JP4926495B2 - イブプロフェン含有コーティング顆粒 - Google Patents
イブプロフェン含有コーティング顆粒 Download PDFInfo
- Publication number
- JP4926495B2 JP4926495B2 JP2006045352A JP2006045352A JP4926495B2 JP 4926495 B2 JP4926495 B2 JP 4926495B2 JP 2006045352 A JP2006045352 A JP 2006045352A JP 2006045352 A JP2006045352 A JP 2006045352A JP 4926495 B2 JP4926495 B2 JP 4926495B2
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- JP
- Japan
- Prior art keywords
- ibuprofen
- granules
- granule
- coated
- weight
- 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.)
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- 229960001680 ibuprofen Drugs 0.000 title claims description 76
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- 125000000217 alkyl group Chemical group 0.000 claims description 17
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- DYWNLSQWJMTVGJ-KUSKTZOESA-N Phenylpropanolamine hydrochloride Chemical compound Cl.C[C@H](N)[C@H](O)C1=CC=CC=C1 DYWNLSQWJMTVGJ-KUSKTZOESA-N 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
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- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
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- LPRLDRXGWKXRMQ-UHFFFAOYSA-N diphenylpyraline hydrochloride Chemical compound [Cl-].C1C[NH+](C)CCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 LPRLDRXGWKXRMQ-UHFFFAOYSA-N 0.000 description 1
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- PFAXACNYGZVKMX-UHFFFAOYSA-N fenethazine Chemical compound C1=CC=C2N(CCN(C)C)C3=CC=CC=C3SC2=C1 PFAXACNYGZVKMX-UHFFFAOYSA-N 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
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- 238000012812 general test Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
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- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
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- 229960002146 guaifenesin Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 229940031702 hydroxypropyl methylcellulose 2208 Drugs 0.000 description 1
- 229940031705 hydroxypropyl methylcellulose 2910 Drugs 0.000 description 1
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- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229960001543 isopropamide iodide Drugs 0.000 description 1
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- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
