JP3116970B2 - Sustained-release preparation of pemirolast potassium - Google Patents
Sustained-release preparation of pemirolast potassiumInfo
- Publication number
- JP3116970B2 JP3116970B2 JP03236741A JP23674191A JP3116970B2 JP 3116970 B2 JP3116970 B2 JP 3116970B2 JP 03236741 A JP03236741 A JP 03236741A JP 23674191 A JP23674191 A JP 23674191A JP 3116970 B2 JP3116970 B2 JP 3116970B2
- Authority
- JP
- Japan
- Prior art keywords
- tbx
- sustained
- release
- tablet
- preparation
- 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 - Fee Related
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- NMMVKSMGBDRONO-UHFFFAOYSA-N potassium;9-methyl-3-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)pyrido[1,2-a]pyrimidin-4-one Chemical compound [K+].CC1=CC=CN(C2=O)C1=NC=C2C1=NN=N[N-]1 NMMVKSMGBDRONO-UHFFFAOYSA-N 0.000 title claims description 51
- 239000003405 delayed action preparation Substances 0.000 title claims description 20
- 229960004811 pemirolast potassium Drugs 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 claims description 23
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 16
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 16
- 238000006467 substitution reaction Methods 0.000 claims description 8
- -1 hydroxypropoxyl group Chemical group 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 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 3
- 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
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 36
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 30
- 239000000203 mixture Substances 0.000 description 18
- 238000013268 sustained release Methods 0.000 description 18
- 239000012730 sustained-release form Substances 0.000 description 18
- 239000008280 blood Substances 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 16
- 239000008187 granular material Substances 0.000 description 15
- 235000019359 magnesium stearate Nutrition 0.000 description 15
- 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 13
- 239000008101 lactose Substances 0.000 description 13
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 11
- 238000004898 kneading Methods 0.000 description 11
- 239000002775 capsule Substances 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 239000011159 matrix material Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 102220240796 rs553605556 Human genes 0.000 description 6
- 238000003860 storage Methods 0.000 description 6
- 239000001993 wax Substances 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000004203 carnauba wax Substances 0.000 description 4
- 235000013869 carnauba wax Nutrition 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- FSXVSUSRJXIJHB-UHFFFAOYSA-M ethyl prop-2-enoate;methyl 2-methylprop-2-enoate;trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CCOC(=O)C=C.COC(=O)C(C)=C.CC(=C)C(=O)OCC[N+](C)(C)C FSXVSUSRJXIJHB-UHFFFAOYSA-M 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000012054 meals Nutrition 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000007939 sustained release tablet Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000209094 Oryza Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 229920001218 Pullulan Polymers 0.000 description 2
- 239000004373 Pullulan Substances 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000012812 general test Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 235000019809 paraffin wax Nutrition 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 235000019423 pullulan Nutrition 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- AWFYPPSBLUWMFQ-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=C2 AWFYPPSBLUWMFQ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000283153 Cetacea Species 0.000 description 1
- 235000010919 Copernicia prunifera Nutrition 0.000 description 1
- 244000180278 Copernicia prunifera Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 239000004163 Spermaceti wax Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000013563 matrix tablet Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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Description
【０００１】[0001]
【産業上の利用分野】本発明は、抗アレルギー性薬物の
徐放性製剤に関し、更に詳しくはペミロラストカリウム
（以下ＴＢＸという。）の経口又は口腔投与可能な徐放
性製剤に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained release preparation of an antiallergic drug, and more particularly to a sustained release preparation of pemirolast potassium (hereinafter referred to as TBX) which can be administered orally or buccally.
【０００２】[0002]
【従来の技術】ＴＢＸは、化学名を９−メチル−３−
（１Ｈ−テトラゾール−５−イル）−４Ｈ−ピリド
［１，２−ａ］ピリミジン−４−オンカリウム塩とい
い、アレルギー性気管支喘息，アレルギー性鼻炎のよう
なアレルギー反応の症状を抑制または予防することが知
られている（特公昭６０−５０１９７号公報）。アレル
ギー第３３巻第９号第７２７〜７２８頁（１９８４年）
にはＴＢＸのＩ型アレルギー反応モデルにおける抑制作
用及びヒスタミン、ＳＲＳ−Ａ（アナフラキシーの遅反
応性物質）などのケミカルメディエーターの遊離抑制効
果について記載され、また、ガストロエンテロロジー
（Ｇａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ）第８８巻第５５
号第１３５４頁（１９８５年）にはＴＢＸの胃細胞保護
作用に基づいた、胃炎、胃炎症治療に対する有効性が記
載されている。2. Description of the Related Art TBX has the chemical name 9-methyl-3-.
(1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one potassium salt, which suppresses or prevents the symptoms of allergic reactions such as allergic bronchial asthma and allergic rhinitis (Japanese Patent Publication No. 60-50197). Allergy Vol. 33, No. 9, pp. 727-728 (1984)
Describes the inhibitory effect of TBX in a type I allergic reaction model and the inhibitory effect of the release of chemical mediators such as histamine and SRS-A (slow-reacting substance of anafluxia). 55
No. 1354 (1985) describes the efficacy of TBX for treating gastritis and gastric inflammation based on its protective effect on gastric cells.
【０００３】また、ＴＢＸの水性製剤については特開平
１−１２５３２１号公報に、軟膏剤については特開平３
−１１８３２３号公報にそれぞれ記載されている。しか
しながら、ＴＢＸ製剤の徐放性製剤については未だ知ら
れていない。Further, an aqueous preparation of TBX is disclosed in JP-A-1-125321, and an ointment is disclosed in JP-A-3-125321.
-118323. However, a sustained-release preparation of a TBX preparation has not yet been known.
【０００４】[0004]
【解決しようとする課題】従来、知られているＴＢＸの
製剤は経口の速放錠であり、１日に２〜３回服用しなけ
ればならなかった。また、ケミカルメディエーター遊離
抑制型の薬剤は作用を発現するまで少なくとも４週間服
用を続けなければならず、その煩わしさと共に、コンプ
ライアンスの低下が問題となっていた。Heretofore, the known preparation of TBX is an oral immediate release tablet, which has to be taken two to three times a day. In addition, the chemical mediator release-inhibiting type drug must be continued for at least 4 weeks until it exerts its action, and there has been a problem with the troublesomeness and the decrease in compliance.
