JPH04103525A - Production of sustainable pharmaceutical preparation for poorly water-soluble medicine - Google Patents
Production of sustainable pharmaceutical preparation for poorly water-soluble medicineInfo
- Publication number
- JPH04103525A JPH04103525A JP21898490A JP21898490A JPH04103525A JP H04103525 A JPH04103525 A JP H04103525A JP 21898490 A JP21898490 A JP 21898490A JP 21898490 A JP21898490 A JP 21898490A JP H04103525 A JPH04103525 A JP H04103525A
- Authority
- JP
- Japan
- Prior art keywords
- poorly water
- nifedipine
- soluble drug
- surfactant
- medicine
- 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
- 239000003814 drug Substances 0.000 title claims abstract description 52
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 54
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960001597 nifedipine Drugs 0.000 claims abstract description 33
- 239000004094 surface-active agent Substances 0.000 claims abstract description 17
- 239000000725 suspension Substances 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000005507 spraying Methods 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229960000278 theophylline Drugs 0.000 claims abstract description 4
- YWXYYJSYQOXTPL-JGWLITMVSA-N [(3r,3ar,6s,6as)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-JGWLITMVSA-N 0.000 claims abstract description 3
- 229940079593 drug Drugs 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 24
- 239000007921 spray Substances 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 14
- 230000005923 long-lasting effect Effects 0.000 claims description 7
- CRFFPDBJLGAGQL-UHFFFAOYSA-N 2-azaniumyl-3-[4-(trifluoromethyl)phenyl]propanoate Chemical compound OC(=O)C(N)CC1=CC=C(C(F)(F)F)C=C1 CRFFPDBJLGAGQL-UHFFFAOYSA-N 0.000 claims description 3
- XLFWDASMENKTKL-UHFFFAOYSA-N molsidomine Chemical compound O1C(N=C([O-])OCC)=C[N+](N2CCOCC2)=N1 XLFWDASMENKTKL-UHFFFAOYSA-N 0.000 claims description 3
- 229960004027 molsidomine Drugs 0.000 claims description 3
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 claims description 3
- 229960002508 pindolol Drugs 0.000 claims description 3
- 125000003158 alcohol group Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 19
- 230000000694 effects Effects 0.000 abstract description 5
- 238000001179 sorption measurement Methods 0.000 abstract description 5
- 239000012530 fluid Substances 0.000 abstract 5
- 239000003826 tablet Substances 0.000 description 24
- 229940088679 drug related substance Drugs 0.000 description 20
- 239000008186 active pharmaceutical agent Substances 0.000 description 19
- 239000000843 powder Substances 0.000 description 19
- 238000004090 dissolution Methods 0.000 description 18
- 239000000523 sample Substances 0.000 description 13
- 239000013078 crystal Substances 0.000 description 10
- 239000008187 granular material Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000001913 cellulose Substances 0.000 description 7
- 229920002678 cellulose Polymers 0.000 description 7
- 238000007922 dissolution test Methods 0.000 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 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 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 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 3
- 229940068968 polysorbate 80 Drugs 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012792 core layer Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000012669 liquid formulation Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007940 sugar coated tablet Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 108010013381 Porins Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005280 amorphization Methods 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- -1 imbropanol Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 239000007942 layered tablet Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 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
- 102000007739 porin activity proteins Human genes 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000009498 subcoating Methods 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 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
Abstract
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は難水溶性薬物の持続性製剤化方法に係る。[Detailed description of the invention] (Industrial application field) The present invention relates to a method for producing a long-lasting formulation of a poorly water-soluble drug.
本発明が対象とする難水溶性薬物としてはニフェジピン
、硝酸インソルビド、テオフィリン、ピンドロール、メ
シル酸ジヒドロエルゴトキシン及びモルシドミン等を例
示することができ、本発明はこれらの薬物を持続性製剤
化し、これにより当該製剤が投与される場合に薬物を緩
徐に放出させ、その生物学的利用率を向上させると共に
薬効の安定発現をもたらすものである。Examples of poorly water-soluble drugs targeted by the present invention include nifedipine, insorbide nitrate, theophylline, pindolol, dihydroergotoxine mesylate, and molsidomine. When the preparation is administered, the drug is released slowly, improving its bioavailability and stably exhibiting drug efficacy.
尚、本発明は上記のような各種の難水溶性薬物を対象と
して実施し得るものであるが、本明細書においては代表
として「ニフェジピン」を例にとって説明する。Although the present invention can be practiced with various poorly water-soluble drugs as described above, in this specification, "nifedipine" will be used as a representative example.
（従来の技術、その問題点及び発明が解決しようとする
課題乃至発明の目的）
ニフェジピンは黄色の結晶性粉末であり、水に対する溶
解度は約１２μｇ／ｍｌであるために結晶粉末をそのま
ま経口投与しても生物学的利用率が低く約２０％である
と云われている［杉本功「インファケムＪ ＶＯｌ、２
． Ｎｏ、 Ｌ ｐａｇｅ １７ （１９８１）］。(Prior art, its problems, problems to be solved by the invention, and objects of the invention) Nifedipine is a yellow crystalline powder, and its solubility in water is about 12 μg/ml, so the crystalline powder can be orally administered as it is. However, it is said that the bioavailability rate is low at about 20% [Isao Sugimoto, “Infachem J VOl, 2
．． No. L page 17 (1981)].
水に難溶性であるニフェジピンの溶解性を改善して持続
的に放出させることにより安定した薬効を示す固形製剤
になす方法を開示している文献、殊に特許関係文献とし
ては特公昭５９−１４４４６号、持分平１−２２２４５
号、特開昭［ｉｏ −２５５７１９号、特開昭６１−８
号、特開昭Ｇｌ −１４８１１４号公報等がある。Documents disclosing methods for producing solid preparations that exhibit stable drug efficacy by improving the solubility of nifedipine, which is sparingly soluble in water, and releasing it continuously, especially patent-related documents such as Japanese Patent Publication No. 59-14446 No., Equity Hei 1-22245
No., JP-A-Sho [io-255719, JP-A-61-8]
No., Japanese Unexamined Patent Publication No. Sho Gl-148114, etc.