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- 229940035436 maltitol Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- GHZNWXGYWUBLLI-UHFFFAOYSA-N p-Lactophenetide Chemical compound CCOC1=CC=C(NC(=O)C(C)O)C=C1 GHZNWXGYWUBLLI-UHFFFAOYSA-N 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical class C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 1
- 229960002305 phenylpropanolamine hydrochloride Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- QFRKWSPTCBGLSU-UHFFFAOYSA-M potassium 4-hydroxy-3-methoxybenzene-1-sulfonate Chemical compound [K+].COC1=CC(S([O-])(=O)=O)=CC=C1O QFRKWSPTCBGLSU-UHFFFAOYSA-M 0.000 description 1
- 229940069505 potassium guaiacolsulfonate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- XXPDBLUZJRXNNZ-UHFFFAOYSA-N promethazine hydrochloride Chemical compound Cl.C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 XXPDBLUZJRXNNZ-UHFFFAOYSA-N 0.000 description 1
- 229960002244 promethazine hydrochloride Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- JWBPVFVNISJVEM-UHFFFAOYSA-M sodium caffeine benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1.CN1C(=O)N(C)C(=O)C2=C1N=CN2C JWBPVFVNISJVEM-UHFFFAOYSA-M 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229960000896 tipepidine Drugs 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960001593 triprolidine hydrochloride Drugs 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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Classifications
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- 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
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Inorganic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
従って、本発明の目的は、長期保存してもコーティング顆粒同士の付着がなく、経時的に溶出性の変化を生じない、安定なイブプロフェン含有放出制御製剤を提供することにある。
また、本発明は、上記のコーティング顆粒とイブプロフェン含有速放性顆粒を含有する顆粒を提供するものである。
さらに、本発明は、上記のコーティング顆粒、又は上記のコーティング顆粒とイブプロフェン含有速放性顆粒を含有するカプセル剤を提供するものである。
これらの市販品は、エマルジョンとして市販されており、アクリル酸エチルとメタクリル酸メチルをポリオキシエチレンノニルフェニルエーテル(100E.O.)を乳化剤として、水溶液中で重合して得られたコポリマーである。
着色剤としては、例えば、各種食用色素、タール色素及び三二酸化鉄などがあり、その配合量は、分散液に対して5重量%以下である。
溶解補助剤としては、例えば、プロピレングリコール及びポリオキシエチレンポリオキシプロピレングリコールなどがあり、その配合量は、分散液に対して5重量%以下である。
着色剤としては、例えば、各種食用色素、タール色素及び三二酸化鉄などがあり、その配合量は、分散液に対して5重量%以下である。
溶解補助剤としては、例えば、プロピレングリコール及びポリオキシエチレンポリオキシプロピレングリコールなどがあり、その配合量は、分散液に対して5重量%以下である。
イブプロフェン2160g、D−マンニトール1091.7g、カルメロースカルシウム189g、結晶セルロース189g、ヒドロキシプロピルセルロース150.3gをハイスピードミキサーに投入し、混合する。その後エタノール水混合液1300mL加えて練合した後、製粒機(HG-30:畑鉄工所社製)、マルメライザー(Q400:ダルトン社製)にて球形顆粒を製し、フローコータ(FLO-5B:フロイント産業社製)にて乾燥し乾燥品を得た。その乾燥品を16メッシュから30メッシュを分取して芯顆粒を製した。
アクリル酸エチル・メタクリル酸メチルコポリマーエマルジョン固形分(商品名オイドラギトNE30:販売会社樋口商会)475g、タルク475g、ヒドロキシプロピルメチルセルロース(商品名TC-5:販売会社信越化学工業)50gを精製水4459gに分散又は溶解し、コーティング液を得た。得られたコーティング液を芯顆粒3000gにフローコータ(FLO-5B:フロイント産業社製)にてコーティングし、イブプロフェン含有コーティング顆粒を得た。