【０００５】たとえば、市販されているＴＢＸ製剤（ア
レギサール錠、東京田辺製薬株式会社；商品名）につい
て第１１改正日本薬局方（一般試験法４６項、Ｂ、４２
４）に準拠した溶出試験を行ったところ、ＴＢＸを７５
％溶出する時間（以下、Ｔ７５％という。）は５分未満
であり徐放性を示さなかった。また、この製剤を経口投
与した場合、生物学的半減期はイヌで１時間、ヒトで４
時間であり、徐放性の付与が望まれていた。[0005] For example, a commercially available TBX preparation (Alegisal Tablet, Tokyo Tanabe Seiyaku Co., Ltd .; trade name) is described in the Japanese Pharmacopoeia of the eleventh revision (General Test Method, Section 46, B, 42).
When a dissolution test according to 4) was performed, TBX was 75
% Elution time (hereinafter referred to as T 75% ) was less than 5 minutes and did not exhibit sustained release. When this formulation is administered orally, the biological half-life is 1 hour in dogs and 4 hours in humans.
It is time, and it is desired to provide sustained release.
【０００６】本発明は、抗アレルギー性薬物であるＴＢ
Ｘの徐放性製剤を提供することを目的とする。[0006] The present invention relates to an antiallergic drug, TB
It is intended to provide a sustained-release preparation of X.
【０００７】徐放性製剤の具備すべき条件としては、速
放性製剤に比べて１日の服用回数が少ないこと、最高血
中濃度（以下Ｃｍａｘという。）が速放性製剤と同程度
であること、薬物の有効血中濃度を長時間維持するこ
と、消化管内における薬物の放出が食事の影響を受けに
くいこと、生物学的利用率が高いこと、長期間保存して
も物理的化学的に安定であり放出性に変動が少ないこ
と、及び服用しやすい大きさの剤形であることが挙げら
れる。[0007] Conditions for the sustained release preparation to be met include that the number of daily doses is less than that of the immediate release preparation, and that the maximum blood concentration (hereinafter referred to as Cmax) is comparable to that of the immediate release preparation. Yes, maintaining the effective blood concentration of the drug for a long period of time, the fact that the release of the drug in the gastrointestinal tract is not easily affected by diet, high bioavailability, physicochemical even after long-term storage It is stable in dosage form and has a small variation in release property, and the dosage form is easy to take.
【０００８】服用回数を少なくするためには、製剤中の
薬物含量を速放性製剤よりも増量することが必要であ
る。[0008] In order to reduce the number of doses, it is necessary to increase the drug content in the preparation compared to the immediate release preparation.
【０００９】しかしながら薬物が一度に放出されると血
中濃度が高くなり、副作用が発現する危険性を伴うこと
になる。従って、薬物を増量したうえで速放性製剤と同
程度のＣｍａｘとするためには、薬物の製剤からの放出
を制御しなければならない。[0009] However, once the drug is released, the concentration in the blood increases, and there is a risk that side effects may occur. Therefore, in order to increase the amount of the drug and obtain a Cmax comparable to that of the immediate-release preparation, the release of the drug from the preparation must be controlled.
【００１０】薬物の有効血中濃度を長時間維持するため
には、薬物の製剤からの放出が長時間にわたり一定であ
ることが必要である。In order to maintain the effective blood concentration of a drug for a long period of time, it is necessary that the drug release from the preparation be constant over a long period of time.
【００１１】食事の影響を受けにくいためには、消化管
内においても製剤からの薬物の放出が一定であることが
必要である。In order to be less susceptible to meals, it is necessary that the drug release from the preparation be constant even in the digestive tract.
【００１２】また、生物学的相対利用率が速放性製剤と
用量相関があるためには、徐放化による生物学的相対利
用率が低下しないことが必要であり、製剤技術的に優れ
ていることである。Further, in order for the relative bioavailability to have a dose correlation with the immediate-release preparation, it is necessary that the biorelative utilization does not decrease due to sustained release. It is that you are.
【００１３】長期間保存しても物理的化学的に安定であ
るためには、製剤中で薬物が分解しないこと、薬物の放
出速度が変化しないことが必要であり、有効性と安全性
が保証されることである。[0013] In order to be physically and chemically stable even when stored for a long period of time, it is necessary that the drug does not decompose in the preparation and the release rate of the drug does not change, and its efficacy and safety are guaranteed. Is to be done.
【００１４】服用しやすい大きさは、錠剤で直径６．５
〜９ｍｍ、好ましくは直径７〜８ｍｍである。カプセル
剤では、２号〜４号の大きさであることが好ましい。The size that is easy to take is 6.5 tablets in diameter.
９9 mm, preferably 7-8 mm in diameter. In the case of a capsule, the size is preferably 2 to 4.
【００１５】徐放性ＴＢＸ製剤を得るために、ＴＢＸ原
体を疎水性基剤でコーティングした場合、複合顆粒剤と
した場合、有核錠とした場合及びスペースタブとした場
合について検討したが、いずれも徐放性を示さないか又
は生物学的相対利用率が低く満足できる結果を得ること
はできなかった。In order to obtain a sustained-release TBX preparation, the case where the TBX base material was coated with a hydrophobic base, a composite granule, a dry coated tablet and a space tab were examined. None of them showed sustained release properties or had a low relative bioavailability, so that satisfactory results could not be obtained.
【００１６】更に、プルラン、ポリビニルアルコール、
オイドラギットＲＳ、カーボポール、アルギン酸ナトリ
ウム等の数種のゲル形成高分子を用いたシングルユニッ
ト型のゲルマトリックス徐放錠について検討したが、い
ずれも満足いく結果は得られなかった。Further, pullulan, polyvinyl alcohol,
Single unit gel matrix sustained-release tablets using several types of gel-forming polymers such as Eudragit RS, Carbopol, and sodium alginate were examined, but none of the results were satisfactory.
【００１７】本発明者等はこれらの知見を自らの実験に
よって確認した。The present inventors have confirmed these findings by own experiments.
【００１８】次に、ＴＢＸの原体をコーティングした場
合、複合顆粒剤とした場合、有核錠とした場合、スペー
スタブとした場合及び数種のゲル形成高分子、アルギン
酸ナトリウム、ポリビニルアルコール、カーボポール、
オイドラギットＲＳを用いてゲルマトリックス錠とした
場合の試験結果を示す。Next, when the base material of TBX is coated, when it is made into a composite granule, when it is made into a dry coated tablet, when it is made as a space tub, several kinds of gel-forming polymers, sodium alginate, polyvinyl alcohol, carbohydrate Pole,
The test result in the case of making a gel matrix tablet using Eudragit RS is shown.