これらの公知技術文献の内で特公昭５９＋４４４ｆｉ号
公報に開示されている方法は比表面積０．５−６ｍ２／
Ｈのニフェジピン結晶を用い且つ常法により経口製剤化
することにより速やかに当該薬物の血中（血漿中）濃度
を増大させ且つ長時間にわたり高い血中濃度を維持させ
ようとするものであるが、使用されるニフェジピン結晶
が限定されてしまう点に問題がある。Among these known technical documents, the method disclosed in Japanese Patent Publication No. 59+444fi has a specific surface area of 0.5-6 m2/
The aim is to rapidly increase the blood (plasma) concentration of the drug and maintain the high blood concentration for a long period of time by using H. nifedipine crystals and making an oral formulation using a conventional method. The problem is that the nifedipine crystals that can be used are limited.
持分平１−２２２４５号公報に開示されている方法は平
均粒子径５μ閣以下のニフェジピン微粉末を用い、一方
に水難溶性物質と腸溶性高分子とからなる被膜を施して
遅放出部とし、これに速放出部として被膜を施こさない
ものを配合することによりニフェジピンの緩慢かつ持続
的な放出をもたらそうとするものであるが、製造工程が
煩雑である点に問題がある。又、特開昭８０−２５５７
１９号に開示されている方法は珪酸マグネシウム、炭酸
マグネシウム等の塩と、カゼインと、ニフェジピンとか
ら得た共粉砕微粉状組成物に腸溶性被覆剤、可塑剤を添
加混合し、次いで共粉砕した後に乾式造粒することによ
り吸収性、持続性に優れた固形製剤とするものであるが
、製造工程が煩雑である点に問題がある。一方、特開昭
６１−８号公報に開示されている方法はニフェジピンに
界面活性剤を加えて調製した速溶性造粒物と、該造粒物
の一部を採取して粉砕し宵機高分子固着剤を加えて調製
した徐放性造粒物とを混合して腸溶性コーティングを施
して核層を形成し、そのまわりに両造粒物を被覆して速
溶性と徐放性とを発揮させようとするものであるが、製
造工程が煩雑である点に問題がある。尚、特開昭ｆｉｌ
−１４８１１４号公報に開示されている方法は、球形
核剤とその表面に付着しているニフェジピンの微粉末と
からなる速効性球形顆粒と、該速効性球形顆粒を腸溶物
質及び難溶性物質で被覆してなる遅効性球形顆粒とを用
いるものであるが、製造工程が煩雑である点に問題があ
従って、本発明が解決しようとする課題乃至発明の目的
はニフェジピンを含む難水溶性薬物に適用することがで
き、薬剤原料（以下、「原体」と称することもある）の
結晶粒径や比表面積等による限定を受けず、処理工程が
簡便であって工業的生産に適する、難水溶性薬物の持続
性製剤化方法を提供することにある。The method disclosed in Jibu No. 1-22245 uses nifedipine fine powder with an average particle size of 5 μm or less, and coats one side with a poorly water-soluble substance and an enteric polymer to form a slow-release part. It is attempted to bring about a slow and sustained release of nifedipine by incorporating an uncoated fast-release part into the drug, but there is a problem in that the manufacturing process is complicated. Also, JP-A-80-2557
The method disclosed in No. 19 involves adding and mixing an enteric coating agent and a plasticizer to a co-pulverized fine powder composition obtained from a salt such as magnesium silicate or magnesium carbonate, casein, and nifedipine, and then co-pulverizing the composition. Although dry granulation is subsequently performed to form a solid preparation with excellent absorbency and sustainability, there is a problem in that the manufacturing process is complicated. On the other hand, the method disclosed in JP-A No. 61-8 uses a fast-dissolving granule prepared by adding a surfactant to nifedipine, and a portion of the granule is collected and pulverized. A sustained release granule prepared by adding a molecular fixing agent is mixed with the core layer and an enteric coating is applied to form a core layer. However, there is a problem in that the manufacturing process is complicated. In addition, Tokukai Sho fil
The method disclosed in Publication No. 148114 consists of fast-acting spherical granules consisting of a spherical core agent and fine powder of nifedipine attached to the surface thereof, and the fast-acting spherical granules being treated with an enteric substance and a poorly soluble substance. However, there is a problem in that the manufacturing process is complicated, and the problem to be solved by the present invention or the purpose of the invention is to use coated delayed-release spherical granules. It is not limited by the crystal grain size or specific surface area of the drug raw material (hereinafter sometimes referred to as "drug substance"), has a simple processing process, and is suitable for industrial production. The object of the present invention is to provide a method for producing a long-lasting drug.
（課題を解決し、目的を達成する手段及び作用）本発明
によれば、上記の課題は難水溶性薬物を溶剤に溶解又は
懸濁させ、次いで噴霧液の液滴径をコントロールして担
体に噴霧吸着させることにより得たる組成物を用いるこ
とにより解決されると共に、上記の目的が達成される。(Means and effects for solving the problem and achieving the object) According to the present invention, the above problem is solved by dissolving or suspending a poorly water-soluble drug in a solvent, and then controlling the droplet size of the spray liquid to spray it onto a carrier. The above object is solved and achieved by using a composition obtained by spray adsorption.
