was conducted on the release granules.
その結果を第１図及び第２図に示した。なお、第２図の
結果は、前記第１液のｐＨを図に示した値に変化させて
得たものである。The results are shown in FIGS. 1 and 2. The results shown in FIG. 2 were obtained by changing the pH of the first solution to the values shown in the figure.
これらの図から、速放性顆粒剤は投与後急速な溶出挙動
を示し、遅放性顆粒剤はほぼ一定の徐放性溶出を示すこ
とがわかる。These figures show that the immediate release granules exhibit rapid dissolution behavior after administration, and the delayed release granules exhibit almost constant sustained release dissolution.
（試験例２）
２４時間絶食した体重約１０ｋｇのピーグル大４頭に、
実施例１の徐放性製剤、実施例５の徐放性製剤及び市販
のエモルファゾン錠剤をそれぞれ経口投与しく１！Ｉに
つき、実施例１と５の製剤はエモルファプンとして３０
０■、市販錠剤は２００■）、血漿中のエモルフプゾン
濃度を測定した。(Test Example 2) Four large peagles weighing about 10 kg were fasted for 24 hours.
The sustained release formulation of Example 1, the sustained release formulation of Example 5, and commercially available emorfazone tablets were each administered orally. For I, the formulations of Examples 1 and 5 contain 30% of emorfapone.
(0■, commercially available tablets: 200■), and the concentration of emorphupzone in plasma was measured.
その結果を第３図に示した。The results are shown in Figure 3.
この図から、本発明徐放性製剤が消炎・鎮痛薬の製剤と
して良好な血中濃度推移をもたらすことがわかる。This figure shows that the sustained-release preparation of the present invention provides a good blood concentration transition as an anti-inflammatory/analgesic drug preparation.
本発明の徐放性製剤によれば、投与後のエモルファゾン
の急激な血中濃度の上昇を適度に抑えることができ、し
たがって即効性を保ちつつ、吐き気等の副作用の発現を
防ぐことができる。また、作用の持続性も大幅に改善さ
れ、その有用性は大である。According to the sustained-release preparation of the present invention, it is possible to appropriately suppress the rapid increase in blood concentration of emorfazone after administration, and therefore, it is possible to prevent side effects such as nausea while maintaining immediate efficacy. In addition, the durability of action is greatly improved, making it highly useful.
第１図及び第２図は、実施例１の速放性顆粒剤と実施例
１〜６の遅放性顆粒剤の溶出試験の結果（溶出曲線）を
示す、第３図は、実施例１と５の徐放性製剤及び市販錠
剤（２００■錠）を、それぞれピーグル大に経口投与し
た後の血中濃度推移を示す。
特許出願人 森下製薬株式会社
第１図
時間（ｈｒ）
一Δ−実施例１の速放性顆粒剤
−・−実施例１の遅放性顆粒剤
一轟一 実施例２の遅放性顆粒剤
一〇−実施例３の遅放性顆粒剤
一一一 実施例４の遅放性顆粒剤
一〇−実施例５の遅放性顆粒剤
第２図
ｐ Ｉ（
一Δ−実施例１の速放性顆粒剤
−〇−実施例２の遅放性顆粒剤
−・−実施例６の遅放性顆粒剤
第３図
一ム一 重版錠剤（２００■錠）
−・−実施例１の徐放性製剤
一〇−実施例５の徐放性製剤Figures 1 and 2 show the dissolution test results (dissolution curves) of the immediate release granules of Example 1 and the delayed release granules of Examples 1 to 6. Figure 5 shows the blood concentration changes after oral administration of sustained-release preparations and commercially available tablets (200 tablets) of No. 5 and No. 5 to a Peagle-sized dog. Patent Applicant Morishita Pharmaceutical Co., Ltd. Figure 1 Time (hr) - Δ - Immediate release granules of Example 1 - - Delayed release granules of Example 1 Ichi Todoroki Delayed release granules of Example 2 10 - Delayed release granules of Example 3 111 Delayed release granules of Example 4 10 - Delayed release granules of Example 5 Figure 2 p I (1 Δ - Delayed release granules of Example 1 Release granules - - Delayed release granules of Example 2 - - Delayed release granules of Example 6 Figure 3 1 Reprinted tablets (200 tablets) - - Extended release of Example 1 Preparation 10 - Sustained release preparation of Example 5
Claims (1)
る速放性顆粒剤と遅放性顆粒剤とを混合してなるエモル
ファゾンの徐放性製剤。 （２）速放性顆粒剤が、エモルファゾンと、デンプン類
、乳糖、ブドウ糖、マンニトールから選ばれた１種又は
２種以上の賦形剤及びヒドロキシプロピルセルロース、
エチルセルロース、メチルセルロース、セルロースから
選ばれた１種又は２種以上の結合剤とを主成分として含
有する顆粒剤である特許請求の範囲第１項記載の徐放性