【００１９】徐放性の評価は、第１１改正日本薬局方
（一般試験法４６項、Ｂ、４２４）の溶出試験方法を準
用し、溶出液に水９００ｍｌを用い、ＴＢＸとして２０
ｍｇ相当の試料を添加し、パドル法にて１００ｒｐｍで
試験した。溶出液の測定は吸光度法にて行った。血液中
のＴＢＸ濃度の測定は、ＴＢＸとして２０ｍｇ相当を経
口投与して静脈から一定量採血した後、血漿中のＴＢＸ
を高速液体クロマトグラフィー蛍光分析法により微量分
析した。Evaluation of the sustained release was carried out according to the elution test method of the Japanese Pharmacopoeia 11th Edition (General Test Method, Section 46, B, 424), using 900 ml of water as the eluate and 20 as TBX.
A sample equivalent to mg was added and tested at 100 rpm by the paddle method. The eluate was measured by the absorbance method. The TBX concentration in blood was measured by orally administering 20 mg equivalent of TBX, collecting a certain amount of blood from a vein, and then measuring TBX in plasma.
Was microanalyzed by high performance liquid chromatography fluorescence analysis.
【００２０】［原体を疎水性基剤でコーティングした場
合］エチルセルロース３〜３０ｇをジクロロメタン５０
〜４００ｍｌに溶解し、撹拌しながらＴＢＸ１０ｇを加
えて、これを分散した。次に、噴霧乾燥機を用いてこの
分散液を乾燥し、試料を得た。また、オイドラギットＲ
Ｓ１０〜３０ｇをジクロルメタン５０〜１５０ｍｌに溶
解し、撹拌しながらＴＢＸ１０ｇを加えて、これを分散
した。次に、噴霧乾燥機を用いてこの分散液を乾燥し、
試料を得た。[When the base is coated with a hydrophobic base] 3 to 30 g of ethyl cellulose is added to 50 parts of dichloromethane.
Ｂ400 ml, and TBX (10 g) was added thereto with stirring to disperse the mixture. Next, this dispersion was dried using a spray drier to obtain a sample. Also, Eudragit R
10 to 30 g of S was dissolved in 50 to 150 ml of dichloromethane, and 10 g of TBX was added with stirring to disperse the mixture. Next, the dispersion is dried using a spray dryer,
A sample was obtained.
【００２１】これらの試料につき溶出試験を行ない、Ｔ
ＢＸの７５％が溶出する時間（Ｔ７５％）を求めたとこ
ろ、いずれも３０分以内であり、これらの試料はいずれ
も徐放性はを示さなかった。結果を表１に示す。An elution test was performed on these samples, and T
When the time (T 75% ) at which 75% of BX was eluted was determined, all were within 30 minutes, and none of these samples showed sustained release. Table 1 shows the results.
【００２２】[0022]
【表１】 [Table 1]
【００２３】［複合顆粒剤とした場合］油脂マトリッ
クス顆粒としてＴＢＸを疎水性にした場合ステアリルア
ルコール、ステアリン酸、ステアリン酸マグネシウム、
ラブリワックス、デカグリン（７ｓ）、ステアリン酸モ
ノグリセライド（ＭＧＳ−Ｆ−７５）１〜５ｇを加熱溶
融し、ＴＢＸ１ｇを加えて撹拌し、室温まで冷却した
後、１２〜４８メッシュで篩過し、試料とした。[When a composite granule is prepared] When TBX is made hydrophobic as an oil / fat matrix granule, stearyl alcohol, stearic acid, magnesium stearate,
1-5 g of Raburi wax, decagrin (7s), and monoglyceride stearic acid (MGS-F-75) were heated and melted, 1 g of TBX was added, stirred, cooled to room temperature, sieved with 12 to 48 mesh, and mixed with the sample. did.
【００２４】これらの試料について溶出試験を行った結
果を表２に示す。いずれもＴ７５％は４５分未満であ
り、徐放性を示さなかった。Table 2 shows the results of the dissolution test performed on these samples. In each case, T 75% was less than 45 minutes and did not show sustained release.
【００２５】[0025]
【表２】 [Table 2]
【００２６】ワックスマトリックス顆粒としてＴＢＸ
を疎水性にした場合カルナバワックス、ライスワック
ス、パラフインワックス、ビーズワックス又は鯨ロウワ
ックス ５０ｇを加熱溶融し、ＴＢＸ１０ｇを添加して
撹拌混合し、撹拌しながら室温まで冷却した。次に、こ
れを粉砕し、１２〜４８メッシュの粒度を用いて徐放性
を評価した。TBX as wax matrix granules
In a case where was made hydrophobic, 50 g of carnauba wax, rice wax, paraffin wax, beeswax or spermaceti wax was melted by heating, 10 g of TBX was added, and the mixture was stirred and mixed, and cooled to room temperature with stirring. Next, this was pulverized, and the sustained-release property was evaluated using a particle size of 12 to 48 mesh.
【００２７】その結果、パラフィンワックスを用いた試
料の溶出率は試験開始後０．５〜５時間で１５％とほぼ
一定となり、それ以上放出しなかった。また、ライスワ
ックスでは２〜５時間で４５％とほぼ一定となり、溶出
率が低く、これらは添加化剤として不適当であった。鯨
ロウ、カルナバ、ビーズワックスの場合はＴ７５％が
１．５時間に延長したが、血中濃度のＴｍａｘは速放錠
と比べてほぼ同等であり、満足できる結果ではなかっ
た。結果を表３に示す。As a result, the dissolution rate of the sample using paraffin wax was substantially constant at 15% in 0.5 to 5 hours after the start of the test, and no further release was made. In the case of rice wax, it became almost constant at 45% in 2 to 5 hours, and the dissolution rate was low, and these were unsuitable as additives. In the case of whale wax, carnauba and beeswax, T 75% was extended to 1.5 hours, but the blood concentration Tmax was almost the same as that of the quick release tablet, which was not a satisfactory result. Table 3 shows the results.