本発明を実施する場合に、難水溶性薬物としてはニフェ
ジピン、硝酸イソソルビド、テオフィリン、ピンドロー
ル、メシル酸ジヒドロエルゴトキシン、モルシドミン等
を挙げることができる。このような難水溶性薬物を溶解
又は懸濁させる溶剤としてはエタノール、メタノール、
インブロパノ−ル等のアルコール類、水、ジクロルメタ
ン、アセトン又はこれらの混合物を挙げることかでき、
必要であれば界面活性剤を配合することができる。When carrying out the present invention, poorly water-soluble drugs include nifedipine, isosorbide nitrate, theophylline, pindolol, dihydroergotoxine mesylate, molsidomine, and the like. Solvents for dissolving or suspending such poorly water-soluble drugs include ethanol, methanol,
Mention may be made of alcohols such as imbropanol, water, dichloromethane, acetone or mixtures thereof;
A surfactant can be added if necessary.
この場合の界面活性剤としてはポリソルベート８０、ラ
ウリル硫酸ナトリウム等を例示することができる。Examples of the surfactant in this case include polysorbate 80 and sodium lauryl sulfate.
得られた難水溶性薬物溶液乃至懸濁液は担体に対して噴
霧されるが、この担体は製剤用の非毒性担体であって乳
糖、低置換度ヒドロキシプロピルセルロース、結晶セル
ロース、カルボキシメチルセルロース、カルボキンメチ
ルセルロースカルシウム、α化澱粉、トウモロフン澱粉
、これらの混合物等を例示することができる。The resulting poorly water-soluble drug solution or suspension is sprayed onto a carrier, which is a non-toxic carrier for pharmaceutical preparations, such as lactose, low-substituted hydroxypropylcellulose, crystalline cellulose, carboxymethylcellulose, or carboxylic acid. Examples include methyl cellulose calcium, pregelatinized starch, corn starch, and mixtures thereof.
難水溶性薬物がニフェジピンの場合には、噴霧液のニフ
ェジピン濃度を溶液としては１．１％以下に、又懸濁液
としては２０％以下に設定し、噴霧液の液滴径を１５０
μｍ以下に設定し、又組成物中のニフェジピン含量を、
界面活性剤が存在する場合には５０％以下に設定し、又
界面活性剤が存在しない場合には２０％以下に設定する
のが、溶出率を適正なものとし、これによって作用持続
性をもたらす観点から好ましい。この場合に、上記の液
滴径は抜出等の実験式［［機械学会論文集ＪＶｏｌ、４
゜ｐａｇｅ １２８ （１９３８）］に基き算出された
ものであり、適正な溶出率の指針としては日本薬局方に
規定されている溶出試験法の内の第２法（パドル法、１
０１００ｒｐにより溶出試験を実施した場合における６
０分後の溶出率（Ｄａｉ１）が５０±２０５ｆの範囲内
の場合である。When the poorly water-soluble drug is nifedipine, the concentration of nifedipine in the spray solution is set to 1.1% or less as a solution, or 20% or less as a suspension, and the droplet diameter of the spray solution is set to 150% or less.
μm or less, and the nifedipine content in the composition is
Setting the dissolution rate to 50% or less when a surfactant is present, and setting the dissolution rate to 20% or less when a surfactant is not present will ensure an appropriate dissolution rate, thereby providing a sustained action. Preferable from this point of view. In this case, the above droplet diameter is determined by the experimental formula such as extraction [[Proceedings of the Japan Society of Mechanical Engineers J Vol. 4]
゜page 128 (1938)], and as a guideline for an appropriate dissolution rate, the second method (paddle method, 1.
6 when the dissolution test was carried out using 0100rp.
This is a case where the elution rate after 0 minutes (Dai1) is within the range of 50±205f.
難水溶性薬物の溶液又は懸濁液を担体に噴霧して得た組
成物は乾燥させて散剤として用いることができ、又常法
により更に製剤化して錠剤、フィルム錠、糖衣錠、カプ
セル剤、顆粒剤、先割、二層錠等になすことができる。A composition obtained by spraying a solution or suspension of a poorly water-soluble drug onto a carrier can be dried and used as a powder, or it can be further formulated by a conventional method to form tablets, film tablets, sugar-coated tablets, capsules, and granules. It can be made into tablets, pre-split tablets, double-layered tablets, etc.
尚、本発明方法により難水溶性薬物が持続性製剤化され
る理由は、 「薬物結晶の溶解に伴う部分的な非晶質化
」、「結晶壁界面への溶剤の侵入に伴う結晶の微細化」
、「凝集した結晶の分散」等が生じ、これらが相乗的に
作用するためと推定される。The reasons why poorly water-soluble drugs can be made into long-lasting formulations by the method of the present invention are ``partial amorphization due to dissolution of drug crystals'' and ``fineness of crystals due to penetration of solvent into the crystal wall interface.'' ”
It is presumed that this is because ``dispersion of aggregated crystals'' and the like occur, and these act synergistically.
（実施例等）
次に、試験例を兼る実施例等により本発明を更に詳細に
且つ具体的に説明する。尚、下記の実施例においては難
水溶性薬物として専らニフェジピンが採用されているが
、他の難水溶性薬物も同様に本発明方法を適用し得るこ
とに留意され度い。(Examples etc.) Next, the present invention will be explained in more detail and concretely using Examples etc. which also serve as test examples. In the Examples below, nifedipine is exclusively used as the poorly water-soluble drug, but it should be noted that the method of the present invention can be applied to other poorly water-soluble drugs as well.