製剤。 （３）遅放性顆粒剤が、速放性顆粒剤に、ｐＨ６以上で
溶解するメタアクリル酸−メチルメタアクリレート共重
合体、ｐＨ５．５以上で溶解するヒドロキシプロピルセ
ルロースフタレート、エチルセルロース、アクリル酸−
メタアクリル酸エステル共重合体、硬化油、ワックス類
から選ばれた１種又は２種以上からなる皮膜を施した顆
粒剤である特許請求の範囲第１項又は第２項に記載の徐
放性製剤。 （３）遅放性顆粒剤が、エモルファゾンと、ｐＨ６以上
で溶解するメタアクリル酸−メチルメタアクリレート共
重合体、ｐＨ５．５以上で溶解するヒドロキシプロピル
セルロースフタレート、エチルセルロース、アクリル酸
−メタアクリル酸エステル共重合体、硬化油、ワックス
類、カルボキシビニルポリマー、ヒドロキシプロピルセ
ルロース、ヒドロキシプロピルメチルセルロース、アク
リル酸重合体から選ばれた１種又は２種以上とを主成分
として造粒して得られた顆粒剤である特許請求の範囲第
１項又は第２項に記載の徐放性製剤。 （５）速放性顆粒剤１重量部に対し、遅放性顆粒剤を０
．５重量部〜３重量部混合してなる特許請求の範囲第１
項、第２項、第３項又は第４項記載の徐放性製剤。[Scope of Claims] (1) A sustained release preparation of emorfazone, which is obtained by mixing immediate release granules and delayed release granules, each containing emorphazone as a medicinal ingredient. (2) The immediate release granules include emorfazone, one or more excipients selected from starches, lactose, glucose, mannitol, and hydroxypropylcellulose;
The sustained release preparation according to claim 1, which is a granule containing as a main component one or more binders selected from ethyl cellulose, methyl cellulose, and cellulose. (3) Delayed release granules include methacrylic acid-methyl methacrylate copolymer that dissolves at pH 6 or higher, hydroxypropyl cellulose phthalate, ethyl cellulose, acrylic acid that dissolves at pH 5.5 or higher, and
The sustained release agent according to claim 1 or 2, which is a granule coated with one or more selected from methacrylic ester copolymers, hydrogenated oils, and waxes. formulation. (3) The delayed-release granules include emorfazone, methacrylic acid-methyl methacrylate copolymer that dissolves at pH 6 or higher, hydroxypropyl cellulose phthalate, ethyl cellulose, and acrylic acid-methacrylate ester that dissolves at pH 5.5 or higher. Granules obtained by granulation with one or more selected from copolymers, hydrogenated oils, waxes, carboxyvinyl polymers, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and acrylic acid polymers as main components. The sustained release preparation according to claim 1 or 2. (5) 0 parts of delayed release granules per 1 part by weight of immediate release granules
．． Claim 1 consisting of a mixture of 5 parts by weight to 3 parts by weight
4. The sustained release preparation according to item 2, item 3, or item 4.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10284587A JPS63267720A (en) | 1987-04-24 | 1987-04-24 | Sustained release preparation of emorfazone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10284587A JPS63267720A (en) | 1987-04-24 | 1987-04-24 | Sustained release preparation of emorfazone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63267720A true JPS63267720A (en) | 1988-11-04 |
Family
ID=14338294
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10284587A Pending JPS63267720A (en) | 1987-04-24 | 1987-04-24 | Sustained release preparation of emorfazone |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63267720A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01279823A (en) * | 1988-01-18 | 1989-11-10 | Alfa Wassermann Spa | Preparation having programmed releasing capacity |
| JPH02193923A (en) * | 1988-11-30 | 1990-07-31 | Riker Lab Inc | Sustained release phlekainide acetate pharmaceuticals |
| JPH04187636A (en) * | 1990-11-20 | 1992-07-06 | Isamu Horikoshi | Narcotic preparation |
| JPH0624991A (en) * | 1991-06-20 | 1994-02-01 | Tokyo Tanabe Co Ltd | Long acting preparation of ursodeoxycholic acid |