【００２８】[0028]
【表３】 [Table 3]
【００２９】［有核錠とした場合］カルナバワックス４
〜１０ｇを加熱溶融し、これにＴＢＸ２ｇを添加して撹
拌混合した後、直径３ｍｍのチューブに吸引して冷却
し、カルナバワックスとＴＢＸ組成比２：１、３：１、
４：１、５：１のマトリックスを得た。次に、マトリッ
クスを取り出し、ＴＢＸとして１５ｍｇになるようにこ
れを切断し、有核錠用の核とした。速放錠を粉砕し、Ｔ
ＢＸとして５ｍｇをとり、速放錠のプラセボーと混合
し、先のマトリックスを核とし、有核錠を調製した。[When used as a dry-coated tablet] Carnauba wax 4
After heating and melting 10 g, 2 g of TBX was added thereto, and the mixture was stirred and mixed. Then, the mixture was sucked into a tube having a diameter of 3 mm and cooled, and the composition ratio of carnauba wax and TBX was 2: 1, 3: 1, and
A 4: 1, 5: 1 matrix was obtained. Next, the matrix was taken out and cut so as to have a TBX of 15 mg, which was used as a core for a dry coated tablet. Crush the quick release tablet,
5 mg of BX was taken and mixed with an immediate-release tablet placebo to prepare a dry-coated tablet using the above matrix as a core.
【００３０】これらの試料のインビトロの試験に於て、
核として用いたカルナバワックスとＴＢＸの組成比２：
１、３：１、４：１、５：１の有核錠のＴ７５％の時間
は、それぞれ２．５、３．５、６．５、９時間と、ワッ
クス比率が高くなるにつれて徐放性を示した。しかし、
インビボに於て、速放錠に対する生物学的相対利用率は
１．０、０．９、０．７、０．４と著しく低く、徐放錠
にはなり得なかった。結果を表４に示す。In an in vitro test of these samples,
Composition ratio of carnauba wax and TBX used as nucleus 2:
The time of T 75% of 1,3: 1,4: 1,5: 1 dry-coated tablets was 2.5, 3.5, 6.5, 9 hours, respectively. Showed sex. But,
In vivo, the relative bioavailability for immediate release tablets was significantly lower at 1.0, 0.9, 0.7, 0.4, and could not be sustained release tablets. Table 4 shows the results.
【００３１】[0031]
【表４】 [Table 4]
【００３２】［スペースタブとした場合］これらのワッ
クスマトリックス核を粉砕し、１２〜２０メッシュの粒
度の徐放部顆粒からＴＢＸとして１５ｍｇを取り、又速
放錠の打錠前の顆粒からＴＢＸとして５ｍｇ相当をと
り、滑沢剤を１％添加した後混合し、ＴＢＸ２０ｍｇの
スペースタブを得た。これら試料はいずれもＴ７５％の
時間は１．０、１．５、３．０、３．５時間、速放錠に
対する生物学的相対利用率は１．６、１．４、１．０、
０．８となったが、これらは、生物学的相対利用率が高
い場合は徐放性を示さず、また徐放性を示した場合は利
用率が低くなり、徐放錠にはなり得なかった。[When used as a space tab] These wax matrix nuclei are pulverized, and 15 mg of TBX is taken from granules of 12-20 mesh as sustained-release granules, and 5 mg of TBX is taken from granules before immediate-release tableting. After taking a considerable amount, 1% of a lubricant was added and mixed to obtain a space tub of 20 mg of TBX. All of these samples had a T 75% time of 1.0, 1.5, 3.0, 3.5 hours and a biorelative availability to immediate release tablets of 1.6, 1.4, 1.0. ,
0.8, but these do not show sustained release if the relative bioavailability is high, and if they show sustained release, the utilization will be low and it may be a sustained release tablet. Did not.
【００３３】結果を表５に示す。Table 5 shows the results.
【００３４】[0034]
【表５】 [Table 5]
【００３５】［その他のゲル形成高分子を用いた場合］
ＴＢＸを１０ｇ量り、ゲル形成高分子としてプルラン、
ポリビニルアルコール、オイドラギットＲＳ、カーボポ
ール、アルギン酸ナトリウムを用い、これを３０ｇ、及
び乳糖５９ｇを加えて混合した。次に、練合水として水
を用いて練合造粒し、熱風送風乾燥機にて乾燥した後、
１６メッシュの篩を用いて篩過した。これに所定量の無
水ケイ酸、ステアリン酸マグネシウムを量り、ポリエチ
レン袋で混合し、８ｍｍ径のパンチを用いて１錠２００
ｍｇとなるように打錠した。これらの溶出性を検討した
結果を表６に示した。[When other gel-forming polymer is used]
Weigh 10 g of TBX, pullulan as gel-forming polymer,
Using polyvinyl alcohol, Eudragit RS, Carbopol, and sodium alginate, 30 g of this was added and mixed with 59 g of lactose and mixed. Next, after kneading and granulating using water as kneading water, and drying with a hot air blow dryer,
The mixture was sieved using a 16-mesh sieve. A predetermined amount of silicic anhydride and magnesium stearate were weighed and mixed in a polyethylene bag, and one tablet was weighed using an 8 mm diameter punch.
Tableting was performed to obtain mg. Table 6 shows the results of examining these dissolution properties.
【００３６】[0036]
【表６】 [Table 6]
【００３７】これらはいずれも溶出試験において徐放性
は示さず、とうてい徐放性製剤にはなりえなかったなか
った。All of these did not show sustained release in the dissolution test, and could not be used as sustained release preparations.
【００３８】以上の通り、ＴＢＸをコーティングした場
合、複合顆粒剤とした場合、有核錠とした場合、スペー
スタブとした場合、その他のゲル形成高分子を用いた場
合、インビトロで徐放性に乏しいか、インビボで持続性
を示しても生物学的相対利用率が著しく低く、徐放性製
剤には成りえなかった。As described above, when coated with TBX, in the case of a composite granule, in the case of a dry-coated tablet, in the case of a space tub, or in the case of using other gel-forming polymers, a sustained release in vitro is obtained. Poor, or sustained in vivo, the bioavailability was significantly lower and could not be a sustained release formulation.