及惠１（散剤）
ニフェジピン （原体）の１．５％エタノール溶液を流
動層造粒乾燥機により担体としての乳糖に噴霧吸着させ
ることにより組成物化すると共に散剤となした。尚、原
体としては比表面積０．２４ｍ２／ｇのものが使用され
、噴霧に際しては条件の調整により液滴径を種々の寸法
に設定し、又担体である乳糖の量割合を種々に設定する
ことにより得られる組成物中の原体濃度を種々に変化さ
せた試料を得、これらの各試料について溶出率［Ｄａｉ
、即ち日本薬局方に規定されている溶出試験法の内の第
２法（パドル法、１０１００ｒｐにより溶出試験を実施
した場合における６０分後の溶出率］を調べた。Orie 1 (powder) A 1.5% ethanol solution of nifedipine (technical substance) was sprayed and adsorbed onto lactose as a carrier using a fluidized bed granulation dryer to form a composition and powder. The active substance used has a specific surface area of 0.24 m2/g, and during spraying, the droplet diameter is set to various sizes by adjusting the conditions, and the amount ratio of lactose, which is a carrier, is set to various sizes. Samples were obtained in which the drug substance concentration in the resulting composition was varied, and the dissolution rate [Dai
That is, the second method (paddle method, dissolution rate after 60 minutes when the dissolution test is carried out at 10,100 rp) of the dissolution test methods prescribed in the Japanese Pharmacopoeia was investigated.
結果は下記の表１に示される通りであり、液滴径を１５
０μｍ以下に設定して噴霧し、組成物中の原体濃度を２
０″Ａ以下になす場合に、溶解性の改善及び作用持続性
判断の指針である５ｏ±２０％の範囲内の値に溶出率を
なし得ることが判明した。The results are shown in Table 1 below, and the droplet diameter was 15
The concentration of the drug substance in the composition is set to 0μm or less and sprayed.
It has been found that when the dissolution rate is below 0''A, the dissolution rate can be achieved within the range of 5o±20%, which is a guideline for improving solubility and determining duration of action.
表中において、
（２）：原体をＩＯＢ含有するように各試料組成物を秤
取し、試験液量を９００１とし、日本薬局方に規定する
溶出試験法の内の第２法（パドル法Ｎ １０１００ｒ
ｐにより溶出試験を実施した際の６０分後の溶出率。In the table, (2): Weigh each sample composition so that it contains IOB of the drug substance, set the test liquid volume to 9001, and use the second method (paddle method) of the dissolution test methods specified in the Japanese Pharmacopoeia. N 10100r
Dissolution rate after 60 minutes when dissolution test was conducted using p.
夫息炎」（散剤）
原体の１．５％エタノール溶液に、界面活性剤としての
ポリンルベー（・８０を１．０％ １１添加した以外は
実施例１と全く同様にして各種の試料組成物（散剤）を
製造した。Various sample compositions were prepared in the same manner as in Example 1, except that 1.0% 11 of porin rubey (.80) as a surfactant was added to a 1.5% ethanol solution of the drug substance (powder). (powder) was manufactured.
これらの各試料組成物に関して、実施例１におけると同
様に溶出試験を実施して６０分経過後の溶出率（Ｄａｇ
）を調べた。結果は下記の表２に示される通りであり、
液滴径を１５０μｍ以下に設定して＠霧し、組成物中の
原体濃度を５０″Ａ以下になす場合に、溶解性の改善及
び作用持続性判断の指針である５０±２０％の範囲内の
値に溶出率をなし得ること、即ち薬剤組成物の調製に際
して界面活性剤を配合しない実施例１の場合には組成物
中の原体濃度を２０％以下に設定する必要性があったが
、界面活性剤を配合することにより組成物中の原体濃度
を５０％程度に高く設定しても所期の効果である溶解性
の改善と薬効の持続性とをもたらし得ることが判明した
。Regarding each of these sample compositions, a dissolution test was conducted in the same manner as in Example 1, and the dissolution rate (Dag) was determined after 60 minutes.
) was investigated. The results are shown in Table 2 below,
When the droplet diameter is set to 150 μm or less and the concentration of the drug substance in the composition is 50″A or less, the range of 50 ± 20% is the guideline for improving solubility and determining the duration of action. In other words, in the case of Example 1 in which no surfactant was added when preparing the drug composition, it was necessary to set the concentration of the drug substance in the composition to 20% or less. However, it has been found that by incorporating a surfactant, the desired effects of improved solubility and sustained drug efficacy can be achieved even if the drug substance concentration in the composition is set as high as about 50%. .
表中において、
（１）：試料（組成物）中の原体濃度、（２）：実施例
■参照。In the table, (1): Concentration of drug substance in sample (composition), (2): See Example ■.
！Ｊｕｌ（散剤）
担体としての乳糖に、原体のエタノール懸濁液を流動層
造粒乾燥機にて噴霧吸着させることによりし組成物化す
ると共に散剤となした。但し、本実施例の場合には比表
面積の異なる原体を用い且つ懸濁液中の原体濃度を変化
させたが、噴霧液滴径は１６μｍに設定し、又組成物中
のニフェジピン濃度は１０％に設定して各種の試料組成
物である散剤を製造し、各試料組成物に関して、実施例
Ｉにおけると同様に溶出試験を実施して６０分経過後の
溶出率（Ｄ６りを調べた。結果は下記の表３に示される
通りであり、原体の比表面積が０．２４騰２７ｇの時に
は懸濁液中のニフェジピン濃度を５ｘ以下に、又０．８
８ｍ２／ｇの時には懸濁液中のニフェジピン濃度を２０
％以下に設定する場合に、原体の溶出率を適正な範囲内
の値になし得ることが判明した。! Jul (powder) An ethanol suspension of the raw material was sprayed and adsorbed onto lactose as a carrier using a fluidized bed granulation dryer to form a composition and a powder. However, in the case of this example, drug substances with different specific surface areas were used and the drug concentration in the suspension was varied, but the spray droplet diameter was set to 16 μm, and the nifedipine concentration in the composition was Powders of various sample compositions were prepared by setting the concentration to 10%, and a dissolution test was conducted for each sample composition in the same manner as in Example I to examine the dissolution rate (D6) after 60 minutes. The results are shown in Table 3 below, and when the specific surface area of the drug substance was 0.24 and 27 g, the nifedipine concentration in the suspension was 5x or less, and 0.8
When the concentration of nifedipine in the suspension is 8 m2/g, the concentration of nifedipine in the suspension is 20
% or less, it was found that the elution rate of the active substance could be brought to a value within an appropriate range.