アクリル酸エチル・メタクリル酸メチルコポリマーエマルジョン固形分(商品名オイドラギトNE30:販売会社樋口商会)375g、タルク375g、ヒドロキシプロピルメチルセルロース(商品名TC-5:販売会社信越化学工業)250gを精製水4792gに分散又は溶解し、コーティング液を得た。得られたコーティング液を芯顆粒3000gにフローコータ(FLO-5B:フロイント産業社製)にてコーティングし、イブプロフェン含有コーティング顆粒を得た。
参考例1のイブプロフェン含有コーティング顆粒においてヒドロキシプロピルメチルセルロースをヒドロキシプロピルセルロース(比較例1:商品名HPC-L:販売会社日本曹達)、ポリビニルアルコール(比較例2:商品名ポバール205S:販売会社クラレ)、コポリピドン(比較例3:商品名プラスドンS-630:販売会社アイエスピー・ジャパン)としたコーティング液を調製し、参考例1と同様の方法でコーティングし、イブプロフェン含有コーティング顆粒を得た。
参考例1のイブプロフェン含有コーティング顆粒においてタルクをステアリン酸マグネシウム(比較例4:商品名ステアリン酸マグネシウム:販売会社太平化学)、軽質無水ケイ酸(比較例5:商品名アドソリダー101:販売会社フロイント産業)としたコーティング液を調製し、参考例1と同様の方法でコーティングし、イブプロフェン含有コーティング顆粒を得た。
参考例1〜2、比較例1〜5のイブプロフェン含有コーティング顆粒の製造直後の外観を確認した。なお、外観は目視で評価を行い、顆粒の付着がないものを○、顆粒の付着が生じたものを×で表示した。結果を表1及び2に示す。
ヒドロキシプロピルメチルセルロース(商品名TC-5:販売会社信越化学工業)80g、含水二酸化ケイ素20g、クエン酸トリエチル10gを精製水737gに分散及び溶解し、コーティング液を得た。得られたコーティング液を参考例1のイブプロフェン含有コーティング顆粒1000gにフローコータ(FLO-5B:フロイント産業社製)にてコーティングし、イブプロフェン含有コーティング顆粒を得た。
実施例1のイブプロフェン含有コーティング顆粒においてヒドロキシプロピルメチルセルロースをヒドロキシプロピルセルロース(比較例6:商品名HPC-L:販売会社日本曹達)、ポリビニルアルコール(比較例7:商品名ポバール205S:販売会社クラレ)、ポリビニルピロリドン(比較例8:商品名コリドンK30:販売会社BASFジャパン)、コポリピドン(比較例9:商品名プラスドンS-630:販売会社アイエスピー・ジャパン)としたコーティング液を調製し、実施例1と同様の方法でコーティングし、イブプロフェン含有コーティング顆粒を得た。
実施例1のイブプロフェン含有コーティング顆粒において含水二酸化ケイ素をステアリン酸マグネシウム(比較例10:商品名ステアリン酸マグネシウム:販売会社太平化学)、タルク(比較例11:商品名タルク:販売会社日本タルク)としたコーティング液を調製し、実施例1と同様の方法でコーティングし、イブプロフェン含有コーティング顆粒を得た。
実施例1、比較例6〜11のイブプロフェン含有コーティング顆粒を40℃・6ヵ月保存後の外観を確認した。なお、外観は目視で評価を行い、顆粒の付着がないものを○、顆粒の付着が生じたものを×で表示した。結果を表3及び表4に示す。
得られた実施例1のイブプロフェン含有放出制御コーティング顆粒134.5mg(イブプロフェン60mg相当量)からの薬物放出特性は、日本薬局方溶出試験法第二法(パドル法)により、毎分100rpmで試験を行った。試験液として日局一般試験法崩壊試験法第2液500mLを用い、パドル回転速度100rpmで行う。各時間毎にサンプリングを行い、サンプリング溶液中のイブプロフェンをHPLCにて定量した。その結果を表5及び図1に示した。
イブプロフェン800g、dl−塩酸メチルエフェドリン300g、ヨウ化イソプロパミド25g、d−マレイン酸クロルフェニラミン17.5g、臭化水素酸デキストロメトルファン240g、無水カフェイン375g、D−マンニトール342.5g、カルメロースカルシウム810g、結晶セルロース350g及びヒドロキシプロピルセルロース50gをハイスピードミキサー(FS-10:深江工業社製)に投入し、混合する。これに予め食用黄色5号0.5gを溶解させたエタノールと精製水1:3(W/W)混液502mLを加えて練合した後、整粒機(HG−30:畑鉄工所社製)、マルメライザー(Q400:ダルトン社製)を用いて球形顆粒を製し、フローコーター(FLO-5B:フロイント産業社製)にて乾燥する。この乾燥品について16メッシュから30メッシュを分取し、速放性顆粒とした。
Claims (5)
- イブプロフェン含有多層コーティング顆粒であって、最内層にイブプロフェンを含有する粒子を有し、その外層にアクリル酸アルキル−メタクリル酸アルキルコポリマー、タルク及びヒドロキシプロピルメチルセルロースを含有する層を有し、さらにその外層に二酸化ケイ素及びヒドロキシプロピルメチルセルロースを含有する層を有することを特徴とするコーティング顆粒。
- さらにその外層に帯電防止剤を含有する層を有するものである請求項1記載のコーティング顆粒。
- 請求項1又は2記載のコーティング顆粒と、イブプロフェン含有速放性顆粒を含有する顆粒。
- 請求項1〜3のいずれか1項記載の顆粒を含有するカプセル剤。
- さらに、有効成分としてイブプロフェン以外の解熱鎮痛剤、抗ヒスタミン剤、鎮咳剤、去痰剤、交感神経興奮剤、催眠鎮静剤及び抗炎症剤から選ばれる1種又は2種以上を含有するものである請求項1〜4のいずれか1項記載の顆粒又はカプセル剤。
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