【００３９】[0039]
【課題を解決するための手段】本発明者らは、上記の問
題点に鑑み、ＴＢＸの徐放性製剤について鋭意研究を行
なったところ、ゲル形成高分子としてヒドロキシプロピ
ルメチルセルロース（以下ＨＰＭＣという。）、又はカ
ルボキシメチルセルロースナトリウム（以下ＣＭＣ−Ｎ
ａという。）を用い、他の賦形剤及び滑沢剤を配合して
調製した錠剤は、溶出試験で徐放性を示し、イヌとヒト
の血中動態は持続性を示し、有効血中濃度の維持時間は
速放性製剤の２倍以上、Ｃｍａｘは０．７〜０．９倍
で、生物学的相対利用率も良好で、食事の影響を受けに
くく、物理化学的に安定であり、更に服用しやすい大き
さの錠剤とすることが可能であることを見出し、本発明
を完成させた。Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies on sustained-release preparations of TBX, and found that hydroxypropylmethylcellulose (hereinafter referred to as HPMC) as a gel-forming polymer. Or sodium carboxymethylcellulose (hereinafter referred to as CMC-N
called a. ), Tablets prepared by blending other excipients and lubricants show sustained release in the dissolution test, show sustained blood kinetics in dogs and humans, and maintain effective blood concentrations The time is more than twice that of the immediate release preparation, the Cmax is 0.7-0.9 times, the biorelative utilization rate is good, it is hardly affected by meals, it is physicochemically stable, The present inventors have found that it is possible to obtain a tablet having a size that is easy to perform, and have completed the present invention.
【００４０】本発明のゲルマトリックス徐放性製剤は製
剤全重量に対してＴＢＸが２〜３０％及びＨＰＭＣを１
０〜９０％又はＣＭＣ−Ｎａを１０〜９０％含有するこ
とが好ましい。The sustained-release preparation of gel matrix of the present invention contains 2 to 30% of TBX and 1% of HPMC based on the total weight of the preparation.
It is preferable to contain 0 to 90% or 10 to 90% of CMC-Na.
【００４１】 ＨＰＭＣとしては、好ましくは置換基で
あるメトキシル基の置換度１．９、１．８又は１．４及
びヒドロキシプロポキシル基の置換度０．２５、０．１
５又は０．２０であり、２％水溶液の粘度が４０〜１１
２００ｃｐであるＨＰＭＣ、更に好ましくはメトキシル
基の置換度が１．８及びヒドロキシプロポキシル基の置
換度が０．２５で２％水溶液の粘度が３０００〜６００
０ｃｐであるＨＰＭＣを使用することができる。As HPMC, the degree of substitution of a methoxyl group, which is a substituent, is preferably 1.9, 1.8 or 1.4, and the degree of substitution of a hydroxypropoxyl group is 0.25, 0.1.
5 or 0.20, and the viscosity of the 2% aqueous solution is 40 to 11
HPMC with 200 cp, more preferably 1.8 degree of methoxyl group substitution and 0.25 degree of hydroxypropoxyl group substitution and 2% aqueous solution viscosity of 3000-600
An HPMC of 0 cp can be used.
【００４２】 例えば信越化学社製商品名「メトローズ
（登録商標）」のグレード60-SH-50、60-SH-4000、65-S
H-400、65-SH-50、65-SH-1500、65-SH-4000、90-SH-10
0、90-SH-400、90-SH-4000、90-SH-15000、90-SH-30000
が挙げられる。For example, grades 60-SH-50, 60-SH-4000, 65-S of “Metroze (registered trademark)” manufactured by Shin-Etsu Chemical Co., Ltd.
H-400, 65-SH-50, 65-SH-1500, 65-SH-4000, 90-SH-10
0, 90-SH-400, 90-SH-4000, 90-SH-15000, 90-SH-30000
Is mentioned.
【００４３】ＣＭＣ−Ｎａとしては、セルロース中のブ
ドウ糖の水酸基のカルボキシメチル基の置換度０．５０
〜０．９４で重合度２１２〜１３００のものであり、１
％水溶液の粘度が１５〜５４１０ｃｐのものが好まし
い。As the CMC-Na, the substitution degree of the carboxymethyl group of the hydroxyl group of glucose in cellulose is 0.50.
0.94 and a degree of polymerization of 212 to 1300;
% Aqueous solution having a viscosity of 15 to 5410 cp is preferable.
【００４４】例えばダイセル社製商品名「ＣＭＣダイセ
ル」のグレード１１２０、１１３０、１１４０、１１５
０、１１６０、１１７０、１１８０、１１９０が挙げら
れる。For example, grades 1120, 1130, 1140 and 115 of the product name “CMC Daicel” manufactured by Daicel Corporation
0, 1160, 1170, 1180, and 1190.
【００４５】本発明徐放性製剤は湿式法により、又は直
打法により錠剤を得ることができ、、必要に応じてフィ
ルムコーティングを施すことができる。本発明徐放性製
剤は経口投与剤はもとより、口腔付着剤などにも利用す
ることができる。また、錠剤とする前の混合物又は造粒
物をカプセルに充填しカプセル剤とすることもでき、こ
のカプセル内容物を鼻炎用吸入器、例えばネーザルイン
サフレーターを用いて鼻に噴霧してもよい。The sustained-release preparation of the present invention can be obtained as a tablet by a wet method or a direct compression method, and can be coated with a film if necessary. The sustained-release preparation of the present invention can be used not only for oral administration, but also for oral adhesives and the like. Alternatively, the mixture or granulated product before being formed into a tablet may be filled into a capsule to form a capsule, and the content of the capsule may be sprayed on the nose using a rhinitis inhaler, for example, a nasal insufflator. .
【００４６】更に、本発明徐放性製剤は、気密瓶中、高
温・高湿の条件で長期間保存してもＴＢＸの分解物が生
ぜず、放出性も変化せず、保存安定性も良好であり、極
めて優れたＴＢＸ徐放性製剤である。Furthermore, the sustained-release preparation of the present invention does not produce TBX degradation products even when stored in an airtight bottle at high temperature and high humidity for a long period of time, does not change its release property, and has good storage stability. Which is a very excellent TBX sustained-release preparation.
【００４７】[0047]
【作用】本発明徐放性製剤の放出性、血中濃度挙動及び
保存安定性について示す。The release, blood concentration behavior and storage stability of the sustained-release preparation of the present invention will be described.
【００４８】［放出性］ＴＢＸ、ＨＰＭＣ（グレード６
０ＳＨ−４０００）、乳糖、無水ケイ酸及びステアリン
酸マグネシウムの所定量を取り、混合した後、１錠２０
０ｍｇになるように調製して錠剤を得た。[Releasability] TBX, HPMC (grade 6)
0SH-4000), lactose, silicic anhydride and magnesium stearate, and after mixing, 1 tablet 20
It was adjusted to 0 mg to obtain a tablet.