表中において、
（２）実施例１参照、
（３）原体にフェジビン結晶）の比表面積、（４）噴霧
用懸濁液中の原体濃度。In the table, (2) See Example 1, (3) Specific surface area of phezibin crystals as the drug substance, and (4) Drug substance concentration in the suspension for spraying.
ＫＬ班」（顆粒剤）
原体のＩＯＸエタノール懸濁液を流動層造粒乾燥機によ
り各種の担体に噴霧吸着させることにより組成物化する
と共に顆粒剤となした。尚、本実施例の場合に噴霧液滴
径は１６μ票に設定され、界面活性剤としてポリソルベ
ート８０が上記のエタノール懸濁液に１．０％量配合さ
れた。又、原体としては比表面積０．１１８ｍ２／ｇの
ものが使用された。KL Group' (Granules) A suspension of IOX in ethanol as a raw material was sprayed and adsorbed onto various carriers using a fluidized bed granulation dryer to form a composition and granules. In this example, the spray droplet diameter was set to 16 μm, and 1.0% of polysorbate 80 was added to the above ethanol suspension as a surfactant. Further, the raw material used had a specific surface area of 0.118 m2/g.
得られた各試料組成物における原体の溶出率（Ｄｓｅ）
を実施例１におけると同様に調べた結果は下記の表４に
示される通りであり、何れも適正な範囲内の値であった
。Dissolution rate (Dse) of the drug substance in each sample composition obtained
were investigated in the same manner as in Example 1, and the results are shown in Table 4 below, and all values were within appropriate ranges.
艮」
表中において、
（１）試料組成物中の原体濃度、
（２）実施例１参照、
（１低１を換度ヒドロキシプロピルセルロース灸厩叢ｊ
（錠剤−フィルム錠）
噴霧液滴径を１６μｍに制御し、次の処方に従い原体（
比表面積０．２４ｍ２／ｇのもの）の１．５％エタノー
ル溶液を流動層造粒乾燥機により担体としての乳糖に噴
霧吸着させることにより組成物化した。In the table, (1) the concentration of the drug substance in the sample composition; (2) see Example 1;
(Tablets - film tablets) Control the spray droplet diameter to 16 μm, and apply the drug substance (
A composition was prepared by spraying and adsorbing a 1.5% ethanol solution of the sample (having a specific surface area of 0.24 m2/g) onto lactose as a carrier using a fluidized bed granulation dryer.
次いで、水・エタノール混液を製造助剤として、上記の
組成物を顆粒化させ、打錠することにより素錠を得た。Next, the above composition was granulated using a water/ethanol mixture as a production aid and compressed to obtain uncoated tablets.
この素錠を、下記の処方のコーテイング液で処理するこ
とによりフィルム錠を得た。尚、コーテイング量は２−
８ｍｇ／錠に設定された。Film tablets were obtained by treating the uncoated tablets with a coating liquid having the following formulation. In addition, the coating amount is 2-
The dose was set at 8 mg/tablet.
コーテイング液の処方：
ヒドロキンプロピルメチルセルロース ７部マクロゴー
ル ２部酸化チタン
１部水
適量得られた各試料錠剤における原体の溶出率（
Ｄａ ａ ）を実施例１におけると同様に調べた結果は
下記の表５に示される通りであり、何れも適正な範囲内
の値であった。Coating liquid formulation: Hydroquinepropyl methylcellulose 7 parts macrogol 2 parts titanium oxide
1 part water
The dissolution rate of the drug substance in each sample tablet obtained in an appropriate amount (
The results of examining Da a ) in the same manner as in Example 1 are shown in Table 5 below, and all values were within appropriate ranges.
表中において、
（２）”実施例１参照、
（５）：結晶セルロース、
（１；） ： カルボキシメチルセルロース、（７）：
界面活性剤（ポリソルベー） ８０）、（８） ニス
テアリン酸マグネシウム。In the table, (2) "See Example 1, (5): Crystalline cellulose, (1;): Carboxymethyl cellulose, (7):
Surfactant (Polysorbet) 80), (8) Magnesium nistearate.
夫胤１（錠剤−素錠）
噴霧液滴径を１６μｍに制御し、次の処方に従い原体（
比表面積０．２４ｍ２／ｇのもの）の５ｘエタノール懸
濁液を流動層造粒乾燥機により担体としての乳糖に噴霧
吸着させることにより組成物化した。Futane 1 (tablet - uncoated tablet) The spray droplet diameter was controlled to 16 μm, and the drug substance (
A suspension of 5x ethanol (with a specific surface area of 0.24 m2/g) was formed into a composition by spray adsorption onto lactose as a carrier using a fluidized bed granulation dryer.
次いで、水争エタノール混液を製造助剤として、上記の
組成物を顆粒化させ、打錠することにより素錠を得た。Next, the above composition was granulated using a water-ethanol mixture as a production aid, and the resulting composition was compressed to obtain uncoated tablets.
得られた各試料錠剤における原体の溶出率（Ｄｏｓ）を
実施例１におけると同様に調べた結果は下記の表６に示
される通りであり、何れも適正な範囲内の値であった。The dissolution rate (Dos) of the active substance in each sample tablet obtained was investigated in the same manner as in Example 1, and the results are shown in Table 6 below, and all values were within appropriate ranges.
Ｌ
表中において、
（２）：実施例１参照、
（５）、結晶セルロース、
（６） ： カルボキノメチルセルロース、（７）・界
面活性剤（ポリソルベート８０）、（８） ： ステア
リン酸マグネシウム、（９） ： ポリビニルピロリド
ン。In the L table, (2): See Example 1, (5): Crystalline cellulose, (6): Carboquinomethyl cellulose, (7): Surfactant (polysorbate 80), (8): Magnesium stearate, ( 9): Polyvinylpyrrolidone.