| JPH09188617A (en) * | 1996-01-08 | 1997-07-22 | Pola Chem Ind Inc | Medicinal composition of sustained release |
| WO2005074896A1 (en) * | 2004-02-10 | 2005-08-18 | Takeda Pharmaceutical Company Limited | Sustained release preparation |
| JP6813922B1 (en) * | 2019-12-10 | 2021-01-13 | ノーベルファーマ株式会社 | Melatonin-containing granules |
-
1987
- 1987-04-24 JP JP10284587A patent/JPS63267720A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01279823A (en) * | 1988-01-18 | 1989-11-10 | Alfa Wassermann Spa | Preparation having programmed releasing capacity |
| JPH02193923A (en) * | 1988-11-30 | 1990-07-31 | Riker Lab Inc | Sustained release phlekainide acetate pharmaceuticals |
| JPH04187636A (en) * | 1990-11-20 | 1992-07-06 | Isamu Horikoshi | Narcotic preparation |
| JPH0624991A (en) * | 1991-06-20 | 1994-02-01 | Tokyo Tanabe Co Ltd | Long acting preparation of ursodeoxycholic acid |
| JPH09188617A (en) * | 1996-01-08 | 1997-07-22 | Pola Chem Ind Inc | Medicinal composition of sustained release |
| WO2005074896A1 (en) * | 2004-02-10 | 2005-08-18 | Takeda Pharmaceutical Company Limited | Sustained release preparation |
| US7662408B2 (en) | 2004-02-10 | 2010-02-16 | Takeda Pharmaceutical Company Limited | Sustained-release preparations |
| JP6813922B1 (en) * | 2019-12-10 | 2021-01-13 | ノーベルファーマ株式会社 | Melatonin-containing granules |
| JP2021151984A (en) * | 2019-12-10 | 2021-09-30 | ノーベルファーマ株式会社 | Melatonin-containing granules |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6117453A (en) | Solid compositions containing polyethylene oxide and an active ingredient | |
| DE60319252T2 (en) | FORMULATION OF ACETAMINOPHES AND TRAMADOL WITH DELAYED RELEASE | |
| ES2606463T3 (en) | Combination of levodopa / carbidopa immediate release and controlled release dosage forms | |
| US5508042A (en) | Controlled release oxycodone compositions | |
| JP2720932B2 (en) | Method for producing acetaminophen tablet for oral administration and bilayer tablet of acetaminophen | |
| US5051263A (en) | Controlled-release formulations | |
| JPH0122245B2 (en) | ||
| JP2514078B2 (en) | Compressed formulation | |
| US6048547A (en) | Process for manufacturing solid compositions containing polyethylene oxide and an active ingredient | |
| JPS6327424A (en) | Sustained release pharmaceutical and production thereof | |
| US20130011543A1 (en) | Controlled release oxycodone compositions | |
| JPH0251402B2 (en) | ||
| JPH11171775A (en) | Sustained release theophylline tablet | |
| US20070275062A1 (en) | Controlled release oxycodone compositions | |
| JPH037238A (en) | Film for controlling release of sustained release preparation | |
| JPS6248618A (en) | Slow-releasing drug preparation and production thereof | |
| US20060039997A1 (en) | Multiparticulate formulations of lithium salts for oral administration suitable for once-a-day administration | |
| WO2006103551A1 (en) | Controlled release formulations of oxycodone | |
| JPH09323926A (en) | Sustained release tablet of sodium valproate | |
| JPS63267720A (en) | Sustained release preparation of emorfazone | |
| JPH0383922A (en) | Ibuprofen-containing composition for oral administration | |
| JPH04234812A (en) | Granule for long-acting pharmaceutical preparation | |
| JP2002068964A (en) | Sustained release tablet for oral administration | |
| JP3929522B2 (en) | Sustained release formulation of poorly water-soluble drugs | |
| JPS618A (en) | Nifedipin-containing drug preparation |