【００４９】また、ＴＢＸ、ＣＭＣ−Ｎａ（グレード１
１４０）及び乳酸の所定量をとり、混合し、練合水を加
えて、練合後熱風送風乾燥機にて乾燥し、無水ケイ酸及
びステアリン酸マグネシウムを所定量添加し、混合した
後、１錠２００ｍｇになるように調製して錠剤を得た。
これらの試料は直径８ｍｍであり、最も服用しやすい大
きさの錠剤である。Further, TBX, CMC-Na (grade 1)
140) and a predetermined amount of lactic acid are taken, mixed, kneaded water is added, and after kneading, the mixture is dried with a hot air blow dryer, and predetermined amounts of silicic anhydride and magnesium stearate are added and mixed. Tablets were prepared to be 200 mg to obtain tablets.
These samples are 8 mm in diameter and are the most easily sized tablets.
【００５０】次にこれらの試料について溶出試験を行っ
た結果を表７及び表８に示した。Next, the results of the dissolution test performed on these samples are shown in Tables 7 and 8.
【００５１】[0051]
【表７】 [Table 7]
【００５２】[0052]
【表８】 [Table 8]
【００５３】表７及び表８の試料はいずれも０次の溶出
パターンを示し、またＴ７５％が２．５時間以上であ
り、明らかに徐放性を示した。Each of the samples in Tables 7 and 8 showed a zero-order elution pattern, and had a T 75% of 2.5 hours or more, and clearly showed sustained release.
【００５４】［血中濃度の挙動］ビーグル犬の血中濃
度パラメーター 表７及び表８中の試料５及び１２について、ビーグル犬
に経口投与した結果を表９に示した。[Behavior of Blood Concentration] Blood Concentration Parameter of Beagle Dog Table 9 shows the results of oral administration of samples 5 and 12 in Tables 7 and 8 to beagle dogs.
【００５５】[0055]
【表９】 [Table 9]
【００５６】表９に示したように、これらは通常製剤よ
りＣｍａｘは０．７〜０．９倍、有効濃度の維持時間は
２倍以上を示し、生物学的相対利用率も２倍となり良好
であった。As shown in Table 9, these have a Cmax of 0.7 to 0.9 times, a maintenance time of an effective concentration of twice or more and a relative bioavailability of 2 times, which are better than those of the normal preparations. Met.
【００５７】ヒトの血中濃度パラメーター 表７及び表８中の試料５及び１２について、ヒトの血中
濃度パラメーターを通常製剤と比較した結果を表１０に
示した。Human Blood Concentration Parameters Table 10 shows the results of comparison of human blood concentration parameters of the samples 5 and 12 in Tables 7 and 8 with those of ordinary preparations.
【００５８】[0058]
【表１０】 [Table 10]
【００５９】食餌の影響 表７中の試料５について、食後３０分にビーグル犬に経
口投与し、得られた血中濃度パラメーターを、表１１に
示した。Influence of diet Table 5 shows the blood concentration parameters of sample 5 in Table 7 which were orally administered to beagle dogs 30 minutes after the meal.
【００６０】[0060]
【表１１】 [Table 11]
【００６１】このように本発明徐放剤は食餌の影響を受
けにくかった。As described above, the sustained-release preparation of the present invention was hardly affected by diet.
【００６２】［保存安定性］表７及び８中の試料１〜１
２を気密瓶に入れて、４０℃、７５％、６箇月間保存し
た試料について、性状・分解物の有無及び放出性を検討
した。[Storage stability] Samples 1 to 1 in Tables 7 and 8
Sample No. 2 was placed in an airtight bottle and stored at 40 ° C., 75% for 6 months, and the properties, presence / absence of decomposed products and release properties were examined.
【００６３】性状は色差計を用いて、錠剤表面のＬ、
ａ、ｂ値を測定し、保存期間の変化を色差（ΔＥ）とし
て表した。分解物の有無の確認は薄層クロマトグラフ法
（ＴＬＣ）を採用し、薄層板はシリカゲルを展開溶媒は
メタノール：ベンゼン：アセトン：アンモニア水（５：
４：１：１）を用いた。観察は４０℃、７５％、６箇月
経過時に行ない、ＴＬＣもその時のものである。Using a color difference meter, the properties of L,
The a and b values were measured, and the change in the storage period was represented as a color difference (ΔE). The presence or absence of decomposition products was confirmed by thin layer chromatography (TLC), and the thin plate was developed using silica gel. The solvent used was methanol: benzene: acetone: aqueous ammonia (5:
4: 1: 1) was used. Observation was made at 40 ° C., 75%, after 6 months, and TLC was also that time.
【００６４】[0064]
【表１２】 [Table 12]
【００６５】このように、いずれの試料も性状に変化が
見られず、分解物も認められず、また、Ｔ７５％に変化
が認められず、極めて安定な製剤である。As described above, no change was observed in the properties of any of the samples, no degradation products were observed, and no change was observed in T 75% , indicating that the preparations were extremely stable.
【００６６】本発明徐放性製剤は、製剤全重量に対して
ＴＢＸを２〜３０％（ｗ／ｗ）、ＨＰＭＣ１０〜９０％
（ｗ／ｗ）又はＣＭＣ−Ｎａ１０〜９０％（ｗ／ｗ）に
調製することにより、有効血中濃度を長時間維持し、分
解物も生ぜず、保存安定性で徐放性が変化しないことか
ら、極めて優れた製剤である。In the sustained-release preparation of the present invention, TBX is 2 to 30% (w / w) and HPMC is 10 to 90% with respect to the total weight of the preparation.
(W / w) or 10 to 90% (w / w) of CMC-Na maintains the effective blood concentration for a long time, does not generate decomposition products, and has a storage stability and does not change sustained release. Therefore, it is a very excellent preparation.
【００６７】次に、本発明徐放性製剤の製造例をもって
示すが、これらが本発明を限定するものではない。Next, production examples of the sustained-release preparation of the present invention will be shown, but these do not limit the present invention.
【００６８】[0068]
【００６９】実施例１ ＴＢＸ１０ｇ、乳糖５８ｇ、ＨＰＭＣ（グレード６５Ｓ
Ｈ−４０００）３０ｇ、ソリダー１ｇ、ステアリン酸マ
グネシウム１ｇを量り、混合した後打錠し、直径８ｍｍ
の１個２００ｍｇの錠剤を得た。Example 1 10 g of TBX, 58 g of lactose, HPMC (grade 65S
H-4000) 30 g, a solid 1 g, and magnesium stearate 1 g were weighed, mixed, and tableted to form a tablet having a diameter of 8 mm.