Ｕ性ｊ（糖衣錠）
実施例６で得た素錠（錠剤４）につき、次に不される処
方のコーテイング液を用いて次々と処理した後に、粉末
力ルナウバワンクスを用℃）で艶出し処理することによ
り糖衣錠を得た。尚、下記のコーテイング液処方中の「
色素液」とは、黄色５号色素３０ｇを精製水２７０ｇ中
に溶解すること番こより調製されたものである。U properties J (Dragage-coated tablets) The uncoated tablets (tablets 4) obtained in Example 6 are then treated one after another with a coating liquid of the same formulation, and then polished with powdered Lunaubawanx (℃). Dragee-coated tablets were thereby obtained. In addition, in the coating liquid formulation below,
The dye solution was prepared by dissolving 30 g of Yellow No. 5 dye in 270 g of purified water.
サブコーティング液：
白糖 ８５０ （ｇ）アラビアゴム末
５０
精製水 ４５０
スムージング液：
白糖 ８５０ （ｇｌゼラチン
５
アラビアゴム末 ２０
精製水 ４５０
沈降炭酸カルシウム １０００
色素液 ５
カラーリング液：
白糖 ｓｓｏ （ｇ）ゼラチン
５
精製水 ４５０
色素液 ３
フィニシング液：
白糖 ｓｓｏ （ｇ）精製水
４５０
色素液 ３ｇ
本実施例において得られた糖衣錠における薬物の溶出率
（Ｄｏｓ）を実施例１におけると同様にして調べた処、
４２．８％であり、適正範囲（５０±２０％）内であっ
た。Sub-coating liquid: White sugar 850 (g) Gum arabic powder 50 Purified water 450 Smoothing liquid: White sugar 850 (gl gelatin)
5 Gum arabic powder 20 Purified water 450 Precipitated calcium carbonate 1000 Coloring liquid 5 Coloring liquid: White sugar sso (g) Gelatin
5 Purified water 450 Color liquid 3 Finishing liquid: White sugar sso (g) Purified water
450 Dye solution 3g The dissolution rate (Dos) of the drug in the sugar-coated tablet obtained in this example was investigated in the same manner as in Example 1.
It was 42.8%, which was within the appropriate range (50±20%).
夫胤１（カプセル剤）
実施例２で得た散剤Ａｔ及びＡ４をニフェジピンとして
各々Ｓｙｒｇ相当量、合計ｌ０ｍｇ相当量採取し、これ
に適量の結晶セルロース及び１％量のステアリン酸マグ
ネ／ウムを配合することにより全量を１４０１ｇとして
混合し、この混合物を硬質カプセル（４号カプセル）に
充填することによりカプセル剤を得た。Futane 1 (capsule) Collect the powders At and A4 obtained in Example 2 as nifedipine in an amount equivalent to Syrg each, a total amount equivalent to 10 mg, and add an appropriate amount of crystalline cellulose and 1% amount of magnesium stearate to this. By doing this, the total amount was adjusted to 1401 g, and the mixture was filled into hard capsules (No. 4 capsules) to obtain capsules.
このカプセル剤における薬物の溶出率（Ｄｅａ）を実施
例１におけると同様にして調べた処、５５．７１であり
、適正範囲（５０±２０％）内であった。The dissolution rate (Dea) of the drug in this capsule was examined in the same manner as in Example 1, and was found to be 55.71, which was within the appropriate range (50±20%).
夫五斑」（三層錠）
実施例２で得た散剤Ａ１をニフェジピンとして５ｍｇ相
当量採取し、これに適量の結晶セルロースと １％相当
量のステアリン酸マグネシウムとを配合して第１暦とな
し、又実施例２で得た散剤（Ａ４）をニフェジピンとし
て５ｍｇ相当量採取し、これに適量の結晶セルロースと
１％相当量のステアリン酸マグネシウムとを配合して第
２層となし、これらの両層を積層し、打錠により一体化
することにより三層錠を得た。Fugoma (three-layer tablet) An amount equivalent to 5 mg of nifedipine was collected from the powder A1 obtained in Example 2, and an appropriate amount of crystalline cellulose and an amount of magnesium stearate equivalent to 1% were mixed therein to prepare the powder A1 obtained in Example 2. None, and an amount equivalent to 5 mg of nifedipine was collected from the powder (A4) obtained in Example 2, and an appropriate amount of crystalline cellulose and an amount of magnesium stearate equivalent to 1% were mixed therein to form a second layer. A three-layer tablet was obtained by laminating both layers and integrating them by tabletting.
この三層錠における薬物の溶出率（Ｄａｓ）を実施例１
におけると同様にして調べた処、５２．１％であり、適
正範囲（５０±２０％）内であった。Example 1 The dissolution rate (Das) of the drug in this three-layer tablet
The result was 52.1%, which was within the appropriate range (50±20%).
成麓Ｊ（血中濃度の推移）
本発明により得られる製剤の有効性（作用持続性）を調
へるために、次に示す試料を各々、健康成人男子８名か
らなるボランティアパネルに経口投与し、経時的に採血
して血漿中の薬物濃度の推移を測定した。Seiroku J (Change in blood concentration) In order to investigate the effectiveness (durability of action) of the preparation obtained by the present invention, the following samples were orally administered to a volunteer panel consisting of eight healthy adult males. Blood samples were then collected over time to measure changes in drug concentration in plasma.
被験試料：
実施例５のフィルム錠（処方３によるものであって、ニ
フェジピンとして２０票ｇ含有、原体結晶の比表面積＋
０．２４ｍ２／ｇ）。Test sample: Film tablet of Example 5 (according to formulation 3, containing 20 grams of nifedipine, specific surface area of drug substance crystal +
0.24m2/g).