Was obtained in a tablet of 200 mg.
【００７０】実施例２ 実施例１のＨＰＭＣのグレードを９０ＳＨ−４０００に
変えた以外は、実施例１と同様に製造した。Example 2 A sample was produced in the same manner as in Example 1 except that the grade of HPMC in Example 1 was changed to 90SH-4000.
【００７１】実施例３ ＴＢＸ１０ｇ、乳糖５８ｇ、ＨＰＭＣ（グレード９０Ｓ
Ｈ−４００）３０ｇ、ソリダー１ｇ、ステアリン酸マグ
ネシウム１ｇを量り、混合した後打錠し、直径８ｍｍの
１個２００ｍｇの錠剤を得た。Example 3 10 g of TBX, 58 g of lactose, HPMC (grade 90S
H-400) 30 g, a solid 1 g, and magnesium stearate 1 g were weighed, mixed and tabletted to obtain a tablet of 200 mg each having a diameter of 8 mm.
【００７２】実施例４ ＴＢＸ１５ｇ、乳糖４２．３４ｇ、ＨＰＭＣ（グレード
６０ＳＨ−５０）４０ｇ、ソリダー１．３３ｇ、ステア
リン酸マグネシウム１．３３ｇを量り、混合した後打錠
し、直径７ｍｍの１個１３３ｍｇの錠剤を得た。Example 4 15 g of TBX, 42.34 g of lactose, 40 g of HPMC (grade 60 SH-50), 1.33 g of solider and 1.33 g of magnesium stearate were weighed, mixed, and tabletted. Tablets were obtained.
【００７３】実施例５ ＴＢＸ１５ｇ、乳糖４２．３４ｇ、ＨＰＭＣ（グレード
６５ＳＨ−４０００）４０ｇ、ソリダー１．３３ｇ、ス
テアリン酸マグネシウム１．３３ｇを量り、混合した後
打錠し、直径７ｍｍの１個１３３ｍｇの錠剤を得た。Example 5 15 g of TBX, 42.34 g of lactose, 40 g of HPMC (grade 65SH-4000), 1.33 g of solider and 1.33 g of magnesium stearate were weighed, mixed, and tabletted. Tablets were obtained.
【００７４】実施例６ ＴＢＸ１０ｇ、乳糖７９ｇ、ＣＭＣ−Ｎａ（グレード１
１４０）１０ｇを量り、練合液に水を用いて練合後、１
２メッシュの篩いを用いて篩過し、乾燥し顆粒を得た。
これにソリダー０．５％、ステアリン酸マグネシウム
０．５％を加えて混合した後打錠し、直径８ｍｍの１個
２００ｍｇの錠剤を得た。Example 6 10 g of TBX, 79 g of lactose, and CMC-Na (grade 1)
140) After weighing 10 g and kneading using water for the kneading liquid, 1
The mixture was sieved using a 2-mesh sieve and dried to obtain granules.
To this, 0.5% of a solid and 0.5% of magnesium stearate were added and mixed, followed by tableting to obtain a tablet of 200 mg each having a diameter of 8 mm.
【００７５】実施例７ ＴＢＸ１０ｇ、乳糖６９ｇ、ＣＭＣ−Ｎａ（グレード１
１３０）２０ｇを量り、練合液に水を用いて練合後、１
２メッシュの篩いを用いて篩過し、乾燥し顆粒を得た。
これにソリダー０．５％、ステアリン酸マグネシウム
０．５％を加えて混合した後打錠し、直径８ｍｍの１個
２００ｍｇの錠剤を得た。Example 7 10 g of TBX, 69 g of lactose, CMC-Na (grade 1)
130) After weighing 20 g and kneading using water as the kneading liquid, 1
The mixture was sieved using a 2-mesh sieve and dried to obtain granules.
To this, 0.5% of a solid and 0.5% of magnesium stearate were added and mixed, followed by tableting to obtain a tablet of 200 mg each having a diameter of 8 mm.
【００７６】実施例８ ＴＢＸ１０ｇ、乳糖５９ｇ、ＣＭＣ−Ｎａ（グレード１
１５０）３０ｇを量り、練合液に水を用いて練合後、１
２メッシュの篩いを用いて篩過し、乾燥し顆粒を得た。
これにソリダー０．５％、ステアリン酸マグネシウム
０．５％を加えて混合した後打錠し、直径８ｍｍの１個
２００ｍｇの錠剤を得た。Example 8 TBX 10 g, lactose 59 g, CMC-Na (grade 1)
150) weigh 30 g, knead the mixture with water
The mixture was sieved using a 2-mesh sieve and dried to obtain granules.
To this, 0.5% of a solid and 0.5% of magnesium stearate were added and mixed, followed by tableting to obtain a tablet of 200 mg each having a diameter of 8 mm.
【００７７】実施例９ ＴＢＸ１０ｇ、乳糖４９ｇ、ＣＭＣ−Ｎａ（グレード１
１６０）４０ｇを量り、練合液に水を用いて練合後、１
２メッシュの篩いを用いて篩過し、乾燥し顆粒を得た。
これにソリダー０．５％、ステアリン酸マグネシウム
０．５％を加えて混合した後打錠し、直径８ｍｍの１個
２００ｍｇの錠剤を得た。Example 9 10 g of TBX, 49 g of lactose, CMC-Na (grade 1)
160) After weighing 40 g and kneading using water as the kneading liquid, 1
The mixture was sieved using a 2-mesh sieve and dried to obtain granules.
To this, 0.5% of a solid and 0.5% of magnesium stearate were added and mixed, followed by tableting to obtain a tablet of 200 mg each having a diameter of 8 mm.
【００７８】実施例１０ ＴＢＸ１５ｇ、乳糖４２．３４ｇ、ＣＭＣ−Ｎａ（グレ
ード１１５０）４０ｇを量り、練合液に水を用いて練合
後、１２メッシュの篩いを用いて篩過し、乾燥し顆粒を
得た。これにソリダー０．５％、ステアリン酸マグネシ
ウム０．５％を加えて混合した後打錠し、直径７ｍｍの
１個１３３ｍｇの錠剤を得た。Example 10 TBX (15 g), lactose (42.34 g), and CMC-Na (grade 1150) (40 g) were weighed, kneaded using water as a kneading solution, sieved using a 12-mesh sieve, dried, and dried to obtain granules. I got To this, 0.5% of a solid and 0.5% of magnesium stearate were added and mixed, followed by tableting to obtain a tablet of 133 mg each having a diameter of 7 mm.