対照試料：
噴霧吸着処理による原体の組成物化を行わなかった点を
除き、被験試料と全く同様に調製されたフィルム錠。Control sample: A film tablet prepared in exactly the same manner as the test sample, except that the active substance was not converted into a composition by spray adsorption treatment.
結果は下記の表７に示される通りであり、本発明方法に
より製造された製剤は投与後速やかに薬物の血中濃度が
高いレベルに達し、１２時間後においても治療上存効と
される血中濃度である １２ｎｇ／ｍｌ ［菊池等「臨
床薬理」Ｖｏｌ、 ＋３． Ｎｏ ４゜ｐａｇｅ ８２
３ （＋９８２）］の値よりも高い値を維持しており、
従って所望の作用持続性を有することが確認された。一
方、対照製剤の場合には、上記の有効血中濃度レベルに
達することはなかった。The results are shown in Table 7 below, and the drug concentration in the blood of the preparation manufactured by the method of the present invention reaches a high level immediately after administration, and even after 12 hours, the drug still remains effective therapeutically. Medium concentration 12 ng/ml [Kikuchi et al. "Clinical Pharmacology" Vol. +3. No 4゜page 82
3 (+982)].
Therefore, it was confirmed that it had the desired duration of action. On the other hand, the control formulation did not reach the above effective blood concentration level.
（発明の効果）
本発明によれば、難水溶性薬物を一旦溶剤に溶解又は懸
濁させ、得られた溶液又は懸濁液を噴霧液の液滴径をフ
ントロールして担体に噴霧吸着させて組成物化すること
により薬物の溶解性を改善することができ、これによっ
て薬効の持続性がもたらされる。(Effects of the Invention) According to the present invention, a poorly water-soluble drug is once dissolved or suspended in a solvent, and the obtained solution or suspension is sprayed and adsorbed onto a carrier by controlling the droplet diameter of the spray liquid. The solubility of the drug can be improved by forming it into a composition, which results in sustained drug efficacy.
従って、本発明方法の実施に際しては原体である薬物が
有している結晶粒径や比表面積による制限を受けず、又
処理方法も上記のように極めて簡便であるので、本発明
は、難水溶性薬物の溶解性を改善し且つ薬効の持続性化
をもたらすための製剤化方法として工業的に極めて優れ
ている。Therefore, when carrying out the method of the present invention, there is no restriction due to the crystal grain size or specific surface area of the drug substance, and the treatment method is extremely simple as described above. This method is industrially excellent as a formulation method for improving the solubility of water-soluble drugs and prolonging their efficacy.
Claims (6)
噴霧液の液滴径をコントロールして担体に噴霧吸着させ
ることにより得たる組成物を用いることを特徴とする、
難水溶性薬物の持続性製剤化方法。(1) It is characterized by using a composition obtained by dissolving or suspending a poorly water-soluble drug in a solvent, and then spraying and adsorbing it onto a carrier while controlling the droplet size of the spray liquid.
A method for producing long-lasting formulations of poorly water-soluble drugs.
、テオフィリン、ピンドロール、メシル酸ジヒドロエル
ゴトキシン及びモルシドミンから選択されたものである
ことを特徴とする、請求項（１）に記載の難水溶性薬物
の持続性製剤化方法。(2) The poorly water-soluble drug according to claim (1), characterized in that the poorly water-soluble drug is selected from nifedipine, isosorbide nitrate, theophylline, pindolol, dihydroergotoxine mesylate, and molsidomine. Long-acting formulation method.
トン又はこれらの混合物であり、場合により界面活性剤
を含有していることを特徴とする、請求項（１）又は（
２）に記載の難水溶性薬物の持続性製剤化方法。(3) Claim (1) or (3) characterized in that the solvent is an alcohol, water, dichloromethane, acetone, or a mixture thereof, and optionally contains a surfactant.
2) The method for producing a long-lasting formulation of a poorly water-soluble drug.
液滴径が１５０μｍ以下に設定されることを特徴とする
、請求項（１）、（２）又は（３）に記載の難水溶性薬
物の持続性製剤化方法。(4) The poorly water-soluble drug according to claim (1), (2) or (3), characterized in that when the poorly water-soluble drug is nifedipine, the droplet diameter of the spray liquid is set to 150 μm or less. Method for long-acting formulation of sex drugs.
のニフェジピン含量が、界面活性剤を含有する場合には
５０％以下に設定され、又界面活性剤を含有しない場合
には２０％以下に設定されることを特徴とする請求項（
１）、（２）、（３）又は（４）に記載の難水溶性薬物
の持続性製剤化方法。(5) When the poorly water-soluble drug is nifedipine, the nifedipine content in the composition is set to 50% or less if it contains a surfactant, and 20% or less if it does not contain a surfactant. Claims characterized in that (
1), (2), (3) or (4), the method for producing a long-lasting formulation of a poorly water-soluble drug.