【００７９】実施例１１ ＴＢＸ１５ｇ、乳糖４２．３４ｇ、ＣＭＣ−Ｎａ（グレ
ード１１３０）４０ｇを量り、練合液に水を用いて練合
後、１２メッシュの篩いを用いて篩過し、乾燥し顆粒を
得た。これにソリダー０．５％、ステアリン酸マグネシ
ウム０．５％を加えて混合した後打錠し、直径７ｍｍの
１個１３３ｍｇの錠剤を得た。Example 11 15 g of TBX, 42.34 g of lactose and 40 g of CMC-Na (grade 1130) were weighed, kneaded with water as a kneading solution, sieved with a 12-mesh sieve, dried, and dried to obtain granules. I got To this, 0.5% of a solid and 0.5% of magnesium stearate were added and mixed, followed by tableting to obtain a tablet of 133 mg each having a diameter of 7 mm.
【００８０】実施例１２ 実施例１の打錠前の混合物２００ｍｇを２号カプセルに
充填し、カプセル剤とした。Example 12 200 mg of the mixture before tableting of Example 1 was filled into No. 2 capsules to give capsules.
【００８１】実施例１３ 実施例５の打錠前の造粒物１００ｍｇを４号カプセルに
充填しカプセル剤とした。Example 13 100 mg of the granulated product before tableting of Example 5 was filled into a No. 4 capsule to give a capsule.
【００８２】実施例１４ ＴＢＸ１ｇ、ＨＰＭＣ（グレード６０ＳＨ−４０００）
１０ｇ、乳糖８８ｇ、ソリダー０．５ｇを量り、混合後
ステアリン酸マグネシウム０．５ｇを量り、更に混合し
て４号カプセルにその５０ｍｇを充填し、鼻用カプセル
剤とした。Example 14 1 g of TBX, HPMC (grade 60SH-4000)
10 g, lactose 88 g, and solid 0.5 g were weighed, and after mixing, 0.5 g of magnesium stearate was weighed and further mixed, and the No. 4 capsule was filled with 50 mg to obtain a nasal capsule.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ Ａ６１Ｐ 27/16 Ａ６１Ｐ 27/16 37/08 37/08 Ｃ０７Ｄ 471/04 １１７ Ｃ０７Ｄ 471/04 １１７Ａ (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/519 A61K 9/22 A61K 47/38 A61P 11/02 A61P 11/06 A61P 27/16 A61P 37/08 C07D 471/04 ＢＩＯＳＩＳ（ＤＩＡＬＯＧ) ＣＡＰＬＵＳ（ＳＴＮ) ＭＥＤＬＩＮＥ（ＳＴＮ) ＥＭＢＡＳＥ（ＳＴＮ)────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. 7 Identification code FI A61P 27/16 A61P 27/16 37/08 37/08 C07D 471/04 117 C07D 471/04 117A (58) Field surveyed (Int. .Cl. 7 , DB name) A61K 31/519 A61K 9/22 A61K 47/38 A61P 11/02 A61P 11/06 A61P 27/16 A61P 37/08 C07D 471/04 BIOSIS (DIALOG) CAPLUS (STN) MEDLINE ( STN) EMBASE (STN)
Claims (3)
ｗ）及びヒドロキシプロピルメチルセルロース１０〜９
０％（ｗ／ｗ）又はカルボキシメチルセルロースナトリ
ウム１０〜９０％（ｗ／ｗ）からなる徐放性製剤。(1) A pemirolast potassium 2 to 30% (w /
w) and hydroxypropyl methylcellulose 10-9
A sustained-release preparation comprising 0% (w / w) or 10-90% (w / w) of sodium carboxymethylcellulose.
ルコースのメトキシル基の置換度が１．９、１．８又は
１．４及びヒドロキシプロポキシル基の置換度が０．２
５、０．１５又は０．２０であり、２％水溶液の粘度が
４０〜１１２００ｃｐである請求項１記載の徐放性製
剤。2. Hydroxypropylmethylcellulose having a glucose methoxyl group substitution degree of 1.9, 1.8 or 1.4 and a hydroxypropoxyl group substitution degree of 0.2.
The sustained-release preparation according to claim 1, wherein the preparation is 5, 0.15 or 0.20, and the viscosity of the 2% aqueous solution is 40 to 11200 cp.
エーテル置換度０．５〜０．９４、重合度２１２〜１３
００であり、１％水溶液の粘度が１５〜５４１０ｃｐで
ある請求項１記載の徐放性製剤。3. A carboxymethylcellulose sodium having a degree of ether substitution of 0.5 to 0.94 and a degree of polymerization of 212 to 13.
2. The sustained-release preparation according to claim 1, wherein the 1% aqueous solution has a viscosity of 15 to 5410 cp.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03236741A JP3116970B2 (en) | 1991-06-12 | 1991-06-12 | Sustained-release preparation of pemirolast potassium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03236741A JP3116970B2 (en) | 1991-06-12 | 1991-06-12 | Sustained-release preparation of pemirolast potassium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04368330A JPH04368330A (en) | 1992-12-21 |
| JP3116970B2 true JP3116970B2 (en) | 2000-12-11 |
Family
ID=17005103
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP03236741A Expired - Fee Related JP3116970B2 (en) | 1991-06-12 | 1991-06-12 | Sustained-release preparation of pemirolast potassium |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3116970B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995032714A1 (en) * | 1994-05-31 | 1995-12-07 | Tokyo Tanabe Company Limited | Arteriosclerosis depressant |
| GB9611328D0 (en) * | 1996-05-31 | 1996-08-07 | Zeneca Ltd | Pharmaceutical compositions |
| CN105748430A (en) * | 2016-04-28 | 2016-07-13 | 江苏飞马药业有限公司 | Preparation method of pemirolast potassium tablets for treating allergic dermatitis and application |
| CN106361709A (en) * | 2016-11-18 | 2017-02-01 | 江苏飞马药业有限公司 | Pemirolast potassium granule composition and preparation method thereof |
| CN106389366A (en) * | 2016-11-18 | 2017-02-15 | 江苏飞马药业有限公司 | Pemirolast potassium tablet composition and preparation method thereof |
-
1991
- 1991-06-12 JP JP03236741A patent/JP3116970B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04368330A (en) | 1992-12-21 |
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