ニフェジピン濃度が溶液としては１．７％以下に、又懸
濁液としては２０％以下に設定されることを特徴とする
、請求項（１）、（２）、（３）、（４）又は（５）に
記載の難水溶性薬物の持続性製剤化方法。(6) A claim characterized in that when the poorly water-soluble drug is nifedipine, the concentration of nifedipine in the spray liquid is set to 1.7% or less as a solution and 20% or less as a suspension. A method for producing a long-lasting formulation of a poorly water-soluble drug according to (1), (2), (3), (4) or (5).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21898490A JPH04103525A (en) | 1990-08-22 | 1990-08-22 | Production of sustainable pharmaceutical preparation for poorly water-soluble medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP21898490A JPH04103525A (en) | 1990-08-22 | 1990-08-22 | Production of sustainable pharmaceutical preparation for poorly water-soluble medicine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04103525A true JPH04103525A (en) | 1992-04-06 |
Family
ID=16728447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP21898490A Pending JPH04103525A (en) | 1990-08-22 | 1990-08-22 | Production of sustainable pharmaceutical preparation for poorly water-soluble medicine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04103525A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998046268A1 (en) * | 1997-04-11 | 1998-10-22 | Fujisawa Pharmaceutical Co., Ltd. | Medicinal composition |
| EP0879599A3 (en) * | 1997-05-18 | 2000-11-02 | Adel Prof. Dr. Abdel-Wadood Gomaa | A topical preparation for treatment of erectile dysfunction comprising theophylline or aminophylline, isosorbide dinitrate and co-dergocrine mesylate |
| JP2007530415A (en) * | 2003-07-02 | 2007-11-01 | アボット・ラボラトリーズ | Method for the manufacture of lipid controlled drug formulations |
| JP2009235073A (en) * | 2005-09-12 | 2009-10-15 | Actelion Pharmaceuticals Ltd | Stable pharmaceutical composition comprising pyrimidine-sulfamide |
| US8062664B2 (en) | 2003-11-12 | 2011-11-22 | Abbott Laboratories | Process for preparing formulations of lipid-regulating drugs |
| US8324232B2 (en) | 2007-08-17 | 2012-12-04 | Actelion Pharmaceuticals Ltd. | 4-pyrimidinesulfamide derivative |
| JP2015511241A (en) * | 2012-02-21 | 2015-04-16 | ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ | Oral pharmaceutical composition of dabigatran etexilate |
-
1990
- 1990-08-22 JP JP21898490A patent/JPH04103525A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998046268A1 (en) * | 1997-04-11 | 1998-10-22 | Fujisawa Pharmaceutical Co., Ltd. | Medicinal composition |
| EP0879599A3 (en) * | 1997-05-18 | 2000-11-02 | Adel Prof. Dr. Abdel-Wadood Gomaa | A topical preparation for treatment of erectile dysfunction comprising theophylline or aminophylline, isosorbide dinitrate and co-dergocrine mesylate |
| JP2012149078A (en) * | 2003-07-02 | 2012-08-09 | Abbott Lab | Process for preparing formulation of lipid-regulating drug |
| JP2007530415A (en) * | 2003-07-02 | 2007-11-01 | アボット・ラボラトリーズ | Method for the manufacture of lipid controlled drug formulations |
| US8062664B2 (en) | 2003-11-12 | 2011-11-22 | Abbott Laboratories | Process for preparing formulations of lipid-regulating drugs |
| US9265762B2 (en) | 2005-09-12 | 2016-02-23 | Actelion Pharmaceuticals Ltd. | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
| US8367685B2 (en) | 2005-09-12 | 2013-02-05 | Actelion Pharmaceuticals, Ltd. | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
| JP2009235073A (en) * | 2005-09-12 | 2009-10-15 | Actelion Pharmaceuticals Ltd | Stable pharmaceutical composition comprising pyrimidine-sulfamide |
| US10117870B2 (en) | 2005-09-12 | 2018-11-06 | Actelion Pharmaceuticals Ltd. | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
| US11648249B2 (en) | 2005-09-12 | 2023-05-16 | Actelion Pharmaceuticals Ltd | Stable pharmaceutical compositions comprising a pyrimidine-sulfamide |
| US8324232B2 (en) | 2007-08-17 | 2012-12-04 | Actelion Pharmaceuticals Ltd. | 4-pyrimidinesulfamide derivative |
| JP2015511241A (en) * | 2012-02-21 | 2015-04-16 | ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ | Oral pharmaceutical composition of dabigatran etexilate |
| US11013729B2 (en) | 2012-02-21 | 2021-05-25 | Towa Pharmaceutical Europe, S.L. Unipersonal | Oral pharmaceutical compositions of dabigatran etexilate |
| US11752142B2 (en) | 2012-02-21 | 2023-09-12 | Breckenridge Pharmaceutical, Inc. | Oral pharmaceutical compositions of dabigatran etexilate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU1816213C (en) | Process for preparation of solid dosage form with controlled releasing of active ingredient | |
| RU2136283C1 (en) | Preparation of controlled drug release and method of its preparing, method of treatment | |
| RU2095054C1 (en) | Solid medicinal formula for oral administration | |
| JP2637981B2 (en) | Absorption control drug composition | |
| JPH0237327B2 (en) | ||
| JP2001511443A (en) | Oral pharmaceutical preparation containing anti-ulcer active compound and method for producing the same | |
| JPH0122245B2 (en) | ||
| US4261971A (en) | Pharmaceutically preparation comprising a cardiac glycoside in combination with a polymer | |
| PL188834B1 (en) | Multiple-dose formulations of tramadol | |
| CA2494017A1 (en) | Delayed release anti-viral product, use and formulation thereof | |
| HU221683B1 (en) | Controlled release morphine preparation | |
| JP3987282B2 (en) | Particles coated with granulated crystalline ibuprofen | |
| WO2002096466A1 (en) | Medicinal composition | |
| JP2003528905A (en) | Stavudine-containing sustained release beads | |
| JP3645816B2 (en) | Pharmaceutical capsule composition containing loratadine and pseudoephedrine | |
| US6482437B2 (en) | Morphine sulfate microgranules, manufacturing process and pharmaceutical preparations | |
| JP2000191519A (en) | Rapid release granule wherein unpleasant functional property of medicinally active ingredient is masked | |
| JPH01230513A (en) | Sustained release preparation | |
| JP3221891B2 (en) | Rotary granulation and taste-masking coating for the preparation of chewable pharmaceutical tablets | |
| JPH04103525A (en) | Production of sustainable pharmaceutical preparation for poorly water-soluble medicine | |
| JP2003055199A (en) | Sustained release micropellet | |
| JP6905781B1 (en) | Granules with masked unpleasant taste and their manufacturing method | |
| JPH0328404B2 (en) | ||
| FI95776C (en) | Method for preparing low dose controlled release aspirin tablets | |
| JP2939069B2 (en) | Nicardipine sustained release preparation and method for producing the same |